Yosprala (aspirin/omeprazole)

Dosage of aspirin must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage. When used at high (e.g., anti-inflammatory) dosages, the development of tinnitus can be used as a sign of elevated serum salicylate concentrations, except in patients with high-frequency hearing impairment.

When preparations containing aspirin in fixed combination with other drugs are used, the cautions, precautions, and contraindications applicable to each ingredient must be considered.

Dosage of omeprazole magnesium is expressed in terms of omeprazole.

Aspirin is usually administered orally, preferably with food or a large quantity (240 mL) of water (unless the patient is fluid restricted) or milk to minimize gastric irritation. In patients unable to take or retain oral medication, aspirin suppositories may be administered rectally; however, rectal absorption may be slow and incomplete. (See Pharmacokinetics: Absorption.) Aspirin tablets should not be administered rectally, since they are likely to cause irritation and erosion of the rectal mucosa. Aspirin preparations should not be used if a strong vinegar-like odor is present. (See Chemistry and Stability: Stability.)

If an unpleasant taste or aftertaste, burning in the throat, or difficulty in swallowing occurs with uncoated aspirin-containing tablets, these effects may be reduced with film-coated tablets. Although specific data are not available, these effects are also likely to be reduced with enteric-coated tablets. If gastric irritation and/or symptomatic GI disturbances occur with uncoated aspirin-containing tablets, these effects may be reduced with enteric-coated tablets or extended-release tablets. If a liquid dosage form of aspirin is desired for short-term treatment of pain, an oral solution may be prepared from commercially available effervescent tablets (e.g., Alka-Seltzer(R)) by dissolving tablets in 120 mL of water; ingest the entire solution to ensure adequate dosing.

In addition to potentially reducing adverse GI effects, some clinicians suggest that enteric-coated tablets may be swallowed more easily by children receiving chronic therapy with the drug and may therefore result in increased compliance.

Aspirin or buffered aspirin preparations should not be chewed before swallowing for at least 7 days following tonsillectomy or oral surgery because of possible injury to oral tissues from prolonged contact with aspirin particles. In addition, aspirin or buffered aspirin tablets should not be placed directly on a tooth or gum surface because of possible injury to tissues.

Capsules containing the fixed combination of aspirin and extended-release dipyridamole should be swallowed whole and should not be chewed.

Chewable aspirin tablets may be chewed, crushed, and/or dissolved in a liquid, or swallowed whole, followed by approximately 120 mL of water, milk, or fruit juice immediately after administration of the drug.

For information on the concomitant administration of aspirin with nonsteroidal anti-inflammatory agents (NSAIAs), see Drug Interactions: Nonsteroidal Anti-inflammatory Agents, in the Salicylates General Statement 28:08.04.24.

Omeprazole delayed-release and immediate-release capsules are administered orally; oral suspensions of the drug are administered orally or through a gastric tube. To avoid decomposition of omeprazole in the acidic pH of the stomach, the commercially available delayed-release capsules and delayed-release oral suspension contain enteric-coated granules of the drug. Immediate-release capsules, immediate-release oral suspension, and the kit for oral suspension (Konvomep(R)) all contain sodium bicarbonate to protect the drug from acid degradation.

Omeprazole magnesium is also available in fixed-combination capsules containing amoxicillin and rifabutin (Talicia(R)). A co-packaged product containing delayed-release omeprazole capsules, clarithromycin tablets, and amoxicillin capsules (Omeclamox-Pak(R)) is also commercially available. See the full prescribing information for administration of these combination products.

Antacids may be administered concomitantly with delayed-release preparations of omeprazole.

For patients receiving continuous feedings via a nasogastric or orogastric tube, enteral feeding should be stopped temporarily for 3 hours before and for 1 hour after administration of preparations of omeprazole oral suspension.

Store omeprazole delayed-release capsules in tight containers or the original carton at 20-25degreesC; protect from light and moisture. Store packets of omeprazole powder for delayed-release suspension at 25degreesC (excursions permitted from 15-30degreesC). Store immediate-release capsules in tight, light-resistant containers at 20-25degreesC and protect from moisture. Store packets of omeprazole powder for immediate-release suspension protected from light and moisture at 25degreesC (excursions permitted from 15-30degreesC). Store omeprazole and sodium bicarbonate powder kit for oral suspension (Konvomep(R)) at 2-8degreesC protected from light; do not freeze.

No dosing information is available for this tab.

In vivo, omeprazole is a substrate and inhibitor of cytochrome P-450 (CYP) isoenzyme 2C19, and a substrate of CYP3A4. Omeprazole is also an inhibitor of CYP2C19 in vitro.

When co-packaged delayed-release omeprazole capsules, clarithromycin tablets, and amoxicillin capsules (Omeclamox-Pak(R)) are prescribed, drug interactions should be considered for each individual component. Refer to the Omeclamox-Pak(R) prescribing information for drug interaction information.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Agents Affecting Growth Hormone/Macimorelin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

CLINICAL EFFECTS: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of macimorelin states concurrent use with agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test. Discontinue growth hormone products at least 1 week before administering the macimorelin diagnostic test. Sufficient washout time of drugs affecting growth hormone release prior to administration of macimorelin is recommended.(1) Agents affecting growth hormone include: - Drugs that directly affect the pituitary secretion of growth hormone (e.g. somatostatin, insulin, glucocorticoids, cyclooxygenase inhibitors) - Drugs that may transiently elevate growth hormone concentrations (e.g. clonidine, levodopa, insulin) - Drugs that may blunt the growth hormone response (e.g. muscarinic antagonists, anti-thyroid medications, growth hormone products)

DISCUSSION: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

Anticoagulant;Antiplatelet;Thrombolytic/Alipogene Tiparvovec

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Alipogene tiparvovec is given as a one-time series of intramuscular (IM)injections. Depending upon patient weight 27 to 60 injections are given, each at a different site.

CLINICAL EFFECTS: Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents increase bleeding risk at IM injection sites.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Antiplatelet or other anticoagulant agents must not be taken for at least one week prior to alipogene tiparvovec therapy. Assure that abnormal bleeding parameters have been corrected prior to administration. Antiplatelet or anticoagulant therapy may be resumed one day after alipogene tiparvovec administration. If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Alipogene tiparvovec is given as a one-time series of intramuscular (IM)injections for the treatment of familial lipoprotein lipase deficiency. Depending upon patient weight 27 to 60 injections are given, each at a different site. Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents increase bleeding risk at IM injection sites.

Anticoagulants; Antiplatelets/Mifepristone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Anticoagulants may result in excessive bleeding following the abortion.

CLINICAL EFFECTS: The concurrent use of mifepristone with anticoagulants may result in excessive bleeding following the abortion.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer of mifepristone states that mifepristone is contraindicated in patients receiving concurrent anticoagulant therapy.(1) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: The manufacturer of mifepristone states that mifepristone is contraindicated in patients receiving concurrent anticoagulant therapy.(1)

Aspirin (> 100 Mg)/Vorapaxar

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Additive effects on hemostasis.(1-3)

CLINICAL EFFECTS: Concurrent use of vorapaxar with high-dose aspirin may increase the risk of bleeding while decreasing the efficacy of vorapaxar.(1-3)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Vorapaxar is indicated for concurrent use with antiplatelet dosages of aspirin. Use of high-dose aspirin should be avoided with vorapaxar. Patients requiring concurrent therapy with vorapaxar and high-dose aspirin should be closely monitored for signs of bleeding.(1-3) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Discontinue vorapaxar in patients with active bleeding. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In the TRA2P and TRACER clinical trials, GUSTO moderate/severe bleeding was increased with higher dosages of aspirin (>= 300 mg), while efficacy of vorapaxar was decreased.(2,3)

Cyp1a2 Inducers/Florquinitau F-18

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Florquinitau F-18 is a CYP1A2 substrate. CYP1A2 inducers may decrease the florquinitau F-18 parent fraction in plasma and reduce brain regional signal intensity.(1)

CLINICAL EFFECTS: Concurrent or recent use of CYP1A2 inducers with florquinitau F-18 may interfere with the interpretation of imaging results using fluoroestradiol F-18.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of florquinitau F-18 states use of CYP1A2 inducers should be avoided. Patients should stop CYP1A2 inducers at least 7 days prior to diagnostic testing with florquinitau F-18.(1)

DISCUSSION: Florquinitau F-18 is a CYP1A2 substrate. CYP1A2 inducers may decrease the florquinitau F-18 parent fraction in plasma and reduce brain regional signal intensity.(1) CYP1A2 inducers linked include: aminoglutethimide, asciminib, carbamazepine, fosphenytoin, leflunomide, marijuana smoking, montelukast, moricizine, nelfinavir, olverembatinib, omeprazole, phenobarbital, phenytoin, primidone, rifampin, ritonavir, teriflunomide, and valproic acid.(2,3)

H2 Antagonists; Proton Pump Inhibit/Posaconazole Suspension

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: H2 antagonists and proton pump inhibitors (PPIs) increase the stomach pH, possibly reducing gastrointestinal absorption of posaconazole suspension.

CLINICAL EFFECTS: Concurrent use of H2 antagonists or proton pump inhibitors (PPIs) may result in decreased effectiveness of posaconazole suspension.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of posaconazole suspension with H2 antagonists or proton pump inhibitors (PPIs).(1) If H2 antagonists or PPI therapy is required, use the tablet formulation or powder mix formulation of posaconazole.

DISCUSSION: Concurrent cimetidine (400 mg twice daily) decreased both posaconazole (200 mg daily) maximum concentration (Cmax) and area-under-curve (AUC) levels by 39%.(1) No significant effects with other H2 blockers have been noted.(1) Esomeprazole (40 mg daily for 3 days) decreased the Cmax and AUC of a single dose of posaconazole suspension (400 mg) by 46% and 32%, respectively.(1) In a study of posaconazole levels in patients with acute myeloid leukemia or myelodysplastic syndrome, use of pantoprazole was associated with decreased posaconazole levels.(3) In a cross-over study in 5 healthy subjects, esomeprazole decreased the Cmax and AUC of posaconazole suspension by 37% and 84%, respectively. Simultaneous intake of Coca-Cola did not completely counteract the effects of esomeprazole.(4) In a study in healthy subjects, esomeprazole decreased the Cmax and AUC of posaconazole suspension by 55% and 49%, respectively. Simultaneous intake of Coca-Cola did not completely counteract the effects of esomeprazole.(5)

H2 Antagonists; Proton Pump Inhibitors/Defactinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The aqueous solubility of defactinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce defactinib absorption.(1)

CLINICAL EFFECTS: Coadministration of H2 antagonists or proton pump inhibitors (PPIs) may reduce the bioavailability of defactinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of defactinib states that concurrent use with H2 antagonists or proton pump inhibitors should be avoided.(1) If concurrent use with an acid-reducing agent cannot be avoided, administer defactinib 2 hours before or 2 hours after the administration of a locally acting antacid.(1)

DISCUSSION: In an interaction study, defactinib area-under-the-curve (AUC) decreased by 79% and maximum concentration (Cmax) decreased by 85% following concomitant use of multiple doses of omeprazole 40 mg daily. The AUC and Cmax of N-desmethyl amide (M4), a major metabolite of defactinib, decreased by 83% and 88%, respectively.(1)

H2 Antagonists; Proton Pump Inhibitors/Levoketoconazole

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The aqueous solubility of levoketoconazole is pH dependent. Higher gastric pH leads to lower solubility. H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) increase gastric pH and may decrease the absorption of levoketoconazole.(1)

CLINICAL EFFECTS: Coadministration of H2RAs or PPIs may reduce the bioavailability of levoketoconazole, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of levoketoconazole with PPIs and H2RAs should be avoided.(1)

DISCUSSION: Levoketoconazole is very slightly soluble in water but soluble below pH 2. H2RAs and PPIs raise gastric pH and may impair dissolution and absorption of levoketoconazole.(1)

H2 Antagonists; Proton Pump Inhibitors/Nirogacestat

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The aqueous solubility of nirogacestat is pH dependent. Higher gastric pH leads to lower solubility which may reduce nirogacestat absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) or H2 antagonists may reduce the bioavailability of nirogacestat, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of nirogacestat with proton pump inhibitors, H2 antagonists, and antacids should be avoided. If coadministration with an acid-reducing agent is unavoidable, take nirogacestat 2 hours before or 2 hours after a locally acting antacid.(1)

DISCUSSION: The solubility of nirogacestat is poor at a pH >= 6.(1) Concomitant use of proton pump inhibitors, H2 antagonists, or antacids are expected to reduce concentrations of nirogacestat.(1)

H2 Antagonists; Proton Pump Inhibitors/Secretin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: H2 antagonists and proton pump inhibitors (PPIs) may result in an incorrect secretin stimulation test result.(1)

CLINICAL EFFECTS: Concurrent use of H2 antagonists and proton pump inhibitors (PPIs) may impact the accuracy of the secretin stimulation test.(1)

PREDISPOSING FACTORS: Patients with alcoholic or other liver disease may be hyperresponsive to stimulation with a secretin stimulation test, masking the presence of coexisting pancreatic disease. Consider additional testing and clinical assessment for diagnosis.(1)

PATIENT MANAGEMENT: The US manufacturer of human secretin states concurrent use of H2 antagonists and proton pump inhibitors (PPIs) at the time of stimulation testing may cause the patient to be hyperresponsive to secretin stimulation and suggest false gastrinoma results. The manufacturer recommends discontinuing H2 antagonists at least 2 days prior to testing. The US manufacturer of vonoprazan recommends stopping vonoprazan at least 4 weeks prior to testing.(2-3) Consult prescribing information for PPIs before administering prior to a secretin stimulation test.(1)

DISCUSSION: Concurrent use of H2 antagonists and proton pump inhibitors (PPIs) may impact the accuracy of the secretin stimulation test.(1)

H2 Antagonists; Proton Pump Inhibitors/Sotorasib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The aqueous solubility of sotorasib is pH dependent. Higher gastric pH leads to lower solubility which may reduce sotorasib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) or H2 antagonists may reduce the bioavailability of sotorasib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of sotorasib with proton pump inhibitors, H2 antagonists, and antacids should be avoided. If coadministration with an acid-reducing agent is unavoidable, take sotorasib 4 hours before or 10 hours after a locally acting antacid.(1) The UK manufacturer of sotorasib states if co-administration with an acid-reducing agent (such as a PPI or an H2 antagonist) is required, sotorasib should be taken with an acidic beverage (such as cola). Alternatively, sotorasib should be taken 4 hours before or 10 hours after administration of a local antacid.(2)

DISCUSSION: The solubility of sotorasib in the aqueous media decreases over the range pH 1.2 to 6.8 from 1.3 mg/mL to 0.03 mg/mL. In an interaction study, coadministration of repeat doses of omeprazole with a single dose of sotorasib decreased sotorasib maximum concentration (Cmax) by 65% and area-under-curve (AUC) by 57% under fed conditions, and decreased sotorasib Cmax by 57% and AUC by 42% under fasted conditions. Under fasted conditions, co-administration of repeat doses of omeprazole with a single dose of sotorasib and 240ml of an acidic beverage (non-diet cola) decreased sotorasib Cmax by 32% and AUC by 23%. The UK manufacturer of sotorasib states the clinical relevance of the decreased sotorasib exposure when co-administered with omeprazole and cola is unclear and sotorasib efficacy might be reduced.(2) Coadministration of a single dose of famotidine given 10 hours prior to and 2 hours after a single dose of sotorasib under fed conditions decreased sotorasib Cmax by 35% and AUC by 38%.(1)

H2 Antagonists; Proton Pump Inhibitors/Taletrectinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The aqueous solubility of taletrectinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce taletrectinib absorption.(1)

CLINICAL EFFECTS: Coadministration of H2 antagonists or proton pump inhibitors (PPIs) may reduce the bioavailability of taletrectinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of taletrectinib states that concurrent use with H2 antagonists or proton pump inhibitors should be avoided.(1) If concurrent use with an acid-reducing agent cannot be avoided, administer taletrectinib 2 hours before or 2 hours after the administration of a locally acting antacid.(1)

DISCUSSION: In an interaction study, taletrectinib area-under-the-curve (AUC) decreased by 40% and maximum concentration (Cmax) decreased by 65% following concomitant use of omeprazole 40 mg daily.(1)

Omepraz(>=20Mg);Lansopra(>=20Mg);Pantopra(>=40Mg)/Pritelivir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The aqueous solubility of pritelivir is pH dependent. Higher gastric pH leads to lower solubility which may reduce pritelivir absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of pritelivir leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of omeprazole or lansoprazole at daily doses above 20 mg with pritelivir.(1) Avoid concomitant use of pantoprazole at daily doses above 40 mg with pritelivir.(1)

DISCUSSION: Coadministration of a single oral dose of 100 mg pritelivir (on Day 1) with esomeprazole 40 mg once daily (from day -3 to Day 1; 4 days total) decreased pritelivir's maximum concentration (Cmax) by 76% and area-under-curve (AUC) by 59% compared to pritelivir administered alone.(1)

Proton Pump Inhibitors/Acalabrutinib Capsules

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The aqueous solubility of acalabrutinib capsules is pH dependent. Higher gastric pH leads to lower solubility which may reduce acalabrutinib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of acalabrutinib capsules, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of proton pump inhibitors is not recommended with acalabrutinib capsules. Separation of doses may not eliminate the interaction with acalabrutinib capsules.(1) Acalabrutinib tablets are not affected by coadministration with proton pump inhibitors and may be used concurrently.(1)

DISCUSSION: In an interaction study, omeprazole (40 mg for 5 days) given simultaneously with acalabrutinib capsules, decreased acalabrutinib area-under-the-curve (AUC) by 43%(1) Proton pump inhibitors linked to this monograph are: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole.

Proton Pump Inhibitors/Atazanavir; Nelfinavir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Proton pump inhibitors increase gastric pH. As gastric pH increases, the solubility of atazanavir and nelfinavir decreases.(1,2) Omeprazole has been shown to inhibit nelfinavir metabolism by CYP2C19.(3)

CLINICAL EFFECTS: Concurrent use of atazanavir(1-2,4-8) or nelfinavir(3,8-9) and a proton pump inhibitor may result in decreased levels and effectiveness of atazanavir or nelfinavir.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US and Australian manufacturer of atazanavir states that treatment naive patients requiring a proton pump inhibitor should receive 300 mg atazanavir with 100 mg ritonavir. The proton pump inhibitor should not exceed a dose comparable to omeprazole 20 mg daily and should be administered 12 hours before atazanavir/ritonavir.(1,2) Atazanavir should not be administered with proton pump inhibitors without concurrent ritonavir in adults or pediatric patients of at least 13 years of age and weighing at least 40 kg.(1,2) The US and Australian manufacturer of atazanavir states that proton pump inhibitors should not be administered with atazanavir in treatment experienced patients.(1,2) Data are insufficient to recommend a dose of atazanavir in patients weighing less than 40 kg and receiving a proton pump inhibitor.(1) The Canadian and UK manufacturer of atazanavir states that the coadministration of atazanavir and proton pump inhibitors is not recommended. If coadministration is necessary, the dose of atazanavir should be increased to 400 mg daily taken with ritonavir 100 mg daily, and the dose of the proton pump inhibitor should not exceed the equivalent of omeprazole 20 mg.(10,11) The UK manufacturer of esomeprazole states that concurrent use with atazanavir is contraindicated.(9) The US manufacturer of esomeprazole(4) and omeprazole(5) states that concurrent use of atazanavir or nelfinavir is not recommended. The US manufacturers of dexlansoprazole (6), lansoprazole,(7) and pantoprazole(8) state that atazanavir and nelfinavir should not be coadministered with proton pump inhibitors.

