Norgesic (orphenadrine citrate/aspirin/caffeine)

Some clinicians suggest that when used as a mild CNS stimulant to overcome fatigue, oral doses of 100-200 mg of anhydrous caffeine are required. The manufacturers state that adults and children 12 years of age or older may receive a dosage of 100-200 mg no more frequently than every 3-4 hours.

For the treatment of apnea of prematurity, commercially available caffeine citrate injection in a loading dose of 20 mg/kg (10 mg/kg when expressed in terms of anhydrous caffeine) is administered by slow IV infusion (i.e., over 30 minutes) using a syringe infusion pump. Beginning 24 hours after the loading dose, maintenance doses of caffeine citrate of 5 mg/kg (2.5 mg/kg when expressed as anhydrous caffeine) may be administered every 24 hours, either orally or via slow IV infusion (i.e., over 10 minutes) using a syringe infusion pump. The manufacturer states that the safety and efficacy of dosing periods exceeding 10-12 days have not been established. Other dosing regimens+ for the treatment of apnea of prematurity have used caffeine doses (in terms of anhydrous caffeine) of 5-10 mg/kg, given IV, IM, or orally as a loading dose, and followed by 2.5-5 mg/kg, given IV, IM, or orally once daily. Maintenance dosage has been adjusted according to the patient's response and tolerance and plasma caffeine concentrations.

When caffeine citrate is used for the treatment of apnea of prematurity in infants with hepatic or renal impairment, serum concentrations of caffeine should be monitored and dosage adjusted to avoid toxicity.

Analeptic use of caffeine is strongly discouraged by most clinicians. However, the manufacturers of caffeine and sodium benzoate injection recommend IM, or in emergency respiratory failure, IV injection of 500 mg of the drug (about 250 mg of anhydrous caffeine) or a maximum single dose of 1 g (about 500 mg of anhydrous caffeine) for the treatment of respiratory depression associated with overdosage of CNS depressants, including opiate analgesics and alcohol, and with electric shock.

Some clinicians recommend that when caffeine and sodium benzoate injection is used in children for CNS stimulation+, an IM, IV, or subcutaneous dose of 8 mg/kg (about 4 mg of anhydrous caffeine per kg) (not to exceed 500 mg) or 250 mg/m2 (about 125 mg of anhydrous caffeine per m2) be given up to every 4 hours if necessary.

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.

Orphenadrine is administered orally or by IM or IV injection. When orphenadrine is administered IV, the drug should be given over a period of about 5 minutes with the patient in a supine position; the patient should remain in this position for 5-10 minutes after the injection. To minimize adverse reactions after parenteral administration of the drug, the patient should be assisted from the recumbent position.

Caffeine may be administered orally. Caffeine citrate is administered orally or by slow IV infusion using a syringe infusion pump. Caffeine and sodium benzoate injection may be administered by IM or slow IV injection; the drug has also been administered subcutaneously.

The preservative-free commercially available injection is for single use only, and any unused portion should be discarded. It is important that such oral solution be measured accurately (e.g., using a 1-mL or other appropriate syringe).

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.

There is no enhanced messaging for this drug.

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)

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)

Aspirin (> 325 Mg); Salicylates/Dichlorphenamide

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: Dichlorphenamide 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 dichlorphenamide 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)

Cyp1a2 Inhibitors/Fezolinetant

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: Inhibitors of CYP1A2 may inhibit the metabolism of fezolinetant.(1-4)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations for concurrent use of fezolinetant with CYP1A2 inhibitors differ in different regions. The US manufacturer of fezolinetant states that concurrent use with strong, moderate, and weak CYP1A2 inhibitors is contraindicated.(1) The Australian, Canadian, and UK manufacturers of fezolinetant state that concurrent use with strong and moderate CYP1A2 inhibitors is contraindicated, while weak CYP1A2 inhibitors are not predicted to cause clinically relevant changes in fezolinetant exposure.(2-4)