DISCUSSION: In a study of 16 subjects, atazanavir (400 mg daily) area-under-curve (AUC), maximum concentration (Cmax) and minimum concentration (Cmin) decreased 94%, 96% and 95% respectively, when given with omeprazole (40 mg daily). Omeprazole AUC and Cmax increased 145% and 124% respectively.(1) In a study of 15 subjects, atazanavir AUC, Cmax and Cmin decreased 76%, 72% and 78% respectively, when given with omeprazole (40 mg daily) and ritonavir (100 mg daily).(1) In a study in 13 subjects, administration of omeprazole (20 mg daily) 12 hours before atazanavir/ritonavir (300/100 mg daily) decreased atazanavir Cmax, AUC, and Cmin by 39%, 42%, and 46%, respectively; however, the atazanavir AUC and Cmin were 10% and 2.4-fold higher than average levels seen with atazanavir 400 mg alone.(1) In a study in 14 subjects, administration of omeprazole (20 mg daily) 1 hour before atazanavir/ritonavir (400/100 mg daily) decreased atazanavir Cmax, AUC, and Cmin by 31%, 30%, and 31%, respectively; however, the atazanavir AUC and Cmin were 32% and 3.3-fold higher than average levels seen with atazanavir 400 mg alone.(1) In a study in 10 healthy subjects, concurrent administration of lansoprazole (60 mg daily for 2 days) with atazanavir (400 mg) decreased atazanavir AUC by 94%.(14) In a case report, concurrent esomeprazole decreased atazanavir, but not fosamprenavir levels in a 65 year-old HIV-positive male.(15) In a study in 16 healthy, HIV-negative subjects, the concurrent administration of omeprazole or ranitidine with ritonavir-boosted darunavir had no effect on darunavir pharmacokinetics.(16) In a study in healthy subjects, the concurrent administration of esomeprazole (20 mg daily) with either fosamprenavir (1400 mg twice daily) or fosamprenavir (700 mg twice daily) and ritonavir (100 mg twice daily) for 14 days had no effect on amprenavir pharmacokinetics.(17) In a study in 19 subjects, concurrent omeprazole (40 mg daily) and nelfinavir (1250 mg twice daily) for 4 days decreased nelfinavir AUC, Cmax, and Cmin by 36%, 37%, and 39%.(7,17) The AUC, Cmax, and Cmin of the active M8 metabolite of nelfinavir decreased by 92%, 89%, and 75%, respectively.(4,17) A retrospective review of nelfinavir levels found concurrent use of omeprazole decreased the median M8/nelfinavir ratio.(12) In a case report a 56 year old HIV infected male received omeprazole (40mg daily) and atazanavir/ritonavir (300/100mg) for ten months. Investigators used Bayesian models to determine atazanavir exposure, and found atazanavir levels to be in the 25th percentile of boosted levels, but still above the 75th percentile for unboosted atazanavir.(20) A retrospective review of 76 patients taking proton pump inhibitors and 66 patients not using proton pump inhibitors found no association with a higher virologic failure rate in patients receiving proton pump inhibitors.(21) In a case report, a 50 year-old HIV-infected male with a CD4 count of 1095 cells/ml and an HIV load of 88 copies/ml on a nelfinavir based regimen was switched to an atazanavir/ritonavir (300/100mg daily) regimen. The patient was taking omeprazole (20mg daily) and admitted to taking the atazanavir at 150mg twice daily. The patients CD4 count dropped to 830 cells/ml, but his HIV load dropped to <75 copies/ml. The investigators summarized concurrent use of omeprazole did not adversely affect this patient's virologic load.(22) In a study in 18 healthy subjects, concurrent omeprazole (40 mg daily) with saquinavir/ritonavir (1000/100 mg twice daily) for 4 days increased saquinavir AUC by 83%. No toxicities were noted.(18) In a study in 12 healthy subjects, concurrent omeprazole (40 mg daily) with saquinavir/ritonavir (1000/100 mg twice daily) for 7 weeks increased saquinavir AUC, Cmin, and Cmax by 54%, 73%, 55% respectively. Omeprazole 2 hours prior to saquinavir/ritonavir increased saquinavir AUC, Cmin, and Cmax by 67%, 97%, and 65% respectively. No toxicities were noted.(23) In a study of 14 healthy subjects, concurrent omeprazole (20 mg daily and 40 mg daily) with indinavir (800mg daily) for 7 days decreased indinavir AUC by 34% and 47% respectively and no statistical changes were seen in the Cmax or Tmax of indinavir. When omeprazole (40mg daily) was given with indinavir/ritonavir (800mg/200mg daily) for 7 days indinavir AUC increased by 55% and no statistical changes were seen in indinavir Cmax or Tmax. Omeprazole (40mg daily) showed a Cmax increase of 50% and a half-life increase of 100% in the presence of ritonavir.(24) In a study of 19 healthy subjects, concurrent omeprazole (20 mg daily) with fosamprenavir/ritonavir (1400/200 mg daily) or atazanavir/ritonavir (300/100)for 3 weeks showed no effect on amprenavir pharmacokinetics, but decreased atazanavir AUC and Cmin by 27%.(25) In a retrospective review of 15 HIV-infected patients receiving indinavir (800mg three times daily), nine patients were also receiving omeprazole (20-40mg daily). Of these nine patients, four had plasma concentrations of indinavir below the 95% confidence interval of plasmas concentration in patients receiving indinavir alone, four were within the 95% confidence interval, and one was above the 95% confidence interval.(26) In a case report, a 40 year-old HIV-infected male with extensive antiretroviral history and virological failure began atazanavir/ritonavir (300/100mg daily). The patient was restarted on lansoprazole during atazanavir/ritonavir therapy, and despite lansoprazole and tenofovir therapy the patients plasma concentrations of atazanavir remained consistent with historical values, and the patients Cmin stayed well above the established values for the combination of atazanavir/ritonavir with tenofovir.(27) In a study of 68 healthy subjects, coadministration of omeprazole (40mg daily) with lopinavir/ritonavir (400/100mg twice daily or 800/200mg once daily) showed no statistical change in pharmacokinetics.(28,29) However, when given with atazanavir/ritonavir (300/100 daily) bioavailability of atazanavir decreased by 48-62%.(28) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Proton Pump Inhibitors/Infigratinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The aqueous solubility of infigratinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce infigratinib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of infigratinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of PPIs, H2 antagonists, and locally acting antacids in patients receiving treatment with infigratinib.(1) If coadministration cannot be avoided and the PPI is replaced with a H2 antagonist, take infigratinib 2 hours before or 10 hours after the H2 antagonist.(1) If coadministration cannot be avoided and the PPI is replaced with an antacid, take infigratinib 2 hours before or 2 hours after the antacid.(1)

DISCUSSION: Infigratinib is practically insoluble at pH 6.8.(1) In a clinical study, lansoprazole decreased the area-under-curve (AUC) and maximum concentration (Cmax) of infigratinib by 45% and 49%, respectively. The AUC and Cmax of the active metabolite BHS697 were decreased by 32% and 44%, respectively, and the active metabolite CQM157's AUC and Cmax were decreased by 72% and 55%, respectively.(1)

Proton Pump Inhibitors/Olverembatinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The aqueous solubility of olverembatinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce olverembatinib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of olverembatinib leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of olverembatinib states that concurrent use with proton pump inhibitors should be avoided.(1)

DISCUSSION: Olverembatinib has pH-dependent solubility.(1)

Proton Pump Inhibitors/Rilpivirine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Rilpivirine requires an acidic medium for absorption. The proton pump inhibitor induced decrease in gastric pH may result in a decrease in rilpivirine absorption.(1)

CLINICAL EFFECTS: Concurrent use of a proton pump inhibitor may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of rilpivirine states that concurrent use of proton pump inhibitors is contraindicated.(1) When substituting antacids for proton pump inhibitors in patients maintained on rilpivirine, administer the antacid at least 2 hours before or 4 hours after rilpivirine.(1) When substituting H2 antagonists for proton pump inhibitors in patients maintained on rilpivirine, administer the H2 antagonist at least 12 hours before or 4 hours after rilpivirine.(1)

DISCUSSION: In a study in 16 subjects, omeprazole (20 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (150 mg daily) by 40%, 40%, and 33%, respectively. The Cmax and AUC of omeprazole decreased by 14% and 14%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 12 hours before a single dose of rilpivirine (150 mg) had no significant effect on rilpivirine Cmax or AUC.(1) In a study in 23 subjects, famotidine (40 mg single dose) administered 2 hours before a single dose of rilpivirine (150 mg) decreased the rilpivirine Cmax and AUC by 85% and 76%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 4 hours after a single dose of rilpivirine (150 mg) increased the rilpivirine Cmax and AUC by 21% and 13%, respectively.(1)

Proton Pump Inhibitors/Rilzabrutinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The aqueous solubility of rilzabrutinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce rilzabrutinib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of rilzabrutinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of rilzabrutinib states that concurrent use with proton pump inhibitors should be avoided.(1) If the PPI is replaced with an H2 antagonist, administer rilzabrutinib at least 2 hours before taking the H2 antagonist.(1) If the PPI is replaced with an antacid, administer rilzabrutinib at least 2 hours before taking the antacid.(1)

DISCUSSION: In an interaction study, coadministration of esomeprazole decreased rilzabrutinib maximum concentration (Cmax) by 55% and area-under-the-curve (AUC) by 51%.(1) In an interaction study, coadministration of famotidine decreased rilzabrutinib Cmax by 35% and AUC by 28%.(1)

Proton Pump Inhibitors/Ziftomenib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The aqueous solubility of ziftomenib is pH dependent. Higher gastric pH leads to lower solubility which may reduce ziftomenib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of ziftomenib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of ziftomenib states that concurrent use with proton pump inhibitors should be avoided.(1) The manufacturer of ziftomenib also states concurrent use with H2 receptor antagonists and antacids should be avoided. If concurrent use cannot be avoided, modify ziftomenib administration time: - Take ziftomenib 2 hours before or 10 hours after administration of an H2 receptor antagonist. - Take ziftomenib 2 hours before or 2 hours after administration of an antacid.(1)

DISCUSSION: In an interaction study, coadministration of proton pump inhibitors (PPIs) decreased ziftomenib area-under-the-curve (AUC) by 53% and maximum concentration (Cmax) by 70%.(1)

Slt Strong & Moderate 2C19 Inhibitor/Cilostazol (> 50Mg Bid)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong and moderate inhibitors of CYP2C19 may inhibit the metabolism of cilostazol.(1-4)

CLINICAL EFFECTS: Concurrent use of strong or moderate inhibitors of CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a metabolite of cilostazol that is 4-7 times as active as cilostazol.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong and moderate inhibitors of CYP2C19.(1) The Australian manufacturer of esomeprazole states concomitant use with cilostazol is contraindicated.(5)

DISCUSSION: In a study in 20 subjects examined the effects of omeprazole (40 mg daily) on a single dose of cilostazol (100 mg). Concurrent omeprazole increased the cilostazol maximum concentration (Cmax) and area-under-curve (AUC) by 18% and 26%, respectively. The Cmax and AUC of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%, respectively. The Cmax and AUC of the OPC-13213 metabolite of cilostazol decreased by 22% and 31%, respectively.(4)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Anticoagulants; Antiplatelets/Inotersen

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inotersen causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia.(1)

CLINICAL EFFECTS: Concurrent use of inotersen with anticoagulants and/or antiplatelet agents may result in additive or synergistic effects, including fatal and non-fatal intracranial hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may also be greater in patients greater than 60 years or have a prior history of major bleeding events. Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Inotersen should be administered with caution in patients receiving anticoagulants and/or antiplatelet agents.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Monitor platelet count frequently. If platelet count is less than 50, stop inotersen treatment and consider discontinuation of any anticoagulant and/or antiplatelet agents. Monitor for signs and symptoms of thrombocytopenia; such as, unusual or prolonged bleeding (petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness, or atypical severe headache.

DISCUSSION: In a clinical study, platelet counts below 100 occurred in 25% of inotersen-treated patients, compared with 2% of patients on placebo. Platelet counts below 75 occurred in 14% of inotersen-treated patients, compared to no patients on placebo. In study 1 and its extension study, 39% of inotersen-treated patients with a baseline platelet count below 200 had a nadir platelet count below 75, compared to 6% of patients with baseline platelet counts 200 or higher. Three inotersen-treated patients (3%) had sudden severe thrombocytopenia (platelet count below 25). One patient experienced a fatal intracranial hemorrhage.(1) Inotersen is only available through a Tegsedi REMS program because of the risk of severe thrombocytopenia and the risk of glomerulonephritis.(1)

Anticoagulants; Antiplatelets; Thrombolytics/Caplacizumab

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bleeding has been reported with the use of caplacizumab.(1)

CLINICAL EFFECTS: Concurrent use of caplacizumab with anticoagulants, antiplatelets, or thrombolytics may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. hemophilia, coagulation factor deficiencies). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Avoid the use of caplacizumab with anticoagulants, antiplatelets, and thrombolytics. Interrupt caplacizumab therapy if clinically significant bleeding occurs. Patients may require von Willebrand factor concentrate to rapidly correct hemostasis. If caplacizumab is restarted, closely monitor for signs of bleeding.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Bleeding has been reported with caplacizumab. In clinical studies, severe bleeding adverse reactions of epistaxis, gingival bleeding, upper gastrointestinal hemorrhage, and metrorrhagia were each reported in 1% of patients. Overall, bleeding events occurred in approximately 58% of patients on caplacizumab versus 43% of patients on placebo.(1) In post-marketing reports, cases of life-threatening and fatal bleeding were reported with caplacizumab.(1)

Antiplatelets; Aspirin (> 100 Mg)/Abrocitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Abrocitinib has been associated with transient, dose-dependent thrombocytopenia. The nadir platelet count occurs at a median of 24 days after receiving abrocitinib 200 mg once daily and a 40% recovery occurs by 12 weeks. Concurrent use with agents that affect platelet aggregation may result in an additive risk of bleeding.(1)

CLINICAL EFFECTS: Concurrent use of abrocitinib with antiplatelet agents may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. pre-existing thrombocytopenia). Abrocitinib is not recommended for patients with a platelet count less than 150,000/mm3.(1) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding.

PATIENT MANAGEMENT: The concurrent use of abrocitinib with antiplatelet agents (except aspirin < or = 81 mg daily) is contraindicated during the first 3 months of abrocitinib therapy. Prior to starting abrocitinib therapy, obtain a complete blood count and recheck at 4 weeks after initiation and 4 weeks after a dose increase. Discontinuation of abrocitinib is required if platelets drop below 50,000/mm3.(1) If concurrent therapy is warranted after the first 3 months of abrocitinib therapy, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Abrocitinib has been associated with transient, dose-dependent thrombocytopenia and is more severe with lower baseline platelet counts. At baseline platelet counts of 170,000/mm3, 220,000/m3 and 270,000/mm3, the nadirs were -41.2%, -33.4%, and -26.5%, respectively. Recovery of platelet count (about 40% recovery by 12 weeks) occurred without discontinuation of the treatment.(1)

Antiplatelets; Aspirin (> 100 Mg)/Apixaban

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Additive effects on hemostasis.(1-4)

CLINICAL EFFECTS: Concurrent use of apixaban with antiplatelets may increase the risk of bleeding.(1-4)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients requiring concurrent therapy with apixaban and an antiplatelet agent should be closely monitored for signs of bleeding. Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Discontinue apixaban in patients with active bleeding. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Concurrent administration of enoxaparin (40 mg single dose) and apixaban (5 mg single dose) resulted in additive effects on anti-Factor Xa activity.(1) Concurrent apixaban and aspirin (325 mg daily) resulted in no pharmacokinetic or pharmacodynamic interactions.(1) Concurrent apixaban with clopidogrel (75 mg daily) or with combination clopidogrel (75 mg daily) and aspirin (162 mg daily) produced no relevant increases in bleeding time, platelet aggregation, or clotting tests (PI, INR, and aPTT) compared either clopidogrel alone or clopidogrel with aspirin without apixaban.(1) Significant bleeding risk was reported with the combination of apixaban, aspirin, and clopidogrel in patients with acute coronary syndrome.(1) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of apixaban and clopidogrel resulted in a ratio of rate ratios (95% CI) of 1.96 (1.53-2.51).(5) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(3)

Antiplatelets; Aspirin (> 100 Mg)/Dabigatran

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation increased bleeding episodes can occur.(1,2)

CLINICAL EFFECTS: Concurrent use of dabigatran with antiplatelet agents may result in additive or synergistic effects resulting in unwanted bleeding episodes.(1,2)

PREDISPOSING FACTORS: Factors associated with an increase risk for bleeding include renal impairment, concomitant use of P-glycoprotein inhibitors, patient age >74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight <50 kg.(1-3) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients requiring concurrent therapy with dabigatran and an antiplatelet agent should be closely monitored for signs of bleeding. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue dabigatran in patients with active bleeding.

DISCUSSION: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation and/or other clotting factors increased bleeding episodes can occur.(1,2) In the RE-LY trial, 40% of patients were on aspirin at baseline.(1) In the RE-MEDY trial, 7.7% of patients were on aspirin at baseline.(1) In the RE-DUAL PCI trial, patients were randomly assigned to one of three treatments: (A) dual therapy with dabigatran 110 mg twice daily plus either clopidogrel or ticagrelor, (B) dual therapy with dabigatran 150 mg twice daily plus either clopidogrel or ticagrelor, or (C) triple therapy with warfarin (goal INR 2-3) plus aspirin (< or = 100 mg daily) plus either clopidogrel or ticagrelor. The incidence of the first major or clinically relevant non-major (CRNM) bleeding event was 15.4% in group A compared with 26.9% in group C (hazard ratio, 0.52; 95% CI 0.42 to 0.63; p<0.001 for noninferiority; p<0.001 for superiority) and 20.2% in group B compared to 25.7% in corresponding group C (hazard ratio, 0.72; 95% CI 0.58 to 0.88; p<0.001 for noninferiority). For major bleeding as defined by Thrombolysis in Myocardial Infarction (TIMI) criteria, the rate was lower in both dual-therapy groups than in the triple-therapy group: 1.4% in group A compared to 3.8% in group C (hazard ratio, 0.37; 95% CI 0.2 to 0.68; p=0.002) and 2.1% in group B compared to 3.9% in corresponding group C (hazard ratio, 0.51; 95% CI 0.28 to 0.93; p=0.03). Incidence of composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization was 13.7% in groups A and B compared to 13.4% in group C (hazard ratio, 1.04; 95% CI 0.84 to 1.29; p=0.005 for noninferiority).(4) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. Compared with DOACs alone, the use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and CRNM bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(5)

Antiplatelets; Aspirin (> 100 Mg)/Edoxaban

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Anticoagulants and antiplatelet agents have additive effects on hemostasis.(1) In addition, aspirin doses greater than or equal to 325 mg daily increase edoxaban exposure.(1)

CLINICAL EFFECTS: Concurrent use of edoxaban with antiplatelets may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: Bleeding risk may be increased in patients with renal impairment and in patients > 75 years of age.(1) Use of multiple agents which affect hemostasis increases the risk for bleeding. The risk for bleeding episodes may be greater in patient with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients requiring concurrent therapy with edoxaban and an antiplatelet agent should be closely monitored for signs of bleeding. Edoxaban and aspirin at dosages of 100 mg or less may be coadministered.(2,3) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Discontinue edoxaban in patients with active bleeding.

DISCUSSION: Concomitant use of edoxaban and antiplatelet agents may increase the risk of bleeding. In edoxaban clinical trials concomitant use of low dose aspirin (< or = 100 mg daily), thienopyridines, and NSAIDs was permitted and resulted in increased rates of clinically relevant bleeding. The rates of major bleeding on edoxaban and warfarin were generally consistent among subgroups. Bleeding rates appeared higher in both treatment arms (edoxaban and warfarin) in patients taking aspirin. Co-administration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.(1) About 30% of the population in ENGAGE-AF received concomitant therapy with aspirin because of co-morbid conditions. While aspirin is known to increase risk for bleeds and the annualized event rate for major bleeds was higher than that in patients not receiving aspirin (3.87% vs. 2.13%), the risk for bleeds in patients receiving edoxaban 60 mg on a background of aspirin was lower than that for warfarin on a background of aspirin (HR 0.78 (95%CI 0.65,0.94). Based on these data no dose adjustments/contraindications are required.(4) Edoxaban and aspirin at dosages of 100 mg or less may be coadministered.(2,3) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(5)

Aspirin (< Or = 300 Mg)/Ketorolac (Injectable)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: There are two potential mechanisms: 1) Possible additive or synergistic pharmacodynamic side effects from concurrent NSAID use.(1,2) 2) Ketorolac is a reversible platelet inhibitor, while aspirin is an irreversible platelet inhibitor.

CLINICAL EFFECTS: Concurrent use of multiple doses of ketorolac with aspirin may result in increased risk for NSAID-related side effects such as bleeding.(1,2) Nonselective NSAIDs such as ketorolac may interfere with the antiplatelet effects of aspirin.(3)

PREDISPOSING FACTORS: Bleeding risk may increase due to disease (e.g. recent GI ulcer or bleed) or other concurrent drugs (e.g.anticoagulants, heparinoids). Elderly patients are at increased risk for severe GI events from ketorolac.(1,2) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (NSAIDs).

PATIENT MANAGEMENT: The manufacturer of prescription extended-release aspirin used for cardiovascular protection notes that concurrent treatment with NSAIDs may interfere with the antiplatelet effect of aspirin and increase the risk for NSAID associated bleeding or renal impairment, but does not contraindicate concurrent use.(3) However, manufacturers of ketorolac state that concurrent use of ketorolac with aspirin is contraindicated.(1,2) If concurrent therapy or ketorolac with low dose aspirin is needed, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Conduct periodic monitoring of renal function, especially in patients with preexisting renal impairment. Instruct patients to report any signs and symptoms of bleeding, such as unusual bruising; red or black, tarry stools; acute abdominal or joint pain and/or swelling.

DISCUSSION: Based upon similar pharmacodynamic effects and potentially cumulative risks for serious NSAID-related adverse events, manufacturers of ketorolac state the concurrent administration of ketorolac with other NSAIDs or aspirin is contraindicated.(1,2) Prescribing information for an FDA approved lower strength prescription aspirin product used for cardiovascular risk reduction describes potential interactions, but does not contraindicate concomitant NSAID use.(3)

Aspirin (< Or = 300 Mg)/Ketorolac (Non-Injectable)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: There are two potential mechanisms: 1) Possible additive or synergistic pharmacodynamic side effects from concurrent NSAID use.(1,2) 2) Ketorolac is a reversible platelet inhibitor, while aspirin is an irreversible platelet inhibitor.

CLINICAL EFFECTS: Concurrent use of multiple doses of ketorolac with aspirin may result in increased risk for NSAID-related side effects such as bleeding.(1,2) Nonselective NSAIDs such as ketorolac may interfere with the antiplatelet effects of aspirin.(3)

PREDISPOSING FACTORS: Bleeding risk may increase due to disease (e.g. recent GI ulcer or bleed) or other concurrent drugs (e.g.anticoagulants, heparinoids). Elderly patients are at increased risk for severe GI events from ketorolac.(1,2) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (NSAIDs).

PATIENT MANAGEMENT: The manufacturer of prescription extended-release aspirin used for cardiovascular protection notes that concurrent treatment with NSAIDs may interfere with the antiplatelet effect of aspirin and increase the risk for NSAID associated bleeding or renal impairment, but does not contraindicate concurrent use.(3) However, manufacturers of ketorolac state that concurrent use of ketorolac with aspirin is contraindicated.(1,2) If concurrent therapy or ketorolac with low dose aspirin is needed, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Conduct periodic monitoring of renal function, especially in patients with preexisting renal impairment. Instruct patients to report any signs and symptoms of bleeding, such as unusual bruising; red or black, tarry stools; acute abdominal or joint pain and/or swelling.

DISCUSSION: Based upon similar pharmacodynamic effects and potentially cumulative risks for serious NSAID-related adverse events, manufacturers of ketorolac state the concurrent administration of ketorolac with other NSAIDs or aspirin is contraindicated.(1,2) Prescribing information for an FDA approved lower strength prescription aspirin product used for cardiovascular risk reduction describes potential interactions, but does not contraindicate concomitant NSAID use.(3)

Aspirin(>100Mg);Salicylates/Slt Anticoagulants (Vit K Antag)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Multiple processes are involved: 1) Salicylate doses greater than 3 gm daily decrease plasma prothrombin levels. 2) Salicylates may also displace anticoagulants from plasma protein binding sites. 3) Aspirin is an irreversible platelet inhibitor. Salicylates impair platelet function, resulting in prolonged bleeding time. 4) Salicylates may cause gastrointestinal(GI) bleeding due to irritation.

CLINICAL EFFECTS: The concurrent use of anticoagulants and salicylates leads to blockade of two distinct coagulation pathways and may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Avoid concomitant administration of these drugs. When aspirin is required for cardioprotection, a low dose (less than 100 mg daily) is recommended to decrease the risk for aspirin-induced GI bleeding. The Australian manufacturer of fluindione states use is contraindicated with anti-inflammatory doses of acetylsalicylic acid (>= 1 g/dose and/or >= 3 g/day) and analgesic or antipyretic doses (>= 500 mg per dose and/or < 3 g per day) with a history of duodenal ulcer. Use is not recommend for analgesic or antipyretic doses (>= 500 mg per dose and/or <3 g per day) in the absence of a history of duodenal ulcer. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: This interaction has been reported between aspirin and warfarin and between aspirin and dicumarol. Diflunisal, sodium salicylate, and topical methyl salicylate have been shown to interact with anticoagulants as well. Based on the proposed mechanisms, other salicylates would be expected to interact with anticoagulants as well. A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and diflunisal resulted in a ratio of rate ratios (RR) (95% CI) of 3.85 (1.34-11.03); warfarin and aspirin ratio of RR 2.13 (1.72-2.64); warfarin and dipyridamole ratio of RR 2.07 (1.65-2.6); and warfarin and clopidogrel ratio of RR 1.69 (1.56-1.84). A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 38 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antiplatelets (OR=1.74; 95% CI 1.56-1.94). Increased bleeding risk was also seen in subgroup analyses with aspirin (OR=1.50; 95% CI 1.29-1.74), clopidogrel (OR=3.55; 95% CI 2.78-4.54), and aspirin plus clopidogrel or ticlopidine (OR=2.07, 95% CI 1.33-3.21).(17)

Aspirin/Anagrelide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Anagrelide may affect platelet function in a way that synergizes with low-dose aspirin.(1)

CLINICAL EFFECTS: Concurrent use of anagrelide and aspirin may increase the risk of hemorrhage.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The concurrent use of anagrelide and aspirin should be approached with caution, especially in patients with a high risk profile for hemorrhage.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In healthy subjects, the administration of of single dose anagrelide (1 mg) and aspirin (900 mg) or multiple dose anagrelide (1 mg daily) and aspirin (75 mg daily) resulted in greater anti-platelet aggregation effects than aspirin alone. Concurrent single doses of both anagrelide and aspirin had no effects on bleeding time, prothrombin time, or activated partial thromboplastin time.(2) A study in 809 patients with essential thrombocythemia compared the combination of low-dose aspirin with hydroxyurea to the combination of low-dose aspirin with anagrelide. While patients receiving low-dose aspirin with anagrelide had lower rates of venous thromboembolism, the combination was associated with increased rates of arterial myelofibrosis, serious hemorrhage, and transformation to myelofibrosis.(1)

Esomeprazole; Omeprazole/Select Cyp2c19 Or Cyp3a4 Inducer

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Proton pump inhibitors are primarily metabolized by CYP2C19, while CYP3A4 also plays a role in metabolism.(1,2) Enzalutamide, rifampin, and St. John's wort are moderate inducers of CYP2C19 and strong inducers of CYP3A4.(3,4) Apalutamide is a strong inducer of CYP2C19 and CYP3A4.(5) Efavirenz and pacritinib are moderate inducers of CYP2C19 and CYP3A4.(3,6) Sparsentan is a moderate inducer of CYP2C19.(8) Fexinidazole is a moderate inducer of CYP3A4.(3)

CLINICAL EFFECTS: Concurrent use of agents which induce both CYP2C19 and CYP3A4 decrease systemic exposure and may result in decreased effectiveness of proton pump inhibitors.(1-7)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid concurrent use of esomeprazole or omeprazole with CYP2C19 or CYP3A4 inducers.(1,2) Monitor patients receiving concurrent therapy for reduced proton pump inhibitor (PPI) effectiveness. Although specific dosing recommendations are not available, a higher dose of the proton pump inhibitor may be considered to maintain PPI efficacy.

DISCUSSION: In an interaction study, subjects with prostate cancer received omeprazole before and after enzalutamide 160 mg daily for at least 55 days. Enzalutamide decreased omeprazole area-under-curve (AUC) by 70.5%.(3,4) In an interaction study, rifampin 600 mg daily for 7 days decreased omeprazole AUC by 89.5%.(3,7) In an interaction study, pacritinib 200 mg twice daily at steady state decreased the Cmax and AUC of a single dose of omeprazole (20 mg) by 27% and 51%, respectively.(6) Concomitant use with sparsentan (moderate CYP2C19 inducer) decreased the exposure of omeprazole Cmax by 49% and AUC by 60%.(8) In an interaction study, St. John's wort decreased the maximum concentration (Cmax) and AUC of omeprazole by 37.5% and 49.6%, respectively. The Cmax and AUC of omeprazole sulfone (via CYP2C19) increased by 160.3% and 136.6%, respectively. The Cmax and AUC of 5-hydroxyomeprazole (via CYP3A4) increased by 38.1% and 37.2%, respectively.(9,10)

Esomeprazole; Omeprazole; Cimetidine/Clopidogrel

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Proton pump inhibitors (PPIs) may inhibit CYP2C19 mediated conversion to the active metabolite of clopidogrel. The magnitude and clinical significance of CYP2C19 inhibition is highly variable between agents.(1)

CLINICAL EFFECTS: Concurrent use of esomeprazole, omeprazole, or cimetidine may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Evaluate patient risk for gastrointestinal(GI) bleeding. When PPIs are needed, use dexlansoprazole, lansoprazole, pantoprazole or rabeprazole as they have a lower interaction risk.(1,3) Consider the use of H2 blockers (such as famotidine, nizatidine, or ranitidine) in patients with a low bleeding risk and reserve the use of PPIs for patients at higher risk of GI bleeding. US manufacturers for clopidogrel and omeprazole state concurrent use of clopidogrel esomeprazole and omeprazole should be avoided.(1,4-5) As esomeprazole and omeprazole are irreversible inhibitors of CYP2C19, separating clopidogrel from esomeprazole or omeprazole administration times does not change the magnitude of this interaction.(1,4,6) The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Moderate CYP2C19 inhibitors, such as omeprazole, and weak CYP2C19 inhibitors, such as cimetidine, may also affect this interaction. Consider alternatives to esomeprazole, omeprazole, and cimetidine in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on esomeprazole, omeprazole, and cimetidine. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: US manufacturer for clopidogrel states omeprazole and esomeprazole have been shown to reduce antiplatelet activity of clopidogrel and recommends against concomitant use. The antiplatelet effect of clopidogrel is reduced by approximately 40% in patients receiving 80 mg per day of omeprazole. Dexlansoprazole, lansoprazole and pantoprazole are described as having less effect on clopidogrel antiplatelet activity.(1,3) In the primary literature, documentation for this interaction is conflicting. However, both in-vitro and retrospective analyses indicate that omeprazole decreases the effectiveness of clopidogrel. Although the half-lives of esomeprazole and omeprazole (a racemic mixture of R- and esomeprazole) are short, the effect on CYP2C19 is long lasting because esomeprazole is an irreversible inhibitor of CYP2C19.(6) In two studies in healthy subjects, concurrent omeprazole decreased the effects of clopidogrel on platelets.(7-8) Several studies have found coadministration of clopidogrel with omeprazole resulted in increased platelet aggregation compared to clopidogrel with pantoprazole, or no PPI.(9-12) In a study, use of omeprazole was associated with a decreased risk of upper gastrointestinal bleeding in patients receiving dual antiplatelet therapy with clopidogrel and aspirin. There was no significant difference between the groups in rate of cardiovascular events.(12) Three studies found that simultaneous omeprazole with clopidogrel reduced clopidogrel concentrations and effects.(13-15) In a cross-over trial, healthy subjects received clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg oral once daily) co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period.(16) In a study in 39 healthy subjects, the effects of omeprazole and rabeprazole on clopidogrel in patients with different CYP2C19 genotypes was examined. In rapid 2C19 metabolizers, simultaneous omeprazole and rabeprazole significantly decreased clopidogrel response. In decreased 2C19 responders, there was wide variation in clopidogrel response and simultaneous omeprazole and rabeprazole had no significant effect on overall clopidogrel effects; however, some subjects became low responders to clopidogrel while on PPI therapy. Staggered dosing of omeprazole had no effect on clopidogrel response in rapid metabolizers, but decreased clopidogrel response in decreased metabolizers.(17) Several retrospective studies found that patients who took clopidogrel with a PPI had increased incidence of major cardiovascular events compared to patients who took clopidogrel without a PPI.(18-22) A retrospective cohort study of 20,596 patients in the Tennessee Medicaid program, evaluated both cardiovascular disease event and GI bleed risk in patients prescribed clopidogrel with or without concurrent PPI use. Pantoprazole was prescribed in 62% of PPI patients. Concomitant PPI and clopidogrel use decreased the risk of hospitalization from GI bleeding by 50%. There was no clear-cut increase risk for serious cardiovascular disease events; however, the 95% CI for this was wide.(23) A post-hoc analysis of the PRINCIPLE-TIMI 44 trial and the TRITON-TIMI trial examined the effects of PPI use on the pharmacodynamic effects and clinical efficacy of clopidogrel. The PRINCIPLE-TIMI 44 trial examined 201 patients undergoing cardiac catheterization with planned percutaneous coronary intervention, 53 of which were taking a PPI at randomization. Patients receiving a PPI had significantly lower rates of inhibition of platelet aggregation at 0.5 hours, 2 hours, 6 hours, and 18-24 hours post-loading dose of clopidogrel. After 15 days of maintenance therapy, there were significantly more non-responders in the group receiving PPI (50% versus 7.9%). The TRITON-TIMI trial examined 13,608 patients who underwent cardiac catheterization with planned percutaneous coronary intervention, 4529 of which were taking a PPI at randomization. Patients received clopidogrel treatment for 6-15 months. There were no significant differences in occurrence of cardiovascular death, non-fatal MI, or non-fatal stroke between patients taking PPIs at randomization and those not; however, use of PPIs was only assessed at randomization and not during the study.(24) A retrospective cohort study of 16,064 patients evaluated the impact of MACE events in patients taking clopidogrel with PPIs/PCABs. Patients taking concurrent PPIs or PCABs with clopidogrel had a higher incidence of MACE compared to clopidogrel monotherapy. Among MACE, stroke recurrence was the highest risk with the PPI and PCAB groups. The PPIs studied included esomeprazole, dexlansoprazole, omeprazole, pantoprazole, ilaprazole, and rabeprazole, with esomeprazole resulting in the highest risk of MACE and stroke recurrence.(29)

H2 Antagonists;Proton Pump Inhibitors/Methylphenidate Xr-Odt

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The solubility of methylphenidate extended release orally disintegrating tablets (XR-ODT) is pH-dependent. At elevated pH, methylphenidate may be released from the tablets more quickly, resulting in increased absorption.(1)

CLINICAL EFFECTS: Coadministration of H2 antagonists or proton pump inhibitors (PPIs) may result in an altered pharmacokinetic profile of methylphenidate XR-ODT, which may change the effectiveness and/or adverse effects of methylphenidate XR-ODT.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of methylphenidate XR-ODT with H2 antagonists or PPIs is not recommended.(1,2)

DISCUSSION: In in vitro studies, when media pH was increased from 1.2 to 6.8, percentage release of methylphenidate from the XR-ODT tablet was increased by 67% at 0.5 hours, and by 93% at 2.5 hours. The increased dissolution of methylphenidate at higher pH may result in increased drug absorption and change the concentration-time profile of methylphenidate, which is correlated with pharmacological effect.(1)

High-Dose Aspirin/Ticagrelor

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Chronic use of high-dose aspirin may decrease the efficacy of ticagrelor.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: After an initial loading dose, low dose aspirin is indicated with concurrent ticagrelor for the prevention of thrombotic events. Specific dosage recommendations vary between countries, however all agree that the maintenance aspirin dose should be < or = 150 mg per day. US prescribing information recommends the following based on indication: -For Acute Coronary Syndrome or Myocardial Infarction - Initiate ticagrelor with a maintenance dose of aspirin 75 mg to 100 mg. -For Coronary Artery Disease but No Prior Stroke or Myocardial Infarction - Use ticagrelor with a daily maintenance dose of aspirin of 75 mg to 100 mg. -For Acute Ischemic Stroke or Transient Ischemic Attack - Use ticagrelor with a loading dose of aspirin (300 mg to 325 mg) and a daily maintenance dose of 75 mg to 100 mg.(1) Canada and UK prescribing information recommends a maintenance aspirin dose of 75 mg to 150 mg daily.(2,3) For use other than platelet aggregation, it would be prudent to recommend an alternative product that does not contain aspirin for patients maintained on ticagrelor.

DISCUSSION: Ticagrelor is indicated with concurrent aspirin for the prevention of thrombotic events. In the PLATO trial, there was a relationship between the maintenance dose of aspirin and efficacy of ticagrelor. At increased aspirin dosages, ticagrelor was less effective.(1-3)

Long Acting Antacids; H2s;Ppis/Selected Cephalosporins

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Absorption of oral cefpodoxime or cefuroxime may be reduced in patients receiving concomitant treatment with acid reducing agents.(1-5)

CLINICAL EFFECTS: Antibiotic efficacy against organisms with a high minimum inhibitory concentration (MIC) to cefpodoxime or cefuroxime could be decreased.

PREDISPOSING FACTORS: Taking cefpodoxime or cefuroxime on an empty stomach magnifies this effect.

PATIENT MANAGEMENT: If possible, avoid the use of H2 antagonists and proton pump inhibitors(PPIs) in patients taking cefpodoxime or cefuroxime. If concurrent therapy is needed with antacids, H2 antagonists, or PPIs, administer cefpodoxime or cefuroxime after eating to maximize oral absorption. Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: In a study of ten subjects, administration of cefpodoxime after single dose famotidine 40 mg decreased both maximum concentration (Cmax) and area-under-curve (AUC) by approximately 40 percent compared with administration of cefpodoxime on an empty stomach.(3) In a study of 17 subjects, administration of cefpodoxime after single dose ranitidine 150 mg decreased Cmax and AUC by approximately 40 percent compared with administration of cefpodoxime on an empty stomach.(4) In a study performed prior to the introduction of PPIs, administration of ranitidine 300 mg and sodium bicarbonate followed by cefuroxime taken on a empty stomach lowered both Cmax and AUC of cefuroxime by approximately 40 per cent compared with administration of cefuroxime alone on an empty stomach. Postprandial administration of cefuroxime in subjects taking ranitidine was similar to that of subjects taking cefuroxime on an empty stomach.(5)

Moderate Cyp2c19 Inhibitors/Mavacamten

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Moderate CYP2C19 inhibitors may decrease the metabolism of mavacamten.(1-3)

CLINICAL EFFECTS: Concurrent use of a moderate CYP2C19 inhibitor increases plasma exposure of mavacamten which may increase the incidence and severity of adverse reactions of mavacamten.(1-3)

PREDISPOSING FACTORS: CYP2C19 rapid and ultrarapid metabolizers may experience an increased incidence or severity of adverse effects.(1-3)

PATIENT MANAGEMENT: The US manufacturer of mavacamten recommends initiating mavacamten at one dose below the recommended starting dose in patients who are on stable therapy with a moderate CYP2C19 inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on mavacamten treatment and intend to initiate a moderate CYP2C19 inhibitor. Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate mavacamten until 12 weeks after inhibitor initiation.(1) Avoid initiation of concomitant moderate CYP2C19 inhibitors in patients who are on stable treatment with the lowest recommended dose of mavacamten because a lower dose is not available.(1) For short-term use (e.g. 1 week), interrupt mavacamten therapy for the duration of the moderate CYP2C19 inhibitor. After therapy with the moderate CYP2C19 inhibitor is discontinued, mavacamten may be reinitiated at the previous dose immediately upon discontinuation.(1) The Canadian manufacturer of mavacamten states concomitant use with moderate CYP2C19 inhibitors is contraindicated.(2) The UK manufacturer of mavacamten states concomitant use with moderate CYP2C19 inhibitors is dependent on CYP2C19 phenotype. Labeling recommends: -In patients who are CYP2C19 poor metabolizers, moderate CYP2C19 inhibitors may be used concurrently without dose adjustment of mavacamten. Monitor left ventricular ejection fraction (LVEF) in 4 weeks then resume usual monitoring schedule. -In patient who are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers: Moderate CYP2C19 inhibitors may be used concurrently without dose adjustment of mavacamten starting dose of 5 mg daily. If starting a moderate CYP2C19 inhibitor, reduce mavacamten dose by one dose level or discontinue 2.5 mg. Monitor LVEF in 4 weeks then resume usual monitoring schedule. -If CYP2C19 phenotype is unknown, consider a mavacamten starting dose of 2.5 mg daily. If starting a moderate CYP2C19 inhibitor, reduce mavacamten dose from 5 mg to 2.5 mg or discontinue mavacamten if on 2.5 mg. Monitor LVEF in 4 weeks then resume usual monitoring schedule.(3)

DISCUSSION: Concomitant use of mavacamten (15 mg) with omeprazole (20 mg), a weak CYP2C19 inhibitor, once daily increased mavacamten area-under-curve (AUC) by 48% with no effect on maximum concentration (Cmax) in healthy CYP2C19 normal metabolizers and rapid metabolizers.(1) Moderate CYP2C19 inhibitors linked to this monograph include: abrocitinib, cannabidiol, esomeprazole, moclobemide, omeprazole, stiripentol, triclabendazole.(4,5)

Nsaids; Aspirin (> 100 Mg); Salicylates/Mifamurtide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: High-dose NSAIDs or salicylates may block the macrophage activating effect of mifamurtide.(1)

CLINICAL EFFECTS: Concurrent use of high-dose NSAIDs or salicylates may decrease the effectiveness of mifamurtide.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of mifamurtide states that concurrent use with high-dose NSAIDs or salicylates is contraindicated.(1)

DISCUSSION: In vitro studies have shown that high-dose NSAIDs or salicylates can block the macrophage activating effect of mifamurtide.(1)

Nsaids; Salicylates/Sodium Phosphate Bowel Cleanser

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bowel cleansing with sodium phosphate causes dehydration, decreased intravascular volume and hyperphosphatemia, which increases phosphate levels in the renal tubules. Abnormally high levels of calcium and phosphate in the renal tubules may precipitate out, resulting in renal injury.(1)

CLINICAL EFFECTS: Use of sodium phosphate for bowel cleansing in patients maintained on nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of acute phosphate nephropathy, which is an acute kidney injury associated with deposits of calcium phosphate crystal in the renal tubules that may result in permanent renal function impairment. Acute phosphate nephropathy presents as acute kidney injury with minimal proteinuria and a bland urine sediment.(2) Use of oral sodium phosphate products at laxative doses has not been associated with acute kidney injury.(3)

PREDISPOSING FACTORS: Patients who may be at an increased risk of acute phosphate nephropathy include those who are over age 55; are hypovolemic or have decreased intravascular volume; have baseline kidney disease, bowel obstruction, or active colitis; and who are using medications that affect renal perfusion or function (such as diuretics, ACE inhibitors, angiotension receptor blockers [ARBs]), and NSAIDs.(2)

PATIENT MANAGEMENT: If possible, use an alternative agent for bowel cleansing.(1) Use sodium phosphate products with caution in patients taking medications that affect kidney function or perfusion, such as ACE inhibitors or ARBs. Obtain baseline and post-procedure labs (electrolytes, calcium, phosphate, BUN, creatinine, and [in smaller, frail individuals] glomerular filtration rate). Instruct patients to drink sufficient quantities of clear fluids before, during, and after bowel cleansing and to avoid other laxatives that contain sodium phosphate. Consider hospitalization and intravenous hydration during bowel cleansing to support frail patients who may be unable to drink an appropriate volume of fluid or who may be without assistance at home.(2) Use of an electrolyte solution for rehydration may decrease the risk of acute phosphate nephropathy.(4,5)

DISCUSSION: Since May 2006, the FDA has received 20 reports of acute phosphate nephropathy associated with the use of Osmo Prep. Concomitant medications included ACE inhibitors or ARBs (11), diuretics (6), and NSAIDs (4).(2) In a retrospective review of colonoscopy patients, simultaneous use of ACE inhibitors or ARBs significantly increased the risk of acute kidney injury from oral sodium phosphate. Diuretic use was also a risk factor.(6) In a case series study of 21 cases of acute phosphate nephropathy in patients who had used oral sodium phosphate, 14 patients received an ACE inhibitor or ARB, 4 used a diuretic, and 3 used an NSAID.(7) Cases have also been reported with rectal products.(8)

Omeprazole; Esomeprazole/Hydantoins

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Omeprazole and esomeprazole may inhibit the CYP2C19 metabolism of hydantoins.(1-3) Hydantoins may induce the CYP3A4 metabolism of omeprazole and esomeprazole.(1-3)

CLINICAL EFFECTS: Concurrent administration of omeprazole or esomeprazole and hydantoins may result in elevated levels of the hydantoin. Phenytoin has a narrow therapeutic range. Early symptoms of phenytoin toxicity may include nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. Severe toxicity may produce organ dysfunction (e.g. coma, irreversible cerebellar dysfunction and atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may be fatal.(1) Concurrent use of omeprazole or esomeprazole with CYP3A4 inducers may result in decreased levels and effectiveness of omeprazole or esomeprazole.(1-3)

PREDISPOSING FACTORS: Renal impairment, hepatic impairment, or hypoalbuminemia.

PATIENT MANAGEMENT: Avoid concomitant use of CYP3A4 inducers with omeprazole or esomeprazole.(2,3) Patients should be monitored for changes in response to hydantoins when omeprazole or esomeprazole are added to or discontinued from hydantoin therapy. Serum hydantoin concentration should be monitored to assist in dosage adjustments.(1) Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting).

DISCUSSION: In a double-blind cross-over study in ten healthy subjects, concurrent phenytoin (300 mg single dose on day seven of omeprazole therapy) and omeprazole (40 mg daily for nine days) therapy resulted in area-under-curve (AUC) increasing 19% when compared to phenytoin and placebo. There were no significant changes in phenytoin peak concentration, (Cmax) time to Cmax, or half-life.(4) In another cross-over study on eight healthy subjects, concurrent phenytoin (250 mg single dose administered intravenously over 30 minutes on day seven of omeprazole therapy) and omeprazole (40 mg daily for eight days) resulted in plasma clearance decreasing 15% and half-life increasing 27% when compared to phenytoin and placebo. There was a small, but not significant, increase in phenytoin plasma concentrations during concurrent omeprazole therapy.(5) The results of these studies are disputed in a study of eight epileptic patients maintained on phenytoin (dosage range 200-450 mg daily). There were no significant changes in phenytoin levels or phenytoin urinary excretion after three weeks of concurrent omeprazole (20 mg daily) therapy when compared to previous steady-state values. The authors speculated that the low dose of omeprazole (20 mg daily) was not enough to produce the inhibition of phenytoin metabolism seen in other studies.(6) In an interaction study, rifampin 600 mg daily for 7 days decreased omeprazole AUC by 89.5%.(8,9)

Proton Pump Inhibitors/Capecitabine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The aqueous solubility of capecitabine is pH dependent. Higher gastric pH leads to lower solubility and altered tablet dissolution which may reduce capecitabine absorption.(1,2)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of capecitabine, leading to decreased systemic levels and effectiveness.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of proton pump inhibitors with capecitabine may decrease bioavailability. When clinically appropriate, consider using H2 blockers or antacids.