DISCUSSION: In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 840%, respectively. Mexiletine (400 mg every 8 hours), a moderate CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%, respectively. Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, centanafadine, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include acyclovir, allopurinol, artemisinin, belumosudil, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, valacyclovir, verapamil, and zileuton.(5-7)

Nsaid; Aspirin (>300Mg); Salicylat/Ketorolac (Non-Injection)

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: Possible additive or synergistic side effects.(1,2)

CLINICAL EFFECTS: Concurrent use of multiple doses of ketorolac with other non-steroidal anti-inflammatory agents (NSAIDs), salicylates or aspirin may result in an increase in NSAID-related side effects such as bleeding or renal impairment.(1-3)

PREDISPOSING FACTORS: Patients with pre-existing renal impairment may be at an increased risk of adverse effects from this interaction. 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, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). 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.

PATIENT MANAGEMENT: Manufacturers of ketorolac state that concurrent use of ketorolac with either other NSAIDs or aspirin is contraindicated.(1,2) 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. Conduct periodic monitoring of renal function, especially in patients with 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 of serious NSAID-related adverse events, manufacturers of ketorolac state the concurrent administration of ketorolac with other NSAIDs or aspirin is contraindicated.(1,2)

Nsaids; Aspirin (>300 Mg); Salicylate/Ketorolac (Injectable)

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: Possible additive or synergistic side effects.(1)

CLINICAL EFFECTS: Concurrent use of multiple doses of ketorolac with other non-steroidal anti-inflammatory agents (NSAIDs), salicylates or aspirin may result in an increase in NSAID-related side effects such as bleeding or renal impairment.(1-3)

PREDISPOSING FACTORS: Patients with pre-existing renal impairment may be at an increased risk of adverse effects from this interaction. 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, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). 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.

PATIENT MANAGEMENT: The manufacturer of ketorolac states that concurrent use of ketorolac with either other NSAIDs, salicylates or aspirin is contraindicated.(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 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.

DISCUSSION: Manufacturers of ketorolac state that concurrent use of ketorolac with either other NSAIDs, salicylates or aspirin is contraindicated.(1,2) 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. Conduct periodic monitoring of renal function, especially in patients with renal impairment.

Xanthine Derivatives/Adenosine; Hexobendine; Regadenoson

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: Xanthine derivatives may antagonize the effects of endogenous(1) and exogenous adenosine,(2,3) regadenoson,(4) and hexobendine.(5)

CLINICAL EFFECTS: Concurrent use of a xanthine derivative use may result in decreased effectiveness of adenosine, hexobendine and regadenoson. Aminophylline may increase the risk of adenosine-induced seizures.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with adenosine and a xanthine derivative should be monitored for decreased effectiveness of adenosine. The dosage of adenosine may need to be increased. Whenever possible, withhold xanthine derivatives for 5 half-lives prior to using adenosine in cardiac stress tests.(6) Methylxanthines should not be used to reverse the effects of adenosine in patients who experience adenosine-induced seizures.(3) Concurrent therapy with hexobendine and a xanthine oxidase derivative should also be monitored for decreased effectiveness of hexobendine.(5) The US manufacturer of regadenoson recommends that patients avoid methylxanthines (e.g. caffeine, pentoxifylline, and theophylline) for 12 hours prior to regadenoson administration. Aminophylline may be used to attenuate severe and/or persistent adverse reactions to regadenoson.(4)

DISCUSSION: In a study in six healthy subjects, theophylline significantly reduced the heart-rate response to adenosine. In addition, theophylline reduced the amount of abdominal and chest discomfort reported by subjects, allowing significantly higher infusion rates of adenosine.(7) Theophylline has also been reported to antagonize the vasorelaxant action of adenosine in human forearm arterioles.(8) In a study in five subjects, theophylline decreased the amounts of adenosine-induced side effects, including chest pain. There was no change in blood pressure or respiratory rate during concurrent adenosine and theophylline.(9) In a study in ten dog and twelve human subjects, the administration of adenosine after hexobendine increased coronary sinus blood flow. Aminophylline administration significantly decreased the coronary vasodilation response to adenosine and hexobendine.(5) In a study in ten healthy subjects, caffeine reduced the mean adenosine-induced increases in systolic blood pressure by 7.2 mmHg and heart rate by 8.4 beats/min when compared to placebo.(2) In another study in ten healthy subjects, caffeine was shown to lower the adenosine-induced response of blood pressure and heart rate.(3) Caffeine has also been reported to reduced adenosine-induced changes in minute ventilation and tidal volume.(3) Aminophylline has been shown to shorten the duration of coronary blood flow response to regadenoson.(3) Coronary flow reserve was 8% lower in patients who received caffeine (200 mg single dose) 2 hours prior to regadenoson administration when compared to subjects who received placebo instead of caffeine.(4)