DISCUSSION: A retrospective study in early stage colorectal cancer patients treated with adjuvant monotherapy capecitabine examined recurrence-free survival (RFS) and overall survival (OS) in 1335 patients with and without concurrent proton pump inhibitor (PPI) therapy. The PPI group was defined as a prescription for a PPI filled at any point in time during capecitabine treatment. Patients in the capecitabine with concurrent PPI group had a statistically significant decrease in 5-year RFS (74% v 83%; hazard ratio (HR) 1.89; 95% confidence interval (CI) 1.07-3.35; p=0.03) compared to capecitabine without PPI therapy. OS was not significantly different between groups (81% PPI v 78% non-PPI; HR 1.13; 95% CI 0.6-2.14; p=0.7). After adjusting for male gender, stage III colorectal cancer, advance age >68, poorer ECOG PS, there was a trend toward decreased RFS in PPI patients (HR 1.65; 95% CI 0.93-2.94; p=0.09).(1) An ad hoc analysis of the TRIO-013/LOCiC trial examined coadministration of PPI therapy, defined as 20% or more overlap between a PPI prescription and trial treatment duration with capecitabine and/or lapatinib, on progression-free survival (PFS) and overall survival (OS). The secondary analysis examined 545 patients in which 42% were on concurrent PPI therapy. Patients in the non-PPI group had an improved median PFS (5.7 v 4.2 months; HR 1.55; 95% CI 1.29-1.81; p<0.001) and median OS (11.3 v 9.2 months; HR 1.34; 95% CI 1.06-1.62; p=0.04) compared with PPI users. A multivariate analysis reviewed effects of PPIs on both PFS and OS with capecitabine alone and found effects of PPI use on both PFS and OS was still significant (HR 1.68; p<0.001 and HR 1.41; p=0.001, respectively).(2) In a study in 12 subjects, concomitant administration of capecitabine with aluminum-magnesium hydroxide containing antacid 20 mL increased area-under-curve (AUC) and concentration maximum (Cmax) by 16% and 35%, respectively.(3) Proton pump inhibitors linked to this monograph include: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole.

Proton Pump Inhibitors/Indinavir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The aqueous solubility of indinavir is pH dependent. Higher gastric pH leads to lower solubility which may reduce indinavir absorption.(1-2)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors may reduce the bioavailability of indinavir, leading to decreased systemic levels and effectiveness.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concomitant administration of indinavir and proton pump inhibitors is not recommended unless indinavir is accompanied by ritonavir, typically dosed as indinavir 800 mg twice daily with ritonavir 100 mg twice daily. Monitor patients receiving concurrent therapy for changes in indinavir effectiveness.(1)

DISCUSSION: A retrospective analysis in 9 HIV+ patients found that indinavir administration with omeprazole (20 mg) decreased the maximum concentration (Cmax) of indinavir by 29%. Indinavir administration with omeprazole (40 mg) decreased the Cmax of indinavir by 41%.(1) In a crossover study in 16 healthy volunteers, concurrent administration of omeprazole (20 mg to 40 mg for 7 days) decreased the indinavir (800 mg single dose) Cmax and area-under-the-curve (AUC) by 29-41% and 34-47%, respectively.(2) Coadministration of omeprazole (40 mg) and indinavir (800 mg single dose) to 14 HIV+ subjects resulted in a 47% decrease in indinavir AUC and a 55% decrease in minimum concentration (Cmin). The addition of ritonavir (200 mg single dose) reversed the effects of omeprazole.(3) In a crossover study in 5 healthy volunteers, concurrent administration of indinavir (400 mg single dose) with a proton pump inhibitor resulted in increased gastric pH and a smaller fraction of indinavir being dissolved and lower intestinal concentrations.(4) In an animal study investigating the solubility of indinavir, solubility of indinavir in aqueous media decreased from more than 100 mg/mL at pH 3 to less than 0.1 mg/mL at pH 5 or above.(5)

Proton Pump Inhibitors/Ledipasvir; Velpatasvir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The aqueous solubility of ledipasvir and velpatasvir is pH dependent. Higher gastric pH leads to lower solubility which may reduce ledipasvir and velpatasvir absorption.(1-3)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of ledipasvir and velpatasvir, leading to decreased systemic levels and effectiveness.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Omeprazole 20 mg daily, or comparable doses of other PPIs, may be administered simultaneously with ledipasvir-sofosbuvir under fasting conditions.(1) Coadministration of proton pump inhibitors is not recommended with sofosbuvir-velpatasvir. When concomitant proton pump inhibitor use is necessary in patients receiving sofosbuvir-velpatasvir, velpatasvir-sofosbuvir should be administered with food and taken 4 hours before omeprazole 20 mg. Use with other proton pump inhibitors has not been studied.(2) Omeprazole 20 mg daily may be administered with sofosbuvir-velpatasvir-voxilaprevir. Use with other proton pump inhibitors has not been studied.(3) When clinically appropriate, consider use of H2 blockers or antacids.(1-3)

DISCUSSION: In an interaction study, omeprazole 20 mg given once daily simultaneously with ledipasvir-sofosbuvir, decreased ledipasvir exposure (AUC) by 4%. When omeprazole 20 mg once daily was given 2 hours prior to ledipasvir-sofosbuvir dose, ledipasvir exposure (AUC) decreased approximately 50%.(1) In an interaction study, omeprazole 20 mg given once daily simultaneously with sofosbuvir-velpatasvir decreased velpatasvir exposure (AUC) by 37%. When omeprazole 20 mg once daily was given 12 hours prior to sofosbuvir-velpatasvir dose, velpatasvir exposure (AUC) decreased 57%. When omeprazole 20 mg once daily was given 2 hours prior to sofosbuvir-velpatasvir dose, velpatasvir AUC decreased 48%. When omeprazole 20 mg once daily was given 4 hours after sofosbuvir-velpatasvir dose, velpatasvir AUC decreased 33%. When omeprazole 40 mg once daily was given 4 hours after sofosbuvir-velpatasvir dose, velpatasvir AUC decreased 56%.(2) In an interaction study, when omeprazole 20 mg once daily was given 2 hours prior to the sofosbuvir-velpatasvir-voxilaprevir dose, sofosbuvir AUC, velpatasvir AUC, and voxilaprevir AUC decreased 27%, 54%, and 20%, respectively. When omeprazole 20 mg once daily was given 4 hours after the sofosbuvir-velpatasvir-voxilaprevir dose, sofosbuvir AUC, velpatasvir AUC, and voxilaprevir AUC decreased 18%, 51%, and 5%, respectively %.(3) Proton pump inhibitors linked to this monograph are: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole.

Proton Pump Inhibitors/Methotrexate (Oncology-Injection )

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Proton pump inhibitors may inhibit the active secretion of methotrexate from the kidney via inhibition of the hydrogen-potassium ATPase(1) and may reduce uptake of methotrexate into breast cancer resistance protein via competitive inhibition.(2,3)

CLINICAL EFFECTS: The concurrent use of methotrexate and proton pump inhibitors may result in elevated levels of methotrexate and increased methotrexate-related adverse effects and toxicities, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: For patients receiving high dose methotrexate with leucovorin rescue, consider discontinuation of proton pump inhibitors for the duration of therapy. Patients receiving concurrent use of methotrexate and proton pump inhibitors should be monitored closely for elevated methotrexate levels and methotrexate toxicity. The US manufacturer of omeprazole states that secretory ability returns gradually over three to five days following discontinuation.(4) Therefore, it would seem prudent to discontinue proton pump inhibitors several days prior to methotrexate therapy.

DISCUSSION: In a clinical trial in 74 patients on high dose (1-5 G/m2) methotrexate therapy, data was examined to determine if proton pump inhibitor (omeprazole, pantoprazole, rabeprazole) use affects methotrexate elimination. Delayed elimination was found to be more frequent in those with co-administration of a proton pump inhibitor (31.7% vs. 13.8%), resulting in higher plasma methotrexate concentrations at 24, 48, and 74 hours. The effect was seen with lansoprazole, omeprazole, pantoprazole, and rabeprazole.(2) There are three case reports(1,5,6) of elevated methotrexate levels or delayed methotrexate elimination resulting from concurrent administration of high dose methotrexate and omeprazole, including one patient(6) that developed severe mucositis. In each case, omeprazole was discontinued and normal methotrexate kinetics were observed on subsequent cycles with no further adverse effects noted. In a case report of a 59 year-old male on low dose (15 mg weekly) methotrexate, administration of pantoprazole (20 mg daily) was found to increase the AUC of the metabolite 7-hydroxymethotrexate by 70%.(7) In a clinical trial, 28 adults with rheumatoid arthritis on low dose (7.5-15 mg weekly) methotrexate were assigned to receive lansoprazole (30 mg daily) and naproxen (500 mg twice daily) on Days 1-7 of therapy. The half life of the metabolite 7-hydroxymethotrexate was prolonged with concurrent administration, but no other statistically significant differences were found in regards to the plasma concentration profiles of methotrexate or 7-hydroxymethotrexate.(8)

Proton Pump Inhibitors/Paltusotine (>= 60 Mg)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The aqueous solubility of paltusotine is pH dependent. Higher gastric pH leads to lower solubility which may reduce paltusotine absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of paltusotine, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of paltusotine states that concomitant use of paltusotine with PPIs may require an increased dosage of paltusotine. Patients who are already on paltusotine 60 mg daily should avoid concomitant use with PPIs.(1)

DISCUSSION: In an interaction study, paltusotine area-under-the-curve (AUC) was decreased by 21% with 20 mg dose and 42% with 60 mg dose levels.(1)

Proton Pump Inhibitors/Pemetrexed

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Proton pump inhibitors may inhibit the active secretion of pemetrexed from the kidney via the organic anion transporter 3 (OAT3).(1,2,3)

CLINICAL EFFECTS: The concurrent use of pemetrexed and proton pump inhibitors may result in increased levels and toxicities of pemetrexed, including severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.

PREDISPOSING FACTORS: Risk factors for pemetrexed toxicity include high-dose oncology regimens, impaired renal function, and concurrent use of nephrotoxic medications.

PATIENT MANAGEMENT: For patients receiving pemetrexed, consider discontinuation of proton pump inhibitors for the duration of pemetrexed therapy. If concurrent use cannot be avoided, monitor closely for elevated pemetrexed levels and toxicity.

DISCUSSION: A prospective observational study of 156 patients receiving pemetrexed-based therapy found that severe hematological toxicity, namely neutropenia and anemia, occurred in 34/55 patients (61.8%) taking concurrent proton pump inhibitors (PPIs) and in 36/101 patients (35.6%) who did not consume PPIs. In Cox regression multivariable analysis, the hazard ratio for severe hematological toxicity with PPI use was 2.51 (95% CI = 1.47-4.26). Esomeprazole, pantoprazole, and lansoprazole were the most consumed PPIs in the study, but no correlation was investigated.(1) A retrospective review of 61 patients investigated medication-related causes of severe hematological toxicity in patients on pemetrexed/carboplatin chemotherapy. Twenty-three patients took PPIs: lansoprazole (n=16), esomeprazole (n=5), omeprazole (n=1), and rabeprazole (n=1). In a multiple logistic regression analysis, use of PPIs in patients receiving pemetrexed/carboplatin combination chemotherapy was associated severe hematotoxicity (odds ratio: 5.34, 95% CI: 1.06-26.94, P = 0.042).(2) In an in vitro analysis and retrospective study, lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan were shown to inhibit OAT3-mediated uptake of pemetrexed, with lansoprazole having the greatest inhibitory effect. In the multivariate analysis of 108 patients, concurrent use of lansoprazole (but not other PPIs) and pemetrexed/carboplatin was a significant risk factor for the development of hematological toxicity (odds ratio: 10.004, P = 0.005).(3) In a retrospective study of 74 patients who received pemetrexed, 24 patients (32%) were on concomitant PPIs. Pemetrexed toxicity was associated with cystatin clearance (p=0.0135), albumin level (p=0.0333), and proton pump inhibitors (p=0.035) on multivariate analysis. Most patients (n=14) took esomeprazole or omeprazole, with the remainder taking lansoprazole (n=5), pantoprazole (n=4) or an unspecified agent.(4)

Proton Pump Inhibitors/Selected Kinase Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The solubility of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib(8), and pexidartinib (9) is pH dependent. Changes in gastric pH from proton pump inhibitors may decrease the absorption of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9)

CLINICAL EFFECTS: Use of proton pump inhibitors may result in decreased levels and effectiveness of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of proton pump inhibitors (PPIs) in patients receiving treatment with bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9) Consider the use of short-acting antacids in these patients.(1-9) If antacids are used, separate the administration times by several hours(1-9) but at least 2 hours for bosutinib,(1) dasatinib,(3) nilotinib,(7) and pexidartinib(9), 6 hours for gefitinib,(5) and 3 hours for neratinib.(6) If PPIs are required with gefitinib, administer gefitinib 12 hours after the last dose or 12 hours before the next dose of the PPI. Administer gefitinib 6 hours before or after H2-antagonists or antacids.(5) If H2 antagonist therapy is used with bosutinib, separate administration by at least 2 hours.(1) If H2 antagonist therapy is required with dacomitinib, dacomitinib must be given once daily 10 hours after the H2 blocker and 6 hours before the next dose of the H2 blocker.(2) If H2 antagonist therapy is required with erlotinib, neratinib, nilotinib, or pexidartinib, the kinase inhibitor must be given 10 hours after the H2 blocker and at least 2 hours before the next dose of the H2 blocker.(4,6,7,9) If H2 antagonist therapy is required with gefitinib, gefitinib should be given at least 6 hours before or after the H2 antagonist.(5) The manufacturer of Phyrago states that it can be administered with gastric acid reducing agents. Administration times should be separated with antacids.

DISCUSSION: In a study, concurrent rabeprazole decreased the Cmax and AUC of dacomitinib by 51% and 39%, respectively.(2) In a study in 24 healthy subjects, administration of a single dose of dasatinib (50 mg) 10 hours after famotidine decreased dasatinib area-under-curve (AUC) and maximum concentration (Cmax) by 61% and 63%, respectively.(3) In a study in 14 healthy subjects, administration of a single dose of dasatinib (100 mg) 22 hours after omeprazole (40 mg at steady state) decreased dasatinib AUC and Cmax by 43% and 42%, respectively.(3) In a study in 24 healthy subjects, simultaneous administration of dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml) decreased dasatinib AUC and Cmax by 55% and 58%, respectively. In the same subjects, administration of the antacid 2 hours before dasatinib decreased dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(3) In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively.(4) In a study, administration of erlotinib two hours after a dose of ranitidine (300 mg), erlotinib AUC and Cmax decreased by 33% and 54%, respectively. Administration of erlotinib 10 hours after and two hours before ranitidine (150 mg twice daily), erlotinib AUC and Cmax decreased by 15% and 17%, respectively.(4) In a case report, a patient that was given erlotinib (150 mg daily,) with algeldrate/magnesium hydroxide (800/400 mg four times daily 4 hours before or 2 hours after erlotinib) did not see a significant reduction in serum trough concentrations of erlotinib. When the patient was switched to intravenous pantoprazole via continuous infusion (8 mg per hour), serum erlotinib levels decreased significantly below minimal trough concentrations for effective tyrosine kinase inhibition. When the patient was switched to oral pantoprazole (40 mg twice daily), serum trough levels of erlotinib returned to therapeutic levels.(9) In a study in healthy subjects, high dose ranitidine with sodium carbonate was administered to maintain gastric pH above 5.0 and gefitinib AUC decreased 47%.(5) In a study in 15 healthy subjects, lansoprazole (30 mg at steady state) decreased the Cmax and AUC of a single dose of neratinib (240 mg) by 71% and 65%, respectively.(6) In a study in 22 healthy subjects, pretreatment with esomeprazole (40 mg daily), decreased the Cmax and AUC of a single dose of nilotinib (400 mg) by 27% and 34%, respectively.(7,10) Increasing the dosage of nilotinib or separating the administration time of nilotinib and the proton pump inhibitor is not expected to eliminate the interaction.(7) There were no significant changes in nilotinib pharmacokinetics when famotidine was administered 10 hours before or 2 hours after nilotinib.(7) There were no significant changes in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered 2 hours before or after nilotinib.(7) In a study in 13 patients, esomeprazole (40 mg daily for 5 days) decreased the Cmax and AUC of pazopanib (400 mg daily) by 42% and 40%, respectively, when compared to the administration of pazopanib alone.(11) In an open-label, crossover study in 17 evaluable patients, omeprazole (40 mg daily) had no significant effects on the pharmacokinetics, pharmacodynamics, or safety of bortezomib (1.3 mg/m2).(12) Coadministration of esomeprazole decreased pexidartinib Cmax and AUC by 55% and 50%. (13) Phyrago is not sensitive to increased gastric pH due to its polymer formulation. No clinically significant dasatinib pharmacokinetic changes were seen with concurrent administration of Phyrago with omeprazole (proton pump inhibitor) or famotidine (H2 receptor antagonist).(14)

Proton Pump Inhibitors/Selpercatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The solubility of selpercatinib is pH dependent. Increase in gastric pH from proton pump inhibitors (PPIs) may decrease the solubility and absorption of selpercatinib.(1)

CLINICAL EFFECTS: Use of proton pump inhibitors may result in decreased levels and effectiveness of selpercatinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of proton pump inhibitors (PPIs), H2 antagonists, and locally acting antacids in patients receiving treatment with selpercatinib. If coadministration with PPIs cannot be avoided, take selpercatinib with food.(1) If the PPI is replaced with a H2 antagonist, take selpercatinib 2 hours before or 10 hours after the H2 antagonist.(1) If the PPI is replaced with an antacid, take selpercatinib 2 hours before or 2 hours after the antacid.(1)

DISCUSSION: In a study, omeprazole decreased the area-under-curve (AUC) and maximum concentration (Cmax) of selpercatinib (administered fasting) by 69% and 88%, respectively. When selpercatinib was administered with food, omeprazole did not significantly affect selpercatinib levels.(1)

Salicylates/Influenza Virus Vaccine Live

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Use of salicylates during influenza infection has been associated with Reye's Syndrome.(1,2)

CLINICAL EFFECTS: Use of the live influenza virus vaccine in children and adolescents (patients age 2-17 years) receiving salicylate therapy may increase the risk of Reye's Syndrome.(1,2) Symptoms of Reye's syndrome include drowsiness, confusion, seizures, coma. In severe cases, Reye's syndrome can result in death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The use of live influenza virus vaccine in children and adolescents (patients age 2-17 years) receiving salicylate therapy is contraindicated.(1,2) Use of salicylates should be avoided for 4 weeks after administration of live influenza vaccine.(1)

DISCUSSION: Because the use of salicylates during influenza infection has been associated with Reye's Syndrome, the use of live influenza virus vaccine in children and adolescents (patients age 2-17 years) receiving salicylate therapy is contraindicated.(1,2)

Salicylates/Varicella Virus Vaccine Live

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Use of salicylates during natural varicella infection has been associated with Reye's Syndrome.(1-4)

CLINICAL EFFECTS: Use of the live varicella virus vaccine in patients receiving salicylate therapy or use of salicylates within 6 weeks after vaccination with the live varicella virus vaccine may increase the risk of Reye's Syndrome.(1-4) Symptoms of Reye's syndrome include drowsiness, confusion, seizures, coma. In severe cases, Reye's syndrome can result in death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian, UK, and US manufacturers of live varicella virus vaccine indicated for the prevention of chicken pox state that vaccine recipients should avoid the use of salicylates for 6 weeks after vaccination.(1-4) There is no such restriction in the labeling for live varicella virus vaccine indicated for the prevention of shingles, which is only indicated for patients age 60 and older.(5)

DISCUSSION: Because the use of salicylates during natural varicella infection has been associated with Reye's Syndrome, the use of salicylates for 6 weeks following vaccination with live varicella virus vaccine should be avoided.(1-4)

Select Cyp2c19 Inhibitors/Citalopram (>20 Mg)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(7,8)

Selected Antiplatelets; Aspirin (> 100 Mg)/Rivaroxaban

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Additive effects on hemostasis.(1)

CLINICAL EFFECTS: Concurrent use of rivaroxaban with anticoagulants, antiplatelets, or thrombolytics may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Avoid concurrent use of rivaroxaban and higher doses of aspirin unless the benefit is expected to outweigh the increased risk of bleeding. In the ROCKET AF trial, concomitant use of low dose aspirin (almost exclusively at less than or equal to 100 mg daily) was identified as an independent risk factor for bleeding.(1) If the benefit of concurrent use of rivaroxaban with other antiplatelets is expected to outweigh the increased risk of bleeding, closely monitor patients for signs or symptoms of bleeding.(1) The UK manufacturer of rivaroxaban states that rivaroxaban 2.5 mg twice daily is indicated with aspirin 75 - 100 mg with or without clopidogrel 75 mg or standard dose ticlopidine for post-acute coronary syndrome and in patients with CAD and PAD, weighing the risk for ischemic events against the bleeding risks. Long-term dual antiplatelet therapy should be avoided. Clinical monitoring is recommended throughout treatment.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In two clinical trials in healthy subjects, concurrent clopidogrel (300 mg loading dose, then 75 mg daily) and rivaroxaban (15 mg single dose) increased bleeding time to 45 minutes in 45% and 30% of subjects. This was twice the maximum increase in bleeding time seen with either agent alone.(1) In the ROCKET AF trial, concomitant aspirin use (almost exclusively at < or = to 100 mg daily) was identified as an independent risk factor for bleeding.(1) In a study, concurrent enoxaparin (40 mg) and rivaroxaban (10 mg) resulted in additive effects on anti-factor Xa activity with no effects on the pharmacokinetics of rivaroxaban.(1) In a study, concurrent warfarin (15 mg) and rivaroxaban (5 mg) resulted in additive effects on factor Xa inhibition and PT with no effects on the pharmacokinetics of rivaroxaban.(1) In a single dose study, there were no pharmacokinetic or pharmacodynamic interactions between rivaroxaban and aspirin.(1) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of rivaroxaban and dipyridamole resulted in a ratio of rate ratios (95% CI) of 3.49 (1.08-6.64); and rivaroxaban and aspirin ratio of rate ratios 2.19 (1.21-2.95).(3) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(4)

Strong; Selected Moderate Cyp2c19 Inhibitors/Clobazam

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clobazam's active metabolite, N-desmethylclobazam, is metabolized by the CYP2C19 isoenzyme.(1) The FDA categorizes N-desmethylclobazam as a sensitive substrate for CYP2C19. Sensitive substrates are drugs whose plasma area-under-curve (AUC) have been shown to increase 5-fold or higher when co-administered with a strong inhibitor of the enzyme.(2)

CLINICAL EFFECTS: Concurrent use of a strong or selected moderate inhibitor of CYP2C19 may result in elevated levels of and toxicity from the active metabolite of clobazam, including profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dosage of clobazam may need to be adjusted when initiating or discontinuing a strong or selected moderate inhibitor of CYP2C19.(1) When initiating a strong or selected moderate inhibitor of CYP2C19 in a patient maintained on clobazam, monitor closely for increased effects from clobazam and adjust dose accordingly.(1) If possible, use an alternative treatment which does not inhibit CYP2C19. When initiating clobazam in a patient maintained on a strong or moderate inhibitor of CYP2C19, it would be prudent to follow the manufacturer's recommendations for dosage adjustments in patients who are CYP2C19 poor metabolizers. In these patients, consider a starting dose of 5 mg/day and reduce weekly dosage adjustments to half the normal increase. Based on clinical response, the dosage may be titrated to normal dosage levels based on weight group at Day 21.(1)

DISCUSSION: The active metabolite of clobazam, N-desmethylclobazam, is metabolized by CYP2C19. Levels of N-desmethylclobazam are 3-5 times higher in poor metabolizers of CYP2C19 and 2 times higher in intermediate metabolizers of CYP2C19. Thus, strong and moderate inhibitors of CYP2C19 are expected to result in a 3 to 5-fold increase in levels of N-desmethylclobazam as well.(1) Strong and selected moderate inhibitors of CYP2C19 include: camizestrant, esomeprazole, fluconazole, fluvoxamine, omeprazole, stiripentol, and ticlopidine.(2) Esomeprazole and omeprazole are irreversible inhibitors of CYP2C19. Although intermittent use may lead to moderate CYP2C19 inhibition, routine use may lead to inactivation of all available CYP2C19, converting patient to the CYP2C19 poor metabolizer phenotype.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Agents Affecting Gastric Ph/Itraconazole; Ketoconazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Antacids, buffers in didanosine products, H2 antagonists, and proton-pump inhibitors increase the stomach pH. Quinapril tablets may contain a high percentage of magnesium. Since some orally administered azole antifungal agents require an acidic medium for optimal absorption, agents may decrease the absorption of azole antifungal agents.

CLINICAL EFFECTS: Simultaneous administration of an antacid, buffered didanosine, a H2 antagonist, or a proton-pump inhibitor may result in decreased therapeutic effects of the azole antifungal.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If the concurrent administration of these two agents cannot be avoided, consider administering two capsules of glutamic acid hydrochloride 15 minutes before administering the antifungal and separate the administration times of the antifungal and the agent affecting gastric pH by at least two hours.

DISCUSSION: Itraconazole, ketoconazole, and posaconazole require an acidic medium for predictable dissolution and absorption decreases as pH increases and proton pump inhibitors are expected to decrease their absorption.(1-4) In a study in 11 healthy subjects, omeprazole (40 mg daily) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of itraconazole (200 mg single dose) by 66% and 64%, respectively.(5) In a study in 15 healthy subjects, omeprazole (40 mg daily) had no effect on the pharmacokinetics of itraconazole solution.(6) In a study in 9 healthy subjects, omeprazole (60 mg) decreased the AUC of ketoconazole (200 mg single dose) by 83.4% compared to control (ketoconazole alone). Administration of Coca-Cola (240 ml) with ketoconazole and omeprazole raised ketoconazole AUC to 65% of control values.(7) Omeprazole has been shown to have no significant effect on the absorption of fluconazole(8) or voriconazole.(9) Case reports and in-vivo studies have documented significant decreases in ketoconazole levels during concurrent therapy with H-2 antagonists, including cimetidine and ranitidine. Concurrent administration of itraconazole and famotidine resulted in a significant decrease in itraconazole levels, but no significant changes in famotidine levels. An interaction should be expected to occur between both ketoconazole or itraconazole and the other H-2 antagonists.(10-14) In randomized, open-labeled, cross-over study in 12 healthy subjects, simultaneous administration of an antacid decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of itraconazole (200 mg) by 66% and 70%, respectively. Time to Cmax (Tmax) increased by 70%.(15) This interaction has also been reported in a case report.(16) In a study in 3 subjects, simultaneous administration of a combination aluminum hydroxide/magnesium hydroxide (30 ml) decreased the AUC of a single dose of ketoconazole (200 mg) by 41%.(172) In a case report, a patient receiving concurrent ketoconazole with aluminum hydroxide, cimetidine, and sodium bicarbonate did not respond to therapy until cimetidine was discontinued and the administration time of aluminum hydroxide and cimetidine was changed to 2 hours after ketoconazole. In a follow-up study in 2 subjects, concurrent cimetidine and sodium hydroxide lowered ketoconazole levels.(18) In a study in 14 subjects, simultaneous administration of aluminum hydroxide/magnesium hydroxide (20 ml, 1800 mg/1200 mg) had no significant effects on fluconazole pharmacokinetics.(3) In a randomized, open-label, cross-over study in 6 subjects, simultaneous administration of itraconazole with buffered didanosine tablets resulted in undetectable levels of itraconazole.(19) In a randomized cross-over study in 12 HIV-positive subjects, administration of buffered didanosine tablets 2 hours after ketoconazole had no effects on ketoconazole levels.(20) In a randomized, cross-over, open-label study in 24 healthy subjects, simultaneous administration of enteric-coated didanosine had no effect on ketoconazole pharmacokinetics.(21) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Anticoagulant;Antiplatelet;Thrombolytic/Icosapent Ethyl

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: In vitro data suggests that fish oils can competitively inhibit cyclooxygenase which decreases synthesis of thromboxane A1 leading to a decrease in platelet aggregation.(1)

CLINICAL EFFECTS: Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents increase bleeding risks.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Specific studies with icosapent ethyl and affects on bleeding risk have not been conducted. Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents may increase bleeding risks by impairing platelet function and prolonging bleeding time.(1) Several case reports have shown increased bleeding time and an increased risk of adverse effects from concurrent therapy.(2,3,4) A randomized placebo controlled study of 40 people taking omega-3 fatty acids and oral anticoagulants showed a significant prolongation in bleeding time.(5)

Anticoagulants; Antiplatelets/Fruquintinib; Surufatinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bleeding has been reported with the use of fruquintinib and surufatinib.(1,2)

CLINICAL EFFECTS: Concurrent use of fruquintinib or surufatinib with either anticoagulants or antiplatelets may increase the risk of hemorrhage.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with fruquintinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in International Normalized Ratio (INR). If a serious bleeding event occurs, the manufacturer recommends permanent discontinuation of fruquintinib.(1) Patients receiving concurrent therapy with surufatinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in INR.If a serious bleeding event occurs, the manufacturer recommends permanent discontinuation of surufatinib.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Bleeding has been reported with fruquintinib in three randomized, double-blinded, placebo-controlled clinical trials. The incidence of grade 1 and grade 2 bleeding events was 28.2%, including gastrointestinal bleeding (10.9%), hematuria (10.6%), and epistaxis (7.5%). The incidence of grade 3 or higher bleeding events was 2.1% and included gastrointestinal bleeding (1.6%) and hemoptysis (0.5%).(1) Bleeding has been reported with surufatinib in clinical trials. Grade 1 and 2 bleeding events included gastrointestinal bleeding, blood in the urine, and gum bleeding. The incidence of grade 3 or greater bleeding events was 4.5%, including gastrointestinal hemorrhage (1.9%), and cerebral hemorrhage (1.1%). Fatalities due to bleeding were reported in 0.3% of patients. The incidence of permanent discontinuation due to bleeding was 2.6% and the incidence of suspension of surufatinib due to bleeding was 3.8%.(2)

Anticoagulants; Antiplatelets/Mifepristone (Cushing)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Mifepristone is an antagonist at the progesterone receptor which can result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding. Concurrent use with anticoagulants or antiplatelets may further increase risk.

CLINICAL EFFECTS: The concurrent use of mifepristone with anticoagulants or antiplatelets may result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant or antiplatelet therapy.(1) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Women experiencing vaginal bleeding during concurrent use should be referred to a gynecologist for further evaluation.

DISCUSSION: The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant or antiplatelet therapy.(1)

Anticoagulants; Antiplatelets/Obinutuzumab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Severe and life-threatening thrombocytopenia has been reported during obinutuzumab therapy.(1) Anticoagulants and antiplatelets may have an additive risk of bleeding.

CLINICAL EFFECTS: Concurrent use of obinutuzumab with anticoagulants or antiplatelet agents may result in additive or synergistic effects, including fatal and non-fatal hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor all patients frequently for thrombocytopenia and signs of bleeding. Consider withholding concomitant anticoagulants and antiplatelets, especially during the first cycle of obinutuzumab.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Obinutuzumab with chemotherapy has been reported to cause severe and life-threatening thrombocytopenia. Fatal hemorrhagic events have occurred in patients with NHL and CLL during obinutuzumab therapy, including during Cycle 1.(1)

Anticoagulants; Antiplatelets/Plasminogen

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bleeding has been reported with the use of plasminogen.(1)

CLINICAL EFFECTS: Concurrent use of plasminogen with either anticoagulants or antiplatelets may increase the risk of active bleeding during plasminogen therapy, including bleeding from mucosal disease-related lesions that may manifest as gastrointestinal (GI) bleeding, hemoptysis, epistaxis, vaginal bleeding, or hematuria.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with plasminogen and anticoagulants and/or antiplatelets should be closely monitored during plasminogen therapy for active bleeding from mucosal disease-related lesions, including GI bleeding, hemoptysis, epistaxis, vaginal bleeding, or hematuria.(1) Prior to initiation of treatment with plasminogen, confirm healing of lesions or wounds suspected as a source of a recent bleeding event. Monitor patients during and for 4 hours after infusion when administering plasminogen with concurrent anticoagulants, antiplatelet drugs, or other agents which may interfere with normal coagulation.(1) If patient experiences uncontrolled bleeding (defined as any gastrointestinal bleeding or bleeding from any other site that persists longer than 30 minutes), seek emergency care and discontinue plasminogen immediately.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Plasminogen has not been studied in patients at an increased risk of bleeding. Bleeding has been reported with plasminogen in a two single-arm, open-label clinical trials as well as in compassionate use programs. The incidence of hemorrhage in patients with Plasminogen Deficiency Type 1 was 16% (3/19 patients).(1) One of the bleeding events occurred two days after receiving the second dose of plasminogen in a patient with a recent history of GI bleeding due to gastric ulcers. The patient received plasminogen through a compassionate use program and the dose was 6.6 mg/kg body weight every 2 days. Endoscopy showed multiple ulcers with one actively bleeding ulcer near the pylorus.(1)

Anticoagulants; Antiplatelets/Tisotumab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bleeding, including hemorrhage, has been reported with the use of tisotumab.(1)

CLINICAL EFFECTS: Concurrent use of tisotumab with either anticoagulants, antiplatelets, or NSAIDs may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with tisotumab and anticoagulants, antiplatelets, and/or NSAIDs should be closely monitored for signs and symptoms of bleeding and changes in platelet count or International Normalized Ratio (INR). For patients experiencing pulmonary or central nervous system (CNS) hemorrhage, permanently discontinue tisotumab. For grade 2 or greater hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage. After resolution, either resume treatment or permanently discontinue tisotumab.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Hemorrhage occurred in 62% of patients with cervical cancer treated with tisotumab across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients.(1)

Anticoagulants; Antiplatelets; Thrombolytics/Drotrecogin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Drotrecogin, anticoagulants, antiplatelets, and thrombolytics all affect hemostasis.(1)

CLINICAL EFFECTS: Concurrent use of drotrecogin with anticoagulants, antiplatelets, or thrombolytics, including heparin and aspirin, may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Drotrecogin should be used with caution with other agents that affect hemostasis, including concurrent heparin for thrombotic or embolic events; recent administration (within 3 days) of thrombolytics; recent administration of oral anticoagulants (within 7 days) or glycoprotein IIb/IIIa inhibitors; or recent administration (within 7 days) of aspirin (greater than 650 mg daily) or other platelet inhibitors.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Because of the increased risk of bleeding, drotrecogin should be used with caution with other agents that affect hemostasis, including concurrent heparin for thrombotic or embolic events; recent administration (within 3 days) of thrombolytics; recent administration of oral anticoagulants (within 7 days) or glycoprotein IIb/IIIa inhibitors; or recent administration (within 7 days) of aspirin (greater than 650 mg daily) or other platelet inhibitors.(1)

Antiplatelets/Donanemab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Microhemorrhage has been reported with the use of donanemab. Radiographic changes on brain MRI have been noted as amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) which included microhemorrhage. In addition, intracerebral hemorrhages (ICH) greater than 1 cm in diameter have occurred in patients treated with donanemab.(1)

CLINICAL EFFECTS: Concurrent use of donanemab with antiplatelets may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Donanemab should be used with extreme caution in patients treated with antiplatelets. Evaluate the risks and benefits of concurrent use of donanemab with antiplatelets.(1) The manufacturer of donanemab recommends testing for AP0E4 status prior to initiation of treatment.(1) Use of antiplatelet agents in patients who are homozygous for the APOE4 gene, may have an increased risk of ARIA with donanemab therapy.(1-3) Patients receiving concurrent therapy with donanemab and antiplatelets should be closely monitored for signs and symptoms of bleeding and changes in platelet count.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of microhemorrhage, including headache, nausea/vomiting, confusion, dizziness, visual disturbance, gait difficulties, and loss of coordination. General signs of blood loss include decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as confusion, headache, dizziness, nausea, visual changes, unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a double-blind, placebo-controlled clinical study of 1736 participants randomized to receive donanemab (n = 860) or placebo (n = 876), donanemab was observed to increase amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), including microhemorrhage and intracerebral hemorrhage (ICH). Radiographic changes were classified as mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10 or more new incidences). The maximum severity of ARIA-H microhemorrhage was observed as mild in 17% (143/853), moderate in 4% (34/853), and severe in 5% (40/853) of patients taking donanemab.(1) Baseline use of antithrombotic medications (aspirin, other antiplatelets, or anticoagulants) was allowed. The majority of exposures to antithrombotic medications were to aspirin. The incidence of ARIA-H was 30% (106/349) in patients taking donanemab with a concomitant antithrombotic medication within 30 days compared to 29% (148/504) who did not receive an antithrombotic within 30 days of an ARIA-H event.(1) The incidence of ICH greater than 1 cm in diameter was 0.6% (2/349 patients) in patients taking donanemab with a concomitant antithrombotic medication compared to 0.4% (2/504) in those who did not receive an antithrombotic. One fatal ICH occurred in a patient taking donanemab in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent.(1)

Antiplatelets/Lecanemab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Microhemorrhage has been reported with the use of lecanemab. Radiographic changes on brain MRI have been noted as amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) which included microhemorrhage. In addition, intracerebral hemorrhages (ICH) greater than 1 cm in diameter have occurred in patients treated with lecanemab.(1)

CLINICAL EFFECTS: Concurrent use of lecanemab with antiplatelets may increase the risk of hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Lecanemab should be used with extreme caution in patients treated with antiplatelets. Evaluate the risks and benefits of concurrent use of lecanemab with antiplatelets.(1) Appropriate use recommendations for lecanemab state antiplatelets may be used at standard doses if patients meet other criteria for lecanemab therapy. Use of antiplatelet agents in patients who are homozygous for the APOE4 gene may have an increased risk of ARIA with lecanemab therapy.(2) Patients receiving concurrent therapy with lecanemab and antiplatelets should be closely monitored for signs and symptoms of bleeding and changes in platelet count or International Normalized Ratio (INR).(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of microhemorrhage, including headache, nausea/vomiting, confusion, dizziness, visual disturbance, gait difficulties, and loss of coordination. General signs of blood loss include decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as confusion, headache, dizziness, nausea, visual changes, unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In clinical studies, lecanemab was observed to increase ARIA-H, including microhemorrhage and intracerebral hemorrhage. Radiographic changes were classified as mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10 or more new incidences. Patients were excluded from clinical trials if taking concurrent anticoagulants or anti-platelets.(1) In Studies 1 and 2, the maximum severity of ARIA-H microhemorrhage was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients. Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.7% (6/898) of patients in Study 2 after treatment with lecanemab compared to 0.1% (1/897) on placebo. Fatal events of intracerebral hemorrhage in patients taking lecanemab have been observed.(1) In Study 2, baseline use of antithrombotic medications (aspirin, other antiplatelets, or anticoagulants) were allowed if patient was on a stable dose. Aspirin was the most common antithrombotic agent. The incidence of ICH was 0.9% (3/328 patients) in patients taking lecanemab with a concomitant antithrombotic medication at the time of the event compared to 0.6% (3/545 patients) in those who did not receive an antithrombotic. Patients taking lecanemab with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79 patients) compared to none in patients who received placebo.

Aspirin (< Or = 100 Mg)/Apixaban

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Additive effects on hemostasis.(1-4)

CLINICAL EFFECTS: Concurrent use of apixaban with aspirin may increase the risk of bleeding.(1-4)

PREDISPOSING FACTORS: Factors associated with an increase risk for bleeding may include renal impairment, concomitant use of P-glycoprotein inhibitors, patient age greater than 74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight less than 50 kg.(5-7) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Concurrent apixaban and aspirin (325 mg daily) resulted in no pharmacokinetic or pharmacodynamic interactions.(1) In a clinical trial examining the use of apixaban in atrial fibrillation, concurrent use of aspirin increased risk of major bleeding with apixaban from 1.8% per year to 3.4% per year and increased the bleeding risk with warfarin from 2.7% per year to 4.6% per year. Concomitant dual antiplatelet therapy was used in 2.1% of patients.(3,4) In a clinical trial examining the use of apixaban in high-risk post acute coronary syndrome patients with multiple cardiac and non-cardiac comorbidities, who received ASA or the combination of ASA and clopidogrel, the risk of major bleeding (defined by ISTH -International Society on Thrombosis and Haemostasis criteria) was increased for apixaban (5.13% per year) compared to placebo (2.04% per year).(3,4) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(8)

Aspirin (< Or = 100 Mg)/Dabigatran

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Additive effects on hemostasis.(1-3)

CLINICAL EFFECTS: Concurrent use of dabigatran with aspirin may increase the risk of bleeding.(1-3)

PREDISPOSING FACTORS: Factors associated with an increase risk for bleeding may include renal impairment, concomitant use of P-glycoprotein inhibitors, patient age greater than 74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight less than 50 kg.(1-3) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulants/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: A Phase II study in patients with atrial fibrillation examined the effects of dabigatran and concurrent aspirin on the risk of major bleeds. Concurrent use of aspirin and dabigatran etexilate (150 mg twice daily) increased the risk for any bleeding from 12 % to 18 % and 24 % with 81 mg and 325 mg ASA, respectively, when compared to dabigatran alone.(3) In the RE-DUAL PCI trial, patients were randomly assigned to one of three treatments: (A) dual therapy with dabigatran 110 mg twice daily plus either clopidogrel or ticagrelor, (B) dual therapy with dabigatran 150 mg twice daily plus either clopidogrel or ticagrelor, or (C) triple therapy with warfarin (goal INR 2-3) plus aspirin (less than or equal to 100 mg daily) plus either clopidogrel or ticagrelor. The incidence of the first major or clinically relevant non-major (CRNM) bleeding event was 15.4% in group A compared with 26.9% in group C (hazard ratio, 0.52; 95% CI 0.42 to 0.63; p<0.001 for noninferiority; p<0.001 for superiority) and 20.2% in group B compared to 25.7% in corresponding group C (hazard ratio, 0.72; 95% CI 0.58 to 0.88; p<0.001 for noninferiority). Major bleeding as defined by Thrombolysis in Myocardial Infarction (TIMI) criteria, the rate was lower in both dual-therapy groups than in the triple-therapy group: 1.4% in group A compared to 3.8% in group C (hazard ratio, 0.37; 95% CI 0.2 to 0.68; p=0.002) and 2.1% in group B compared to 3.9% in corresponding group C (hazard ratio, 0.51; 95% CI 0.28 to 0.93; p=0.03). Incidence of composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization was 13.7% in groups A and B compared to 13.4% in group C (hazard ratio, 1.04; 95% CI 0.84 to 1.29; p=0.005 for noninferiority).(4) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. Compared with DOACs alone, the use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and CRNM bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(5)

Aspirin (< Or = 100 Mg)/Rivaroxaban

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Additive effects on hemostasis.(1)

CLINICAL EFFECTS: Concurrent use of rivaroxaban with antiplatelets may increase the risk of bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (NSAIDs).

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or blood pressure and promptly evaluate patients with any symptoms. Discontinue rivaroxaban in patients with active pathological bleeding.(2) The US manufacturer states concurrent use of rivaroxaban 2.5 mg and aspirin 81 mg is an approved indication for the reduction of cardiovascular events in patients with coronary artery disease (CAD) or peripheral artery disease (PAD). Discontinue rivaroxaban in patients with active pathological bleeding. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In the ROCKET AF trial, concomitant aspirin use (almost exclusively at less than or equal to to 100 mg daily) was identified as an independent risk factor for bleeding.(1-2) In a single dose study, there were no pharmacokinetic or pharmacodynamic interactions between rivaroxaban and aspirin.(1) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of rivaroxaban and aspirin resulted in a ratio of rate ratios (95% CI) of 2.19 (1.21-2.95).(3) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(4) In the VOYAGER PAD trial, 6564 patiens were enrolled with peripheral artery disease (PAD). Rivaroxaban 2.5 mg twice daily in combination with aspirin 81 mg was found to reduce the total number of arterial and venous events by 23% compared to aspirin 81 mg alone. The combination increased the risk of bleeding. If 10,000 patients were treated, 181 cardiovascular events would be prevented at a cost of 29 bleeding events, a 6:1 benefit to risk ratio.(5) The COMPASS trial enrolled 27,395 patients with PAD or coronary artery disease (CAD) to determine whether combined rivaroxaban and aspirin reduced the risk of cardiovascular events more than aspirin alone. The combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg daily reduced mortality by 18% compared to aspirin alone.(6) A secondary analysis of incidence and predictors of major gastrointestinal (GI) bleeding in patients enrolled in the COMPASS trial demonstrated that compared to the use of aspirin (100 mg daily) alone, use of rivaroxaban (5 mg twice daily) significantly increased the odds of overall GI bleeding (OR 1.44; 95% CI 1.05-1.99), and the use of the combination of rivaroxaban (2.5 mg twice daily) and aspirin (100 mg daily) further increased the odds (OR 2.17; 95% CI 1.61-2.93).(7)

Aspirin (< Or = 100Mg)/Slt Anticoagulants (Vit K Antagonist)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Multiple processes are involved: 1)Aspirin is an irreversible platelet inhibitor. It impairs platelet function, resulting in prolonged bleeding time. 2) Aspirin may cause gastrointestinal (GI) bleeding due to irritation.