Xanthine Derivatives/Dipyridamole Injectable

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 xanthine derivatives are adenosine receptor antagonists. Concurrent administration may inhibit dipyridamole-induced increases in endogenous plasma adenosine levels, thus decreasing dipyridamole's vasodilator effects.(1)

CLINICAL EFFECTS: Concurrent administration may result in a decrease in dipyridamole's vasodilator effects. This may produce false-negative results during dipyridamole-thallium imaging tests.(1-3)

PREDISPOSING FACTORS: In patients with congestive heart failure and decreased hepatic function, the metabolism of xanthine derivatives may be decreased. These patients may need a longer xanthine-free period prior to dipyridamole-thallium imaging tests.(2)

PATIENT MANAGEMENT: Patients scheduled for dipyridamole-thallium imaging tests should have a xanthine-free period (including caffeine-containing products) for at least 24 hours prior to their exam.(3)

DISCUSSION: In a study in eight male subjects with documented coronary artery disease, intravenous dipyridamole administered during a dipyridamole-thallium 201 SPECT image test produced a significant increase in heart rate, a decrease in blood pressure, and angina in seven patients and ST segment depression in four patients. SPECT imaging showed reversible perfusion defects in myocardial segments supplied by stenotic coronary arteries. When the exam was repeated when the subjects were receiving therapeutic dosages of theophylline, there was no appearance of angina, ST depression, or hemodynamic changes and SPECT imaging shown total absence of reversible perfusion defects.(1) A study in eight patients with coronary artery disease evaluated the effects of caffeine on dipyridamole-201Tl myocardial imaging. The administration of dipyridamole alone resulted in chest pain and ST-segment depression in four patients. Concurrent caffeine infusion decreased the dipyridamole-induced decrease in blood pressure and heart rate. No patients experience chest pain or ST-segment depression. Six patients had false negative test results.(2) Another study found that the attenuation of the hemodynamic response to dipyridamole by caffeine was dose-dependent.(3)

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

Anticholinergics/Clozapine

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

MECHANISM OF ACTION: Clozapine has potent anticholinergic properties and inhibits serotonin receptors, including 5-HT3.(1-4) Both of these properties may cause inhibition of gastrointestinal (GI) smooth muscle contraction, resulting in decreased peristalsis.(3,4) These effects may be compounded by concurrent use of anticholinergic agents.(1-6)

CLINICAL EFFECTS: Concurrent use of clozapine with other anticholinergic agents may increase the risk of constipation (common) and serious bowel complications (uncommon), including complete bowel obstruction, fecal impaction, paralytic ileus and intestinal ischemia or infarction.(1-6)

PREDISPOSING FACTORS: The risk for serious bowel complications is higher with increasing age, higher frequency of constipation, and in patients on higher doses of clozapine or multiple anticholinergic agents.(1,5)

PATIENT MANAGEMENT: Avoid the use of other anticholinergic agents with clozapine.(1-6) If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(2) Consider a prophylactic laxative in those with a history of constipation or bowel obstruction.(2) Review patient medication list for other anticholinergic agents. When possible, decrease the dosage or number of prescribed anticholinergic agents, particularly in the elderly. Counsel the patient about the importance of maintaining adequate hydration. Encourage regular exercise and eating a high-fiber diet.(2)