CLINICAL EFFECTS: The concurrent use of anticoagulants and aspirin leads to blockade of two distinct coagulation pathways and may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Weigh the patient specific benefits versus risk for concomitant use. If concurrent therapy of low dose aspirin and an anticoagulant is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. The Australian manufacturer of fluindione states use is not recommended with antiplatelet doses (from 50 mg to 375 mg per day) with a history of duodenal ulcer. When applicable, perform agent-specific laboratory test (e.g. INR) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; severe headache, acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: This interaction has been reported between aspirin and warfarin and between aspirin and dicumarol. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated, altered, or discontinued. A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and aspirin resulted in a ratio of rate ratios (95% CI) of 2.13 (1.72-2.64). A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 38 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antiplatelets (OR=1.74; 95% CI 1.56-1.94). Increased bleeding risk was also seen in subgroup analyses with aspirin (OR=1.50; 95% CI 1.29-1.74), clopidogrel (OR=3.55; 95% CI 2.78-4.54), and aspirin plus clopidogrel or ticlopidine (OR=2.07, 95% CI 1.33-3.21).(16)

Aspirin (< Or = 325 Mg)/Betrixaban

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Additive effects on hemostasis.(1)

CLINICAL EFFECTS: Concurrent use of betrixaban with aspirin may increase the risk of bleeding.(1-2)

PREDISPOSING FACTORS: Factors associated with an increase risk for bleeding may include renal impairment, concomitant use of P-glycoprotein inhibitors, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk.(1)

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In the APEX trial, if aspirin was required for cardiovascular disease, doses were limited to less than 165mg daily, with the exception of patients who were receiving aspirin for ischemic stroke or TIA indication, who could take 325mg daily. Concomitant use of aspirin and betrixaban resulted in a slightly increased incidence of major/clinically relevant non-major (CRNM) bleeding compared to those who did not use aspirin (3.7% vs. 2.89%). Concomitant use of aspirin with betrixaban resulted in an increased incidence of major bleeding twice as much as those who did not use aspirin with betrixaban (0.93% vs. 0.46%).(2) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and CRNM bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(3)

Aspirin (<= 100 Mg)/Edoxaban

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Edoxaban and aspirin have additive effects on hemostasis.(1) In addition, aspirin doses greater than or equal to 325 mg daily increase edoxaban exposure.(1)

CLINICAL EFFECTS: Concurrent use of edoxaban with aspirin may increase the risk of bleeding compared to either agent alone.(1)

PREDISPOSING FACTORS: Bleeding risk may be increased in patients with renal impairment and in patients greater than 75 years of age.(1) Use of multiple agents which affect hemostasis increases the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients requiring concurrent therapy with edoxaban and aspirin should be closely monitored for signs of bleeding. Edoxaban and aspirin at dosages of 100 mg or less may be coadministered.(2,3) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Discontinue edoxaban in patients with active bleeding.

DISCUSSION: Concomitant use of edoxaban and antiplatelet agents may increase the risk of bleeding. In edoxaban clinical trials concomitant use of low dose aspirin (less than or equal to 100 mg daily), thienopyridines, and NSAIDs was permitted and resulted in increased rates of clinically relevant bleeding. The rates of major bleeding on edoxaban and warfarin were generally consistent among subgroups. Bleeding rates appeared higher in both treatment arms (edoxaban and warfarin) in patients taking aspirin. Co-administration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.(1) About 30% of the population in ENGAGE-AF received concomitant therapy with aspirin because of co-morbid conditions. While aspirin is known to increase risk for bleeds and the annualized event rate for major bleeds was higher than that in patients not receiving aspirin (3.87% vs. 2.13%), the risk for bleeds in patients receiving edoxaban 60 mg on a background of aspirin was lower than that for warfarin on a background of aspirin (HR 0.78 (95%CI 0.65,0.94). Based on these data no dose adjustments/contraindications are required.(4) Edoxaban and aspirin at dosages of 100 mg or less may be coadministered.(2,3) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(5)

Aspirin (<= 325 Mg)/Dichlorphenamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbonic anhydrase inhibitors (eg, acetazolamide) may reduce blood pH, causing a shift of salicylates from plasma into tissues (eg, central nervous system).(1) Alternatively, toxicity may be due to salicylate-induced displacement of the carbonic anhydrase inhibitor from its protein binding sites and inhibition of renal tubular secretion.

CLINICAL EFFECTS: An increase in the pharmacologic effects of salicylates with possible toxicity may occur. Anorexia, tachypnea, lethargy, and coma have been reported.(1)

PREDISPOSING FACTORS: High doses of salicylates, low body weight.

PATIENT MANAGEMENT: The concurrent use of high-dose aspirin or other salicylates with dichlorphenamide is contraindicated. If it is necessary to administer a low-dose salicylate concurrently, use the lowest dose possible or replace it with a non-salicylate anti-inflammatory agent. Monitor salicylate levels and serum bicarbonate concentrations, and monitor the patient for symptoms of toxicity. Adjust the dose as needed.(1)

DISCUSSION: An 8-year-old boy with unimpaired renal and hepatic function was found to have developed metabolic acidosis after treatment for glaucoma and joint pain with a combination of aloxiprin 3.6 gram daily and dichlorphenamide 25 mg three times daily. His symptoms resolved after discontinuation of both aloxiprin and dichlorphenamide and did not recur on subsequent therapy with naproxen and dichlorphenamide.(2) A 75-year old woman taking dichlorphenamide 100 mg to 150 mg daily for therapy of glaucoma and high doses of aspirin (975 mg 4 to 5 times daily) for arthritis developed severe acid-base imbalance and salicylate intoxication. The patient did not exhibit ill effects when taking high aspirin doses without dichlorphenamide.(3)

Aspirin (<=330 Mg)/Methotrexate (Oncology-Injection)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Salicylates may inhibit the renal tubular excretion of methotrexate.

CLINICAL EFFECTS: The concurrent use of methotrexate and salicylates may result in an increase in the therapeutic and toxic effects of methotrexate, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Anti-inflammatory doses of aspirin/salicylates - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: US manufacturer prescribing information for methotrexate states nonsteroidal anti-inflammatory drugs including aspirin should not be administered prior to or concomitantly with high doses of methotrexate. If concurrent therapy is warranted, methotrexate plasma levels should be monitored and patients should be observed for methotrexate toxicity. The dosage of methotrexate may need to be adjusted. Use caution when administering higher doses of salicylates with lower doses of methotrexate. Salicylate doses > or = 2 grams per day have been associated with hepatic impairment or impaired renal elimination of methotrexate. It would be prudent to avoid high-dose aspirin, especially near the time of methotrexate dosage in patients receiving intermittent methotrexate therapy, and in patients with renal impairment.

DISCUSSION: Several studies and case reports have reported increased and prolonged methotrexate levels in patients receiving concurrent aspirin. One study noted an effect with average weekly doses of methotrexate of 16.6 mg, but not weekly doses of 7.5 mg. Decreased renal function has also been reported with the combination. Single ingredient aspirin or buffered aspirin products with strengths < or = to 325 mg or formulations which are associated with once daily use for cardiovascular protection are included in this interaction. Other aspirin and salicylate products are linked to higher severity level interactions.

Aspirin (> 100 Mg); Salicylates/Acetazolamide; Methazolamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Acetazolamide and methazolamide may reduce blood pH, causing a shift of salicylates from plasma into tissues (eg, central nervous system). Alternatively, toxicity may be due to salicylate-induced displacement of the carbonic anhydrase inhibitor from its protein binding sites and inhibition of renal tubular secretion.

CLINICAL EFFECTS: An increase in the pharmacologic effects of salicylates with possible toxicity may occur.

PREDISPOSING FACTORS: High doses of salicylates, low body weight.

PATIENT MANAGEMENT: Avoid the combination if possible. If it is necessary to administer these drugs concurrently, monitor salicylate levels and monitor the patient for symptoms of toxicity. Adjust the dose as needed.

DISCUSSION: Two young patients with unimpaired renal and hepatic function were found to have developed metabolic acidosis after treatment for glaucoma and joint pain with a combination of salicylates and carbonic anhydrase inhibitors in normal doses.(1) A 67-year old woman and a 75-year old woman taking carbonic anhydrase inhibitors for therapy of glaucoma and high doses of aspirin for arthritis developed severe acid-base imbalance and salicylate intoxication.(2) Neither patient exhibited ill effects when taking high aspirin doses without a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitor-induced acidemia increases the risk of developing salicylate intoxication in patients receiving high aspirin doses. Two elderly patients, who were chronically receiving aspirin developed lethargy, incontinence, and confusion after dosing with acetazolamide.(3) These effects could have been due to either drug (see mechanism).

Aspirin (> 100 Mg); Salicylates/Antidiabetics, Oral

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Complex. Salicylates appear to have intrinsic glucose lowering properties via several proposed mechanisms. Also, salicylates may cause protein binding displacement of antidiabetics. Decreased renal clearance may also occur.

CLINICAL EFFECTS: Potentiation of hypoglycemic effects may be observed.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Hypoglycemic signs and blood glucose levels should be monitored. Adjust the antidiabetic dose as needed. Particular caution should be taken when salicylates are started or stopped in patients previously stabilized on antidiabetics.

DISCUSSION: Additional documentation is necessary to confirm this potential interaction.

Aspirin (> 81Mg And <= 325 Mg)/Pemetrexed

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Higher doses of aspirin may decrease the clearance of pemetrexed.(1) This decreased clearance may be the result of chronic renal toxicity or competition with pemetrexed for renal tubular secretion.(2)

CLINICAL EFFECTS: Concurrent use of pemetrexed and higher aspirin doses may result in elevated levels of and toxicity from pemetrexed, including myelosuppression, neutropenia, renal toxicity, and gastrointestinal toxicity.(1)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with mild to moderate renal insufficiency (creatine clearance (CrCl) of 45 ml/min to 79 ml/min).(1)

PATIENT MANAGEMENT: Aspirin in low to moderate doses (325 mg every 6 hours) does not affect the pharmacokinetics of pemetrexed.(1) If higher dose aspirin (or an NSAID) is required, patients should be monitored for pemetrexed toxicity, especially myelosuppression, renal toxicity, and gastrointestinal toxicity.(1) The manufacturer of pemetrexed recommends in patients with mild to moderate renal insufficiency (CrCl from 45 ml/min to 79 ml/min), NSAIDs with short half-lives should be avoided for 2 days before, the day of, and 2 days after pemetrexed administration. (1) NSAIDs and salicylates with long half-lives should be avoided for at least 5 days before, the day of, and 2 days following pemetrexed administration in all patients.(1,2)

DISCUSSION: In patients with normal renal function, ibuprofen (400 mg 4 times daily) decreased the clearance of pemetrexed by 20% and increased its area-under-curve (AUC) by 20%.(1) In a Phase I clinical trial, two patients receiving high dose pemetrexed therapy experienced severe toxicity, both were receiving a NSAID. Following these reports, all patients were required to stop aspirin or other NSAIDs 2 days before and not resume these agents until 2 days after pemetrexed.(2) In two randomized, controlled cross-over trials, 27 cancer patients with a creatinine clearance (CrCl) less than or equal to 60 ml/min received pemetrexed (500 mg/m2) infusion on Day 1 of a 21-day cycle and either aspirin 325 mg or ibuprofen 400 mg orally every 6 hours starting 2 days before pemetrexed administration. Coadministration of aspirin did not affect pemetrexed pharmacokinetics. Ibuprofen decreased the clearance of pemetrexed by 16%, increased its maximum concentration (Cmax) by 15%, and increased the AUC by 20%.(3) Aspirin products linked to this monograph are single ingredient aspirin or buffered aspirin products with strengths greater than 81 mg and less than or equal to 325 mg strength. Combination aspirin products (e.g. aspirin combined with a statin) where aspirin greater than 81 mg or less than or equal to 325 mg is used for cardiovascular protection are excluded from this monograph.

Aspirin (>100 Mg); Indomethacin/Tiludronate Disodium

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Simultaneous administration of aspirin may decrease levels and effectiveness of tiludronate. Simultaneous administration of indomethacin may increase levels of and side effects from tiludronate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of tiludronate disodium states that aspirin or indomethacin should not be administered within 2 hours of tiludronate disodium.(1)

DISCUSSION: Aspirin may decrease tiludronate disodium bioavailability by 50% when taken 2 hours after tiludronate disodium.(1) Indomethacin may increase the bioavailability of tiludronate disodium by 2-fold to 4-fold. Tiludronate disodium bioavailability is not affected by diclofenac.(1)

Aspirin (>100 Mg); Salicylates/Uricosurics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not clearly established. Protein binding displacement is a possibility.

CLINICAL EFFECTS: May observe hyperuricemia and gout resulting from reduced uricosuric response.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid chronic, moderate to high doses of salicylates.

DISCUSSION: This interaction is well documented. Occasional small doses of salicylates do not appear to inhibit the action of uricosurics.

Aspirin/Ticlopidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ticlopidine inhibits adenosine diphosphate mediated platelet aggregation and aspirin inhibits arachidonic acid mediated platelet aggregation. In addition, ticlopidine potentiates the effect of aspirin-induced inhibition of collagen mediated platelet aggregation.

CLINICAL EFFECTS: Concurrent therapy may result in increased inhibition of platelet aggregation resulting in increased bleeding times and possible hemorrhage.

PREDISPOSING FACTORS: This interaction may be more significant in patients with a predisposition to bleeding, such as those with ulcers.(1) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Concurrent therapy is indicated to reduce the incidence of subacute stent thrombosis in patients undergoing successful coronary stent implantation; however, safety of concurrent use beyond 30 days has not been established. Long-term concurrent therapy is not recommended.(1) When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Studies have shown that concurrent ticlopidine and aspirin therapy potentiates inhibition of collagen mediated platelet aggregation. Also, bleeding times were increased during concurrent therapy when compared to baseline, to aspirin given alone, or to ticlopidine given alone. In one study comparing concurrent therapy with aspirin given alone and ticlopidine given alone, there was an increase in hemorrhage in the group receiving concurrent therapy.

Esomeprazole; Omeprazole/Carbamazepine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Esomeprazole and omeprazole are primarily metabolized by CYP2C19. CYP3A4 plays a smaller role in metabolism.(1,2) Carbamazepine is a strong inducer of CYP2C19 and CYP3A4.(2) Esomeprazole and omeprazole are weak CYP3A4 inhibitors and may also affect the metabolism of carbamazepine by CYP3A4.(2)

CLINICAL EFFECTS: Concurrent use of agents which induce both CYP2C19 and CYP3A4 decrease systemic exposure and may result in decreased effectiveness of esomeprazole and omeprazole. Concurrent use of esomeprazole or omeprazole with carbamazepine may increase systemic exposure and may result in increased toxicity of carbamazepine.(1-8)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with carbamazepine for reduced proton pump inhibitor (PPI) effectiveness. Although specific dosing recommendations are not available, a higher dose of esomeprazole or omeprazole may be considered to maintain PPI efficacy. Monitor patients receiving concurrent therapy for increased carbamazepine effects. Therapeutic drug monitoring should be completed routinely when carbamazepine is coadministered with esomeprazole or omeprazole.(7,8)

DISCUSSION: In an interaction study, omeprazole increased the maximum concentration (Cmax), area-under-curve (AUC) and elimination half-life (t1/2) of carbamazepine. The effect of carbamazepine on omeprazole was not studied in these trials (3,4) or in other investigations. The effects of other CYP2C19 inducers on the pharmacokinetics of omeprazole have been reported. In an interaction study, subjects with prostate cancer received omeprazole before and after enzalutamide 160 mg daily (an inducer of CYP2C19 and CYP3A4) for at least 55 days. Enzalutamide decreased omeprazole AUC by 70.5%.(2,5) In an interaction study, rifampin 600 mg daily (an inducer of CYP2C19 and CYP3A4) for 7 days decreased omeprazole AUC by 89.5%.(2,6) In an interaction study, St. John's wort (an inducer of CYP2C19 and CYP3A4) decreased the Cmax and AUC of omeprazole by 37.5% and 49.6%, respectively. The Cmax and AUC of omeprazole sulfone (via CYP2C19) increased by 160.3% and 136.6%, respectively. The Cmax and AUC of 5-hydroxyomeprazole (via CYP3A4) increased by 38.1% and 37.2%, respectively.(7,8)

H2 Antagonists; Proton Pump Inhibitors/Amphetamines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: H2 antagonists and proton pump inhibitors (PPIs) may alter the timing of absorption of amphetamines.

CLINICAL EFFECTS: Concurrent use of amphetamines and H2 antagonists or PPIs may result in an increased absorption rate and a change in timing of peak amphetamine levels.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that patients receiving concurrent amphetamines and H2 antagonists or PPIs should be monitored for changes in the timing and clinical effects of amphetamines.(1) Monitor patients receiving concurrent therapy for changes in amphetamine effectiveness and side effects. The Canadian manufacturer states that concurrent use of proton pump inhibitors and amphetamines should be avoided.(3)

DISCUSSION: During concurrent use of a proton pump inhibitor, the median time to maximum concentration (Tmax) of Adderall XR decreased from 5 hours to 2.75 hours.(3) In a 4-way crossover study in healthy subjects, omeprazole had no effect on the total exposure a single dose of mixed amphetamine salts (20 mg); however median Tmax decreased from 5 hours to 2.75 hours. Approximately 50% of subjects had a decrease in Tmax of equal to or greater than 1 hour.(4)

High-Dose Aspirin/Ace Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and decreased renal blood flow. ACE inhibitors can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate.

CLINICAL EFFECTS: Concurrent use of aspirin may result in decreased antihypertensive effects of the ACE inhibitor. Concurrent use of ACE inhibitors with aspirin and diuretics may result in increased risk of acute kidney injury (AKI).

PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and use of diuretics can lead to hypovolemia and increased risk of AKI.

PATIENT MANAGEMENT: Monitor patients receiving doses of aspirin higher than 150 mg daily for decreased antihypertensive effects of their ACE inhibitor. The use of alternative agents may need to be considered. Concurrent use of ACE inhibitors with aspirin and diuretics should be used with caution and monitored for signs of AKI.

DISCUSSION: Several studies have documented decreased effectiveness of various ACE inhibitors, including captopril, enalapril, and lisinopril following the addition of aspirin therapy. Conflicting evidence exists on the use of small (less than 150 mg) daily doses of aspirin with ACE inhibitors, although some guidelines still suggest they may be beneficial. In a population based cohort study, the concurrent use of NSAIDs with renin-angiotensin system (RAS) inhibitors in 5,710 hypertensive patients stabilized on antihypertensive therapy required hypertension treatment intensification. Adjusted hazard ratios (HR) for hypertension treatment intensification were 1.34 [95% CI 1.05-1.71] for NSAIDs in general, 1.79 (95% CI 1.15-2.78) for diclofenac and 2.02 (95% CI 1.09-3.77) for piroxicam. There were significant interactions between NSAIDs and angiotensin converting enzyme inhibitors (ACE inhibitors; HR 4.09, 95% CI 2.02-8.27) or angiotensin receptor blockers (ARBs; HR 3.62, 95% CI 1.80-7.31), but not with other antihypertensive drugs. In a computational study, the risk of AKI using triple therapy (combination of a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID) was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(20,21) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(22) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

High-Dose Aspirin/Angiotensin Ii Receptor Block (Arb)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Angiotensin II receptor blockers (ARBs) can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate. NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and may negate any decrease in blood pressure.

CLINICAL EFFECTS: Concurrent use of aspirin may result in decreased antihypertensive effects of the ARB. In patients with existing renal impairment, the use of these agents may also result in further deterioration of renal clearance caused by renal hypoperfusion. Concurrent use of ARBs with aspirin and diuretics may result in increased risk of acute kidney injury (AKI).

PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and use of diuretics can lead to hypovolemia and increased risk of AKI.

PATIENT MANAGEMENT: Monitor patients receiving doses of aspirin higher than 150 mg daily for decreased antihypertensive effects of their ARB. The use of alternative agents may need to be considered. Concurrent use of ARBs with aspirin and diuretics should be used with caution and monitored for signs of AKI.

DISCUSSION: In a population based cohort study, the concurrent use of NSAIDs with renin-angiotensin system (RAS) inhibitors in 5,710 hypertensive patients stabilized on antihypertensive therapy required hypertension treatment intensification. Adjusted hazard ratios (HR) for hypertension treatment intensification were 1.34 [95% CI 1.05-1.71] for NSAIDs in general, 1.79 (95% CI 1.15-2.78) for diclofenac and 2.02 (95% CI 1.09-3.77) for piroxicam. There were significant interactions between NSAIDs and angiotensin converting enzyme inhibitors (ACE inhibitors; HR 4.09, 95% CI 2.02-8.27) or angiotensin receptor blockers (ARBs; HR 3.62, 95% CI 1.80-7.31), but not with other antihypertensive drugs. In a computational study, the risk of AKI using triple therapy (combination of a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID) was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(4,5) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(6)

Nsaids; Salicylates/Aliskiren

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. It is believed to be related to inhibition of prostaglandin synthesis by the NSAIDs. Use of an NSAID in combination with aliskiren, whose hypotensive effects may be related to the increase in hypotensive prostaglandins, may negate any decrease in blood pressure.

CLINICAL EFFECTS: Concurrent use of aliskiren with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients maintained on aliskiren should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of aliskiren. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent aliskiren therapy.

DISCUSSION: Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril.

Nsaids; Salicylates/Loop Diuretics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: During concurrent administration of a loop diuretic and a nonsteroidal anti-inflammatory drug (NSAID), patients may retain sodium as a result of NSAID-induced prostaglandin inhibition.

CLINICAL EFFECTS: The pharmacological effects of loop diuretics may be decreased due to reduced antihypertensive and diuretic actions. Concurrent use of NSAIDs with loop diuretics and renin-angiotensin system (RAS) inhibitors may result in increased risk of acute kidney injury (AKI).

PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individuals susceptibility to AKI.

PATIENT MANAGEMENT: Monitor patients for a decrease in the effects of the loop diuretic. It may be necessary to administer a higher dose of the diuretic or an alternative anti-inflammatory agent. Concurrent use of NSAIDs with loop diuretics and RAS inhibitors should be used with caution and monitored closely for signs of AKI.

DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, RAS inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(19,20) In an observational study, current use of a triple therapy with a diuretic, RAS inhibitor, and NSAID, was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46). (21) Administration of indomethacin alone has been reported to decrease sodium excretion and increase blood pressure. In patients receiving a loop diuretic (e.g., bumetanide, furosemide), these effects interfere with clinical management. Several NSAIDs have been shown to interact with loop diuretics interfering with the pharmacological effects of the diuretic. In volunteers on sodium restricted diets, ibuprofen and indomethacin inhibited furosemide diuresis.

Nsaids; Salicylates/Minoxidil

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Oral minoxidil functions as a direct-acting peripheral vasodilator, lowering elevated systolic and diastolic blood pressure by reducing resistance in peripheral blood vessels. This triggers a compensatory increase in cardiac output and renin secretion and results in sodium and water retention. NSAIDs inhibit prostaglandin synthesis and also result in sodium and water retention.(1,2)

CLINICAL EFFECTS: The risk of heart failure may increase with oral minoxidil and NSAIDs due to their combined effects on blood vessel dilation, fluid retention, and altered sodium balance. Minoxidil efficacy may be compromised.(1,2)

PREDISPOSING FACTORS: Higher doses of oral minoxidil have been associated with serious adverse events, including hypotensive syncope, pericarditis, pericardial effusion, and myocardial infarction.(1-5)

PATIENT MANAGEMENT: Closely monitor body weight, fluid and electrolyte balance, and blood pressure when using oral minoxidil and NSAIDs concurrently. Minoxidil tablets should be co-administered with an appropriate diuretic to prevent fluid retention and potential congestive heart failure. A high-ceiling (loop) diuretic is often necessary alongside vigilant monitoring of body weight. Without concurrent diuretic use, minoxidil may lead to the retention of salt and water within a few days.(1,2)

DISCUSSION: While the manufacturer of minoxidil does not provide specific recommendations regarding NSAID co-administration, it emphasizes the necessity of combining minoxidil with a beta-blocker to prevent tachycardia and increased myocardial workload. Additionally, concurrent use with a diuretic is recommended to avert serious fluid accumulation and potential congestive heart failure. NSAID labeling warns about fluid retention, edema, an elevated risk of heart failure, and potential drug interactions with beta-blockers and diuretics which can result in a blunting of the antihypertensive and cardiovascular effects of these agents.(1-5)

Nsaids; Salicylates/Sparsentan

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Sparsentan is an endothelin and angiotensin II receptor antagonist.(1) Angiotensin II receptor blockers can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate. NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction.

CLINICAL EFFECTS: Concurrent use of sparsentan with NSAIDs (including selective COX-2 inhibitors) may result in renal hypoperfusion and deterioration of renal clearance, including possible acute kidney injury (AKI). These effects are usually reversible.(1)

PREDISPOSING FACTORS: Patients older than 75 years old, with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion (including from diuretic use and dehydration) may be at greater risk for AKI.(1-3)

PATIENT MANAGEMENT: Monitor for signs of worsening renal function if an NSAID (including selective COX-2 inhibitors) is used concurrently with sparsentan. If renal function deteriorates, the NSAID may need to be discontinued.(1)

DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(2,3) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(4)

Nsaids; Salicylates/T Cell Immunotherapies

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: NSAIDs augment the immune system. Concurrent use with NSAIDs may interfere with the activity of CAR-T cell immunotherapies.(1)

CLINICAL EFFECTS: NSAIDs may decrease the efficacy of CAR-T cell immunotherapies.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: NSAIDs should be used with caution with or after CAR-T cell immunotherapy.(1)

DISCUSSION: An in vitro study showed aspirin and celecoxib negatively affected CD19.CAR-T cells through their effects on the induction of apoptosis, reduction of activation, and impairment of proliferation.(1)

Omeprazole; Pantoprazole/Voriconazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Voriconazole is a strong CYP3A4 inhibitor and a moderate inhibitor of CYP2C19. Omeprazole and pantoprazole are predominantly metabolized by CYP2C19 but are also a substrate of CYP3A4. Voriconazole may inhibit the metabolism of omeprazole and pantoprazole by CYP2C19 and CYP3A4.(1-3)

CLINICAL EFFECTS: The concurrent use of voriconazole and either omeprazole or pantoprazole may result in elevated levels of omeprazole and pantoprazole, and increase the risk of proton pump inhibitor (PPI) related side effects including gastroenteritis, Clostridioides difficile associated diarrhea, fractures, hypomagnesemia and vitamin B12 deficiency.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of voriconazole states that when voriconazole is initiated in patients receiving dosages of omeprazole of 40 mg/day or greater, the dosage of omeprazole should be reduced by one-half.(1) The manufacturer of voriconazole states concurrent use of other proton pump inhibitors (PPIs) that are CYP2C19 substrates such as pantoprazole may also require a dose adjustment.(1)

DISCUSSION: In healthy subjects, concurrent voriconazole (400 mg every 12 hours Day 1, 200 mg Days 2-7) with omeprazole (40 mg daily for Days 1-7) increased the maximum concentration (Cmax) and area-under-curve (AUC) of omeprazole by 2-fold and 4-fold, respectively. Therefore, the manufacturer of voriconazole recommends that when voriconazole is initiated in patients receiving dosages of omeprazole of 40 mg/day or greater, the dosage of omeprazole should be reduced by one-half.(1) In healthy subjects, concurrent voriconazole (400 mg every 12 hours Day 1, 200 mg Days 2-10) with omeprazole (40 mg once daily) increased the Cmax and AUC of voriconazole by 15% and 40%, respectively. The manufacturer of voriconazole does not recommend a dosage adjustment of voriconazole when administered with omeprazole.(1)

Platelet Aggregation Inhibitors/Lepirudin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lepirudin is a highly specific direct inhibitor of thrombin.(1) Platelet aggregation inhibitors enhance the effects of lepirudin.

CLINICAL EFFECTS: Concurrent use of lepirudin and platelet aggregation inhibitors may increase the risk of bleeding complications and may enhance the effect of lepirudin on aPTT prolongation.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The manufacturer recommends close monitoring of patients taking this combination.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: A study using lepirudin in combination with platelet aggregation inhibitors concluded that caution should be exercised when using this combination because of the increased risk of bleeding complications.(2)

Proton Pump Inhibitors/Belumosudil

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Belumosudil is best absorbed in an acidic environment. Proton pump inhibitors (PPIs) decrease gastric acidity and may decrease belumosudil absorption and systemic concentrations.(1)

CLINICAL EFFECTS: Coadministration of PPIs with belumosudil decreases systemic concentrations of belumosudil, which may decrease the efficacy of belumosudil.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Increase the dosage of belumosudil to 200 mg twice daily when coadministered with PPIs.(1)

DISCUSSION: Coadministration of rabeprazole decreased belumosudil maximum concentration (Cmax) by 87% and area-under-curve (AUC) by 80%, and omeprazole decreased belumosudil Cmax by 68% and AUC by 47% in healthy subjects.(1)

Proton Pump Inhibitors/Belumosudil (400 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Belumosudil is best absorbed in an acidic environment. Proton pump inhibitors (PPIs) decrease gastric acidity and may decrease belumosudil absorption and systemic concentrations.(1)

CLINICAL EFFECTS: Coadministration of PPIs with belumosudil decreases systemic concentrations of belumosudil, which may decrease the efficacy of belumosudil.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Increase the dosage of belumosudil to 200 mg twice daily when coadministered with PPIs.(1)

DISCUSSION: Coadministration of rabeprazole decreased belumosudil maximum concentration (Cmax) by 87% and area-under-curve (AUC) by 80%, and omeprazole decreased belumosudil Cmax by 68% and AUC by 47% in healthy subjects.(1)

Proton Pump Inhibitors/Immune Checkpoint Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction has not been fully investigated. Proposed mechanisms include: 1. Proton pump inhibitor (PPI)-induced changes of the microbiota (dysbiosis) causing resistance to immune checkpoint inhibitors, 2. Co-administration of PPIs with corticosteroids or non steroidal anti-inflammatory drugs (NSAIDs) and immune checkpoint inhibitors resulting in poorer prognosis.(1)

CLINICAL EFFECTS: PPIs may decrease the therapeutic effects of immune checkpoint inhibitors. Several observational studies have shown a reduction in progression free survival (PFS), overall survival (OS), and tumor response in patients on concurrent treatment with immune checkpoint inhibitors and PPIs.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of immune checkpoint inhibitors and PPIs should be approached with caution. Manufacturers of immune checkpoint inhibitors do not provide recommendations on the concurrent use of PPIs. Primary literature on the concurrent use of these agents include recommendations to evaluate the risks and benefits of PPI use and consideration of alternative therapy when possible such as histamine H2-receptor antagonists (H2RAs) or antacids.(1-3)

DISCUSSION: A meta analysis of 23 studies evaluating the impact of acid suppressing therapy on the efficacy of immune checkpoint inhibitors found coadministration of a PPI decreased PFS (HR 1.34 [95% confidence interval (CI), 1.13 to 1.58]) and OS (HR 1.43 [95% CI, 1.21 to 1.69]) compared with patients not treated with PPIs. Furthermore, the meta analysis identified that H2RAs did not affect OS. These results were consistent across cancer types.(1) In another meta analysis of 22 studies (5 prospective and 17 retrospective, n=16,072) evaluating the impact of concomitant medications on survival outcomes in patients treated with systemic therapy for advanced unresectable or metastatic renal cell carcinoma, concomitant use of PPIs (n=3959) was significantly associated with worse OS in patients treated with immune checkpoint inhibitors (HR 1.22, P=0.01).(4) A retrospective analysis of 635 patients treated with immune checkpoint inhibitors found PPI use was associated with significantly decreased OS (9 vs 26.5 months), PFS (3.5 vs. 8 months), and tumor response (61% vs. 72%).(5) Analysis of retrospective data from clinical trials of atezolizumab for urothelial carcinoma and non-small-cell lung cancer, among patients using a PPI within 30 days before or after therapy initiation, OS was significantly worse for patients randomized to treatment with atezolizumab than for patients randomized to chemotherapy.(6,7) A retrospective study of 381 patients treated with immune checkpoint inhibitors found use of acid-suppression therapy (n=168 PPIs, n=37 potassium competitive acid blocker, n=13 H2RAs) was associated with significantly shorter PFS and OS (2.9 vs. 6.2 months and 12.3 vs. 24 months, respectively) compared with patients who did not use acid-suppression therapy. However, when stratified by concomitant use of corticosteroids or NSAIDs, use of acid-suppression therapy was not associated with worse progression-free or overall survival.(8) In a retrospective cohort study of patients with advanced non-small-cell lung cancer treated with pembrolizumab, exposure to PPIs was associated with worse OS (HR, 1.13; 95% CI, 1.10-1.17).(9) Analysis of US and Japanese adverse drug event reporting system databases found administration of immune checkpoint inhibitors and PPIs was associated with an increased risk of adverse events including acute kidney injury (10) and congenital, familial and genetic disorders.(11) In a meta analysis of 14 observational studies, the risk of immune checkpoint inhibitor related AKI (ICI-AKI) in cancer patients concurrently using PPIs was found to be significantly higher (pooled OR of 1.84 [95% CI 1.16-2.90]) in comparison to the overall incidence of AKI from all-causes (1.57 [95% CI 1.02-2.40]).(12) In contrast to these findings, other studies have not found a negative effect on PFS or OS when patients are co-administered PPIs and immune checkpoint inhibitors. In a retrospective study of 159 patients treated with ipilimumab, coadministration of PPIs was associated with increased odds of experiencing a partial or complete response to ipilimumab (OR 3.73 [95% CI, 1.26 to 11.04]).(13) In another retrospective study of 233 patients who received nivolumab or pembrolizumab, use of PPI had no effect on OS (HR 1.2 [95% CI, 0.8-1.9]) or PFS (HR 1.1 [95% CI, 0.8 to 1.5]).(14) A nested case-control study of patients (n=38,930) with cancer who were new PPI or immune checkpoint inhibitor users and had no history of AKI before cohort entry, found the risk of AKI in patients treated with both PPIs and immune checkpoint inhibitors was not higher than then additional or multiplication of the risks in those who were treated with PPIs or immune checkpoint inhibitors alone. The study reinforces the association between PPIs and immune checkpoint inhibitors use and the increased risk of AKI and the need for careful monitoring and evaluation of kidney function when treated with both medicines.(15)

Proton Pump Inhibitors/Methotrexate(Low Strength Inj, Oral)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Proton pump inhibitors(PPIs) may inhibit the active secretion of methotrexate from the kidney via inhibition of the hydrogen-potassium ATPase(1) and may reduce uptake of methotrexate into breast cancer resistance protein via competitive inhibition.(2,3)

CLINICAL EFFECTS: The concurrent use of methotrexate and proton pump inhibitors may result in elevated levels of methotrexate and increased methotrexate-related adverse effects and toxicities, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.(1-7,9)

PREDISPOSING FACTORS: High dose methotrexate therapy appears to increase the risk for and severity of this interaction.(4,9)

PATIENT MANAGEMENT: Patients receiving concurrent use of methotrexate and proton pump inhibitors should be monitored closely for elevated methotrexate levels and methotrexate toxicity. The US manufacturer of omeprazole states that secretory ability returns gradually over three to five days following discontinuation.(4) This interaction has best described in patients receiving high dose methotrexate for cancer treatment. Therefore, it would seem prudent to discontinue proton pump inhibitors several days prior to high dose methotrexate therapy. The magnitude and frequency of this interaction in patients receiving less than or equal to 15 mg weekly is less clear. While a small study suggested lansoprazole was safe in rheumatoid arthritis patients taking 7.5 - 15 mg weekly(8), at least one case report of PPI associated methotrexate toxicity at a low dose (15 mg IM weekly) has been described.(7)

DISCUSSION: In a clinical trial in 74 patients on high dose (1-5 G/m2) methotrexate therapy, data was examined to determine if proton pump inhibitor (omeprazole, pantoprazole, rabeprazole) use affects methotrexate elimination. Delayed elimination was found to be more frequent in those with co-administration of a proton pump inhibitor (31.7% vs. 13.8%), resulting in higher plasma methotrexate concentrations at 24, 48, and 74 hours. The effect was seen with lansoprazole, omeprazole, pantoprazole, and rabeprazole.(2) There are three case reports(1,5,6) of elevated methotrexate levels or delayed methotrexate elimination resulting from concurrent administration of high dose methotrexate and omeprazole, including one patient(6) that developed severe mucositis. In each case, omeprazole was discontinued and normal methotrexate kinetics were observed on subsequent cycles with no further adverse effects noted. In a case report of a 59 year-old male on low dose (15 mg weekly) methotrexate, administration of pantoprazole (20 mg daily) was found to increase the AUC of the metabolite 7-hydroxymethotrexate by 70%.(7) In a manufacturer sponsored clinical trial, 28 adults with rheumatoid arthritis on low dose (7.5-15 mg weekly) methotrexate were assigned to receive lansoprazole (30 mg daily) and naproxen (500 mg twice daily) on Days 1-7 of therapy. The half life of the metabolite 7-hydroxymethotrexate was prolonged with concurrent administration, but no other statistically significant differences were found in regards to the plasma concentration profiles of methotrexate or 7-hydroxymethotrexate.(8)

Proton Pump Inhibitors/Mycophenolate Mofetil

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. One theory is that proton pump inhibitors may prevent mycophenolate mofetil from being converted to mycophenolic acid in the gastrointestinal tract.(1-5)

CLINICAL EFFECTS: Concurrent use of proton pump inhibitors (PPIs) may result in decreased mycophenolic acid levels and effects, including increased risk of transplant rejection.

PREDISPOSING FACTORS: Other factors which may affect systemic mycophenolate exposure include renal function, serum albumin, gender, race, the choice of calcineurin inhibitor (CNI), and use of other drugs which inhibit absorption or enterohepatic recirculation of mycophenolate.

PATIENT MANAGEMENT: If concurrent treatment of mycophenolate mofetil and a PPI is needed, evaluate predisposing risk factors (e.g. renal function, gender, race, and presence of other interacting drugs) which may increase or decrease mycophenolate exposure. If a patient is at risk for low mycophenolic acid levels, options may include converting to delayed release mycophenolic acid (mycophenolate sodium) which is not susceptible to this interaction (4,8,9), or monitoring mycophenolic acid levels to assure therapeutic concentrations are attained.

DISCUSSION: A study compared 21 heart transplant patients maintained on mycophenolate mofetil and pantoprazole (40 mg daily) to 12 patients maintained on mycophenolate without pantoprazole. There was no significant difference in mycophenolate dose between the groups. However, mycophenolic acid levels at 30 minutes, 1 hour, 2 hours, and 12 hours were significantly lower in patients who received pantoprazole (63%, 44%, 34%, 52%, respectively). Mycophenolic acid area-under-curve (AUC) and maximum concentration (Cmax) were also significantly lower in patients who received pantoprazole (30% and 78%, respectively). There was a trend for more acute rejection episodes and transplant vasculopathy in patients receiving pantoprazole.(1) A study compared 23 patients with autoimmune diseases maintained on mycophenolate mofetil and pantoprazole (40 mg daily) to 13 patients maintained on mycophenolate without pantoprazole. There was no significant difference in mycophenolate dose between the groups. The AUC and Cmax of mycophenolic acid decreased by 37% and 60%, respectively, in patients treated with pantoprazole. The activity of mycophenolic acid decreased by 42% in patients receiving pantoprazole.(2) In a study in 22 heart transplant patients receiving mycophenolate mofetil (1000 mg twice daily), mycophenolic acid levels at 30 and 60 minutes post-dose were 55% and 37% lower, respectively, when patients were receiving pantoprazole (40 mg daily). The AUC and Cmax of mycophenolic acid were both 41% when patients were receiving pantoprazole. The time to reach Cmax (Tmax) was 29% longer.(3) A study in 12 healthy subjects compared the effects of pantoprazole (40 mg twice daily) on single doses of mycophenolate mofetil (1000 mg) and enteric-coated mycophenolate sodium (720 mg). Pantoprazole decreased the Cmax and AUC of mycophenolic acid following mycophenolate mofetil administration by 57% and 27%, respectively. There were no effects on mycophenolate acid following mycophenolate sodium administration.(4) A study in renal transplant patients, patients receiving mycophenolate mofetil and tacrolimus without PPI therapy (n=22) were compared to patients receiving concurrent mycophenolate mofetil, tacrolimus, and lansoprazole (30 mg, n=22) and patients receiving concurrent mycophenolate mofetil, tacrolimus, and rabeprazole (10 mg, n=17). Mycophenolic acid Cmax, dose-adjusted Cmax, and AUC(0-6h) were significantly lower in patients receiving lansoprazole when compared to patients not receiving PPI therapy. There were no significant differences between patients receiving rabeprazole and those not receiving PPI therapy; however, rabeprazole acid lowering effects are lower than lansoprazole.(5) A cross-sectional, retrospective analysis of renal transplant patients on omeprazole, mycophenolate, and a calcineurin inhibitor found that in the first week post-transplant the mycophenolate active moiety levels were reduced to a point of clinical significance. However, after that first week, the effect seemed to be less clinically significant.(6) In a study of heart transplant patients, use of pantoprazole (20 mg to 80 mg daily) significantly reduced the AUC of mycophenolic acid produced from a mean daily dose of 2.2+/-0.8 mycophenolate mofetil (p=0.02). However, mycophenolic acid minimum concentration (Cmin) was not significantly different.(7) In a study in healthy subjects, the Cmax and AUC of mycophenolic acid were decreased when mycophenolate mofetil was administered with omeprazole (20 mg BID); however, there was no effect on the Cmax or AUC of mycophenolic acid when enteric-coated mycophenolate mofetil was administered with omeprazole.(8) In a study in heart or lung transplant patients, concurrent pantoprazole had no effect on the Cmax, Tmax, or AUC of mycophenolic acid following administration of enteric-coated mycophenolate sodium. Additionally no significant difference of inosine 5?-monophosphate dehydrogenase (IMPDH) activity was seen with EC-mycophenolate given alone or with pantoprazole.(9) In a subanalysis of the CLEAR Study, there were no significant effects of omeprazole or pantoprazole on mycophenolic acid levels in the study group randomized to received intensified dosing with mycophenolate mofetil (1.5 g BID for 5 days, then 1 g BID).(10)

Proton Pump Inhibitors/Palbociclib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction is not fully understood and may involve dysbiosis or gastric pH changes resulting from proton pump inhibitors (PPIs).(1,2) The aqueous solubility of palbociclib is pH-dependent. Higher gastric pH leads to lower solubility which may reduce palbociclib absorption.(1)

CLINICAL EFFECTS: Coadministration of PPIs may reduce the bioavailability of palbociclib, leading to decreased systemic levels and effectiveness.(1) Although administration of palbociclib with food minimizes the decrease in absorption,(1) retrospective studies and a meta-analysis have found lower survival rates among patients on concurrent PPIs.(2-7)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of palbociclib capsules states that palbociclib should be taken with food, whereas palbociclib tablets may be taken with or without food. There are no constraints on concurrent use of proton pump inhibitors.(1) Given the decreased survival rates observed in patients who received PPIs with palbociclib, the authors of some studies on concurrent use of these agents have made various recommendations, including avoiding PPIs with palbociclib, using ribociclib instead of palbociclib, using low strengths of PPIs, or using H2-antagonists or antacids.(2-7)

DISCUSSION: Palbociclib solubility decreases significantly above pH 4.(1) In a study with healthy volunteers, rabeprazole decreased the maximum concentration (Cmax) and area-under-curve (AUC) of single-dose palbociclib without food by 80% and 62%, respectively. In another study of healthy volunteers in a fed state, rabeprazole decreased Cmax and AUC of single-dose palbociclib by 41% and 13%, respectively.(1) A systematic review and meta-analysis examined studies of HER2-negative, hormone receptor-positive patients with metastatic breast cancer treated with palbociclib or ribociclib with or without concomitant PPIs that reported on survival outcomes. Eight studies consisting of 2,584 patients (830 on PPIs, 1754 not on PPIs) were included. Patients on concurrent PPIs had a significantly higher risk of all-cause mortality (HR, 2.03; 95% CI, 1.49 to 2.77) and disease progression (HR, 1.75; 95% CI, 1.26 to 2.43) compared to patients not on PPIs, though there was a high degree of heterogeneity in disease progression.(2) A retrospective cohort of patients with advanced or metastatic breast cancer treated with palbociclib capsules (344 patients on PPIs, 966 patients not on PPIs) revealed that patients on PPIs had shorter progression-free survival (PFS) (HR 1.76 (95% CI, 1.46-2.13) and lower overall survival (HR, 2.71 [95% CI, 2.07-3.53]).(3) A post-hoc analysis of the phase 2 PARSIFAL trial evaluated PFS in patients on palbociclib capsules. 326 patients were PPI-naive, 64 patients were early users of PPIs (started on PPIs since starting palbociclib), and 91 patients were long-term users of PPIs. PPI use was associated with a shorter PFS (HR in early PPI users 1.5; 95% CI 1.1-2.2; HR in long-term PPI users 1.4; 95% CI 1.1-1.9).(4) A retrospective study of 50 patients with metastatic breast cancer on palbociclib found that concurrent PPI use was associated with a shorter PFS.(5) In an observational study of patients with metastatic breast cancer on palbociclib capsules, PFS was compared between 65 patients on PPIs and 40 patients not on PPIs. On multivariate analysis, PPI usage was an independent predictor of shorter PFS (HR 5.60; 95% confidence interval: 1.98-15.85).(6) A retrospective observational cohort of metastatic breast cancer patients on palbociclib found that patients on concurrent PPIs had a shorter PFS than those not on PPIs (14.0 versus 37.9 months, p < 0.0001).(7) In contrast to these findings, other studies have not found a detrimental effect of PPIs on palbociclib efficacy. A retrospective observational study focused on 112 patients with endocrine-resistant metastatic breast cancer on palbociclib capsules (n=58) and tablets (n=20). There was no difference in PFS in patients on concurrent PPIs compared to those not on PPIs.(8) A study looking at 82 patients with metastatic breast cancer treat 1st line with palbociclib tablets(9) and a retrospective observational study on metastatic breast cancer patients on palbociclib capsules(10) also did not find a significantly different PFS between patients with and without concurrent PPIs.

Proton Pump Inhibitors/Paltusotine (< 60 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The aqueous solubility of paltusotine is pH dependent. Higher gastric pH leads to lower solubility which may reduce paltusotine absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of paltusotine, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of paltusotine states that concomitant use of paltusotine with PPIs may require an increased dosage of paltusotine. Patients who are already on paltusotine 60 mg daily should avoid concomitant use with PPIs.(1)

DISCUSSION: In an interaction study, paltusotine area-under-the-curve (AUC) was decreased by 21% with 20 mg dose and 42% with 60 mg dose levels.(1)

Proton Pump Inhibitors/Saquinavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction is not clear. Saquinavir is a poorly soluble drug with a low bioavailability. It is possible that proton pump inhibitors (PPIs) induced elevation of gastric pH increases systemic absorption of saquinavir.(1)

CLINICAL EFFECTS: Concurrent use of proton pump inhibitors may lead to elevated saquinavir concentrations and an increased risk for toxicities including gastrointestinal symptoms, hypertriglyceridemia, deep vein thrombosis (DVT) and QT prolongation.(1)

PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, concurrent use of more than one agent known to cause QT prolongation, and with higher blood concentrations of saquinavir.(2)

PATIENT MANAGEMENT: The manufacturer of saquinavir recommends monitoring for saquinavir toxicities including gastrointestinal symptoms, hypertriglyceridemia, DVT and QT prolongation in patients receiving saquinavir and a PPI. No specific saquinavir dose adjustments are recommended.(1) If a PPI is newly added to existing saquinavir therapy it would be prudent to assure the patient has been evaluated for QT prolongation risk factors and that laboratory tests (e.g. potassium, magnesium, calcium) are normal.

DISCUSSION: A study performed in 19 subjects of concurrent omeprazole 40 mg daily with saquinavir/ritonavir (1000/100 mg twice daily) increased area-under-curve (AUC) and maximum-concentration (Cmax) by 82% and 75%, respectively.(1) Concurrent use of omeprazole 40 mg with saquinavir/ritonavir increased saquinavir AUC, minimum concentration (Cmin), and Cmax by 54%, 73%, and 55%, respectively. Staggered administration of omeprazole 40 mg with saquinavir/ritonavir by 2 hours increased AUC, Cmin, and Cmax by 67%, 97%, and 65%, respectively.(3)

Salicylates/Valproic Acid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Multiple mechanisms appear to be involved. Salicylates may displace valproic acid from plasma protein binding sites. Salicylates may also affect the metabolism of valproate by increasing conjugation and decreasing oxidation of valproic acid.

CLINICAL EFFECTS: Concurrent use of salicylates may increase the unbound fraction of serum valproic acid concentration, resulting in toxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent salicylate therapy should be observed for signs of valproic acid toxicity (e.g., ataxia, drowsiness, nystagmus, tremor). The dosage of valproic acid may need to be adjusted.

DISCUSSION: In two studies involving 6 epileptic children taking valproic acid, concurrent aspirin led to an increase in serum valproic acid free fraction and an increased half-life. Renal clearance of free valproic acid was found to decrease.(1,2) In another study involving 5 children, concurrent valproic acid and aspirin resulted in a decrease in free valproic acid clearance although total valproic acid levels did not change significantly.(3) However, one study reported that the concurrent use of valproic acid and aspirin leads to an increased excretion of valproic acid and a decreased total salicylate excretion.(4) In 3 case reports, aspirin given to children taking valproic acid resulted in valproic acid toxicity (tremor, nystagmus, truncal ataxia). There was an increase in free valproic acid levels in two cases, however, a reduction in the free fraction and the total valproic acid levels occurred in the third patient.(5) In another case report, a patient was maintained on divalproex sodium (2500 mg/day) and aspirin (325 mg/day) with a trough valproate level of 24.7 ng/ml and a total valproate level of 64.0 ng/ml. Five days after aspirin was discontinued for a procedure, trough valproate levels fell to 3.9 ng/ml and a total valproate level fell to 36.0 ng/ml with no change in divalproex dosing.(6) In a study in 7 healthy males, concurrent diflunisal (250 mg twice daily) increased the unbound fraction of valproic acid (200 mg twice daily) by 20%. The area-under-curve (AUC) of 3-oxo-valproic acid increased by 35%. There were no effects on diflunisal levels.(7)

Selected Anticoagulants; Antiplatelets/Ibrutinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ibrutinib administration lowers platelet count in the majority of patients.(1,2) In addition, ibrutinib has been shown to inhibit collagen-mediated platelet aggregation.(3-4) Bleeding has been reported with the use of ibrutinib,(1-4) anticoagulants, or antiplatelets alone.

CLINICAL EFFECTS: Concurrent use of ibrutinib with either anticoagulants or antiplatelets may increase the risk of hemorrhage.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The Canadian product monograph for ibrutinib recommends concurrent use with anticoagulants or antiplatelets should be approached with caution. If therapeutic anticoagulation is required, consider temporarily withholding ibrutinib therapy until stable anticoagulation in achieved.(2) The US prescribing information for ibrutinib states patients receiving concurrent therapy with ibrutinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in International Normalized Ratio (INR). Carefully weigh the risks vs. benefits of concurrent therapy in patients with significant thrombocytopenia. If a bleeding event occurs, follow manufacturer instructions for ibrutinib dose adjustment.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Bleeding has been reported with ibrutinib alone.(1-3) Across 27 clinical trials, grade 3 or higher bleeding events, e.g. subdural hematoma, gastrointestinal bleeding or hematuria, have occurred in up to 4% of patients, with 0.4% fatality. Grade 3 or 4 thrombocytopenia occurred in 5-19% of patients. Bleeding events of any grade occurred in 39% of patients treated with ibrutinib.(1) Concurrent use of anticoagulants or antiplatelets has been reported to increase the risk for major bleeding. In clinical trials, major bleeding occurred in 3.1% of patients taking ibrutinib without concurrent anticoagulants or antiplatelets, 4.4% of patients on concurrent antiplatelets with or without anticoagulants, and 6.1% of patients on concurrent anticoagulants with or without antiplatelets.(1) In an open-label, phase 2 trial of patients with relapsed/refractory mantle cell lymphoma on ibrutinib, 61 patients (55%) on concurrent anticoagulants or antiplatelets had a higher rate of bleeding (69% any grade, 8% grade 3-4) than patients not on anticoagulants or antiplatelets (28% any grade, 4% grade 3-4).(5) A retrospective trial found a hazard ratio of 20 (95% CI, 2.1-200) for patients on ibrutinib with concurrent anticoagulants and antiplatelets. There was a trend towards an increased bleeding risk in patients on either anticoagulants or antiplatelets, but this was not statistically significant on multivariate analysis.(6) A case report of 2 patients with chronic lymphocytic leukemia (CLL) on ibrutinib and dabigatran demonstrated no stroke nor bleeding events during the mean 11.5 month follow-up.(7) A case report of 4 patients with lymphoproliferative disease on concurrent dabigatran and ibrutinib demonstrated no stroke nor major bleeding events. 1 patient experienced grade 2 conjunctival hemorrhage whilst on both ibrutinib and dabigatran. The anticoagulant was withheld and successfully re-initiated at a lower dose with no further bleeding events.(8)

Selected Cyp2c19 Inhibitors/Citalopram (<= 20 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, hypocalcemia, hypomagnesemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(7,8)

Selected Cyp2c19 Inhibitors/Escitalopram (<= 15 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(4)

Selected Cyp2c19 Inhibitors/Escitalopram (> 15 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(4)

Selected Nsaids; Aspirin/Ssris; Snris

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor(1-7,13) or a serotonin-norepinephrine reuptake inhibitor(8-10) and a NSAID may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., anticoagulants, antiplatelets, or corticosteroids. Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(15)

PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-7,13) or serotonin-norepinephrine reuptake inhibitors(8-10) and NSAIDs should be used concurrently with caution. Patients should be warned about the increased risk of bleeding and be educated about signs and symptoms of bleeding.(1-11,13) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anti-platelet agents in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(11) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(12)

Selected Proton Pump Inhibitors/Tacrolimus

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Some proton-pump inhibitors (PPIs) may inhibit the metabolism of tacrolimus by CYP3A4 and intestinal CYP3A5.

CLINICAL EFFECTS: Concurrent use may increase tacrolimus levels in some patients and result in toxic effects, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.

PREDISPOSING FACTORS: This interaction may be is more severe in patients who are poor metabolizers of CYP2C19. The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(17) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(17)

PATIENT MANAGEMENT: Consider monitoring tacrolimus levels when initiating or discontinuing a PPI other than pantoprazole in patients who are poor metabolizers of CYP2C19 or whose genotype is unknown. The dosage of tacrolimus may need to be adjusted. Pantoprazole may be an alternative to other PPIs in patients maintained on tacrolimus. When concurrent therapy of selected proton pump inhibitors and tacrolimus is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In vitro studies have shown that omeprazole inhibits the metabolism of tacrolimus.(1,2) In a case report, tacrolimus levels increased 1.8-fold in a pediatric live-transplant patient following the initiation of omeprazole.(3) In another report, the tacrolimus concentration/dose ratio was higher during omeprazole therapy when compared to rabeprazole therapy.(4) In a study in 48 renal transplant patients, the dose/weight normalized trough levels of tacrolimus decreased 15% following the switch of cimetidine to omeprazole.(5) In contrast, in a study in 51 renal transplant patients found no difference in tacrolimus level/dose ratio following the discontinuation of omeprazole.(6) In a study in 12 renal transplant patients who were CYP3A5-nonexpressors, there was no effect by omeprazole on tacrolimus pharmacokinetics.(7) A study in 89 liver transplant patients showed that the interaction between omeprazole and tacrolimus was more severe in patients that are either poor or intermediate metabolizers of CYP2C19.(8) There are three reports of elevated tacrolimus levels during the use of lansoprazole.(9,10,11,12) In a study in 73 renal transplant patients, lansoprazole and rabeprazole had significant effects on tacrolimus levels only in patients who were poor or intermediate metabolizers of CYP2C19.(13) In a study in 19 healthy subjects, lansoprazole increased tacrolimus levels in extensive and poor CYP2C19 metabolizers by 81% and 20%, respectively.(14) In contrast, a study in 55 liver-transplant patients, rabeprazole had no effect on tacrolimus concentrations regardless of CYP3A5 or CYP2C19 genotype.(15) In a study in 12 transplant recipients, pantoprazole had no effect on tacrolimus levels.(16)

Slt Moderate And Weak Cyp3a4 Inhibit/Sirolimus Protein-Bound

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate and weak CYP3A4 inhibitors may inhibit the metabolism of sirolimus by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of moderate or weak CYP3A4 inhibitors may result in elevated levels of and side effects from sirolimus.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: In an open, randomized, cross-over trial in 18 healthy subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10 mg) increased sirolimus area-under-curve (AUC) and maximum concentration (Cmax) by 60% and by 43%, respectively. Sirolimus apparent oral clearance and volume of distribution decreased by 38% and 45%, respectively. There were no effects on diltiazem pharmacokinetics or pharmacodynamics.(2) In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold and 2.3-fold, respectively. The AUC and Cmax of the active S-enantiomer of verapamil each increased by 1.5-fold. Verapamil time to Cmax (Tmax) was increased by 1.2 hours.(2) Moderate and weak CYP3A4 inhibitors linked to this monograph include: amlodipine, anamorelin, aprepitant, avacopan, azithromycin, berberine, berotralstat, bicalutamide, blueberry, brodalumab, camizestrant, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clofazimine, conivaptan, crizotinib, daclatasvir, daridorexant, delavirdine, diltiazem, diosmin, elinzanetant, estrogen, flibanserin, fluvoxamine, fosaprepitant, fosnetupitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, gepotidacin, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, oral lefamulin, lenacapavir, levamlodipine, linagliptin, lomitapide, lumateperone, lurasidone, mavorixafor, netupitant, nicardipine, omeprazole, osilodrostat, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, rimegepant, roxithromycin, scutellarin, sevabertinib, simeprevir, sitaxsentan, stiripentol, ticagrelor, tofisopam, tolvaptan, trofinetide, vonoprazan, and voxelotor.(3,4)

Slt Strong & Moderate 2C19 Inhibitor/Cilostazol (<=50Mg Bid)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong and moderate inhibitors of CYP2C19 may inhibit the metabolism of cilostazol.(1-4)

CLINICAL EFFECTS: Concurrent use of strong or moderate inhibitors of CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a metabolite of cilostazol that is 4-7 times as active as cilostazol.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong and moderate inhibitors of CYP2C19.(1) The Australian manufacturer of esomeprazole states concomitant use with cilostazol is contraindicated.(5)

DISCUSSION: In a study in 20 subjects examined the effects of omeprazole (40 mg daily) on a single dose of cilostazol (100 mg). Concurrent omeprazole increased the cilostazol maximum concentration (Cmax) and area-under-curve (AUC) by 18% and 26%, respectively. The Cmax and AUC of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%, respectively. The Cmax and AUC of the OPC-13213 metabolite of cilostazol decreased by 22% and 31%, respectively.(4)

*Known hypersensitivity reactions (including anaphylaxis) to omeprazole, esomeprazole, or other substituted benzimidazoles (e.g., lansoprazole, pantoprazole, rabeprazole), or any ingredient in the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria.

*Concomitant use of proton-pump inhibitors (PPIs), including omeprazole, and rilpivirine is contraindicated.

• Aspirin exacerbated respiratory disease
• Gastrointestinal hemorrhage
• Hemolytic anemia from pyruvate kinase and g6PD deficiencies
• Hemorrhage
• Increased risk of bleeding due to coagulation disorder
• Lactation
• Pregnancy
• Reye's syndrome

• Alcohol use disorder
• Clostridioides difficile infection
• Gastrointestinal ulcer
• Hypoprothrombinemia
• Increased risk of bleeding due to coagulation disorder
• Interstitial nephritis
• Salicylate intoxication
• Subacute cutaneous lupus erythematosus
• Systemic lupus erythematosus
• Systemic mastocytosis
• Thrombocytopenic disorder
• Thrombotic thrombocytopenic purpura

• Anemia
• CYp2c19 poor metabolizer
• Disease of liver
• Fracture
• Gout
• Hypomagnesemia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Nasal polyp
• Osteoporosis
• Vitamin b12 deficiency
• Vitamin K deficiency

Adverse effects reported in >=2% of adults receiving omeprazole in clinical trials include headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence.

Adverse effects reported in pediatric patients 2--16 years of age receiving omeprazole were similar to those reported in adults, except for more frequently reported respiratory system events and fever.

Rare or Very Rare

• Abnormal hepatic function tests
• Acute eruptions of skin
• Acute generalized exanthematous pustulosis
• Agranulocytosis
• Allergic dermatitis
• Anaphylaxis
• Anaphylaxis
• Anemia
• Anemia
• Angioedema
• Angioedema
• Anterior ischemic optic neuropathy
• Atrophic gastritis
• Blistering skin
• Bradycardia
• Bronchospastic pulmonary disease
• Bronchospastic pulmonary disease
• Bullous dermatitis
• Cardiac arrhythmia
• Cholestatic hepatitis
• Clostridioides difficile infection
• DRESS syndrome
• DRESS syndrome
• Drug-induced hepatitis
• Dyspnea
• Erythema multiforme
• Esophageal candidiasis
• Exfoliative dermatitis
• Fracture
• Gastrointestinal hemorrhage
• Gastrointestinal perforation
• Gastrointestinal ulcer
• Hematuria
• Hemolytic anemia
• Hemorrhage
• Hepatic failure
• Hepatitis
• Hyperbilirubinemia
• Hypertension
• Hypocalcemia
• Hypoglycemic disorder
• Hypokalemia
• Hyponatremia
• Increased alanine transaminase
• Increased aspartate transaminase
• Interstitial nephritis
• Interstitial nephritis
• Intracranial bleeding
• Leukocytosis
• Leukopenia
• Leukopenia
• Neutropenic disorder
• Optic neuritis
• Pancreatitis
• Pancytopenia
• Platelet aggregation inhibition
• Proteinuria
• Purpura
• Rectal bleeding
• Renal papillary necrosis
• Seizure disorder
• Stevens-johnson syndrome
• Stevens-johnson syndrome
• Subacute cutaneous lupus erythematosus
• Systemic lupus erythematosus
• Thrombocytopenic disorder
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Toxic epidermal necrolysis
• Urticaria
• Urticaria
• Wheezing

More Frequent

• Abdominal pain with cramps
• Acute abdominal pain
• Diarrhea
• Flatulence
• Gastric acid hypersecretory conditions
• Gastrointestinal irritation
• Headache disorder
• Heartburn
• Nausea
• Vomiting
• Vomiting

Less Frequent

• Back pain
• Chest pain
• Constipation
• Cough
• Dizziness
• Fever
• General weakness
• Nausea
• Pruritus of skin
• Sore throat
• Upper respiratory infection

Rare or Very Rare

• Abdominal distension
• Abnormal hepatic function tests
• Alopecia
• Anorexia
• Anorexia
• Arthralgia
• Benign fundic gland polyposis of stomach
• Black tarry stools
• Blurred vision
• Cramps
• Diplopia
• Discolored feces
• Drowsy
• Dry eye
• Dry skin
• Dysgeusia
• Dyspepsia
• Ecchymosis
• Epistaxis
• Epistaxis
• Erectile dysfunction
• Erythema
• Fatigue
• Gastritis
• Gingival bleeding
• Glycosuria
• Gynecomastia
• Hematoma
• Hyperhidrosis
• Hypomagnesemia
• Irritable bowel syndrome
• Leg pain
• Malaise
• Muscle weakness
• Myalgia
• Ocular irritation
• Pain
• Palpitations
• Paresthesia
• Peripheral edema
• Petechiae
• Pruritus of skin
• Purpura
• Skin inflammation
• Skin photosensitivity
• Skin rash
• Skin rash
• Sleep disorder
• Stomatitis
• Tachycardia
• Testicular pain
• Tinnitus
• Tinnitus
• Tremor
• Urinary tract infection
• Vertigo
• Vitamin b12 deficiency
• Weight gain
• Xerostomia

No enhanced messaging available.

Safety and efficacy of omeprazole magnesium delayed-release oral suspension have been established for the treatment of erosive esophagitis due to acid-mediated gastroesophageal reflux disease (GERD) in pediatric patients >=1 month of age. Safety and efficacy of omeprazole magnesium delayed-release oral suspension have also been established for the treatment of symptomatic GERD and maintenance of healing of erosive esophagitis in pediatric patients 1-16 years of age. Safety and efficacy of omeprazole delayed-release capsules have been established for the treatment of symptomatic GERD and maintenance of healing of erosive esophagitis in pediatric patients 2-16 years of age. Use in pediatric patients is supported by adequate and well-controlled studies in adults and uncontrolled safety, efficacy, and pharmacokinetic studies in pediatric and adolescent patients.

Safety and efficacy of omeprazole magnesium delayed-release oral suspension are not established in pediatric patients <1 month of age or for other uses in pediatric patients. Safety and efficacy of omeprazole delayed-release capsules in pediatric patients <1 year of age for the treatment of symptomatic GERD or maintenance of healing of erosive esophagitis have not been established. Safety and efficacy of omeprazole delayed-release capsules have not been established in pediatric patients for the treatment of active duodenal ulcer, H. pylori eradication to reduce the risk of duodenal ulcer recurrence, treatment of active benign gastric ulcer, or pathological hypersecretory conditions. Safety and efficacy of omeprazole immediate-release capsules and oral suspension have not been established in pediatric patients.

Safety and efficacy of omeprazole and sodium bicarbonate powder kit for oral suspension (Konvomep(R)) have not been established in pediatric patients.

Safety and efficacy of co-packaged omeprazole delayed-release capsules, clarithromycin tablets, and amoxicillin capsules (Omeclamox-Pak(R)) have not been established in pediatric patients with H. pylori.

Respiratory adverse reactions and accidental injuries have been reported more frequently in pediatric patients of all ages than in adults. Otitis and fever have been reported more frequently in patients less than one year of age and patients from one month to less one year to less than 2 years of age, respectively, than in other pediatric and adult patients.

Reproductive studies in rats and rabbits using omeprazole dosages during organogenesis of up to 138 and 69.1 mg/kg daily (about 34 times the human dosage of 40 mg daily based on body surface area (BSA)), respectively, have not revealed evidence of teratogenicity. However, in rabbits given omeprazole dosages of 6.9-69.1 mg/kg daily during organogenesis (about 3.4-34 times the human dosage of 40 mg daily based on BSA), dose-related increases in embryolethality, fetal resorptions, and pregnancy loss occurred. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from administration of omeprazole in dosages of 13.8-138 mg/kg daily (about 3.4-34 times the human dosage of 40 mg daily based on BSA) prior to mating through the lactation period.

Reproductive studies of oral esomeprazole (an enantiomer of omeprazole) in rats and rabbits during organogenesis using dosages approximately 68 and 42 times the usual human dosage of 40 mg daily based on BSA, did not reveal evidence of embryo/fetal toxicity. When administered through most of pregnancy and lactation, effects on bone morphology were observed in rat offspring at dosages approximately 34 times the human dosage of 40 mg daily based on BSA of esomeprazole; however, when confined to administration during the gestational period only, no effects on bone morphology were observed in another study.

There are no adequate and well controlled studies using omeprazole in pregnant women. Available epidemiologic data have not demonstrated an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester exposure to omeprazole. Reproductive studies in rats and rabbits using omeprazole dosages approximately 3.4-34 times the human dosage of 40 mg daily (based on BSA) resulted in dose-dependent increases in embryolethality.

A population-based retrospective cohort epidemiologic study using data from the Swedish Medical Birth Registry reported on outcomes in infants whose mothers used omeprazole during pregnancy; most (about 86%) were exposed to omeprazole during the first trimester, 5% during and beyond the first trimester, and about 14% were exposed only after the first trimester of pregnancy. The number of infants exposed to omeprazole in utero with any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population.

In a population-based retrospective cohort study in Denmark reporting on 1800 live births whose mothers received omeprazole during the first trimester and 837,317 live births whose mothers did not receive a PPI, the overall rate of birth defects was 2.9% in infants whose mothers received omeprazole during the first trimester and 2.6% in infants born to mothers not exposed to any PPI during the first trimester.

In a retrospective cohort study, the incidence of congenital malformations in 689 women who received omeprazole or histamine H2-antagonists in the first trimester of pregnancy was compared with a control group of women who were not exposed to acid-suppressant drugs. The malformation rate associated with histamine H2-antagonists exposure was 5.5%, the malformation rate for nonexposed women was 4.1%, and the malformation rate associated with omeprazole exposure was 3.6%.

A small prospective cohort study followed women exposed to omeprazole (89% during the first trimester) during pregnancy; major congenital malformations occurred in 4% of live births in omeprazole-exposed women, 2.8% of disease-paired controls, and 2% exposed to non-teratogenic agents. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups.

The manufacturers state that several studies reported that adverse short-term effects were not observed in infants when a single oral or IV dose of omeprazole was administered to pregnant women as premedication for cesarean section under general anesthesia.

Available data on sodium bicarbonate administration during pregnancy have not identified a drug-associated risk of major fetal malformations or miscarriage.

Limited data suggest omeprazole is distributed into human milk. The effects of omeprazole on milk production and on the breast-fed infant are unknown. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for the drug and any potential adverse effects on the breast-fed infant from omeprazole or from the underlying maternal condition.

Although the elimination rate of omeprazole is somewhat decreased in geriatric patients and the bioavailability increased, no adjustment of the usual recommended dosage is required in geriatric patients.

In US and European clinical trials, more than 2000 patients treated with omeprazole were >=65 years of age. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.