DISCUSSION: In a prospective cohort study of 26,720 schizophrenic patients in the Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus was 1.99 with clozapine and 1.48 with anticholinergics. The OR for fatal ileus was 6.73 with clozapine and 5.88 with anticholinergics. Use of anticholinergics with 1st generation antipsychotics (FGA) increased the risk of ileus compare to FGA alone, but this analysis was not done with clozapine.(5) A retrospective cohort study of 24,970 schizophrenic patients from the Taiwanese National Health Insurance Research Database found that the hazard ratio (HR) for clozapine-induced constipation increased from 1.64 when clozapine is used alone, to 2.15 when used concomitantly with anticholinergics. However, there was no significant difference in the HR for ileus when clozapine is used with and without anticholinergics (1.95 and 2.02, respectively).(6) In the French Pharmacovigilance Database, 7 of 38 cases of antipsychotic-associated ischemic colitis or intestinal necrosis involved clozapine, and 5 of these cases involved use of concomitant anticholinergic agents. Three patients died, one of whom was on concomitant anticholinergics.(3) In a case series, 4 of 9 cases of fatal clozapine-associated GI dysfunction involved concurrent anticholinergic agents.(4)

Anticholinergics/Glucagon (Diagnostic)

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

MECHANISM OF ACTION: Glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility.(1)

CLINICAL EFFECTS: Concurrent use of glucagon with anticholinergic agents may increase the risk of gastrointestinal hypomotility, including constipation and bowel complications.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of glucagon as a diagnotic aid is not recommended with the use of anticholinergic agents.(1) If concurrent use is necessary, evaluate the patient's bowel function. Monitor for symptoms of constipation and gastrointestinal hypomotility.

DISCUSSION: Both glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility and increase the risk of gastrointestinal adverse effects.(1)

Anticholinergics/Solid Oral Potassium Capsules

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

MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16))

CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with anticholinergics may result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16)

PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21)

PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(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. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal 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 clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. The lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17)

Anticholinergics/Solid Oral Potassium Tablets

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

MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16)

CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with anticholinergics may result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16)

PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21)

PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(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. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal 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 clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. Some lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17)

Anticholinergics; Opioids/Eluxadoline

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

MECHANISM OF ACTION: Eluxadoline is a mixed mu-opioid and kappa-opioid agonist and delta-opioid antagonist and may alter or slow down gastrointestinal transit.(1)

CLINICAL EFFECTS: Constipation related adverse events that sometimes required hospitalization have been reported, including the development of intestinal obstruction, intestinal perforation, and fecal impaction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid use with other drugs that may cause constipation. If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(1) Instruct patients to stop eluxadoline and immediately contact their healthcare provider if they experience severe constipation. Loperamide may be used occasionally for acute management of severe diarrhea, but must be discontinued if constipation develops.(1)

DISCUSSION: In phase 3 clinical trials, constipation was the most commonly reported adverse reaction (8%). Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving eluxadoline doses of 75 mg and 100 mg.(1)

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)

Antiplatelets; Aspirin (> 325 Mg)/Betrixaban

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

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

CLINICAL EFFECTS: Concurrent use of betrixaban 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, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk.(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 betrixaban 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 betrixaban in patients with active bleeding. The anticoagulant effect of betrixaban is expected to persist for at least 72 hours after the last dose.

DISCUSSION: Betrixaban is a factor Xa inhibitor and when taken with agents that effect platelet aggregation and/or other clotting factors increased bleeding episodes can occur.(1,2) 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(>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)

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)

Muscle Relaxants/Opioids (Cough And Cold)

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

MECHANISM OF ACTION: Concurrent use of opioids and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Avoid prescribing opioid-including cough medications for patients taking CNS depressants such as muscle relaxants.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

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/Selected Immunosuppressants

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

MECHANISM OF ACTION: Cyclosporine increases the production of prostaglandin E2 and I2. Prostaglandin E2 has been shown to prevent cyclosporine -induced renal toxicity in animals. NSAIDS and salicylates may increase cyclosporine-induced renal toxicity by blocking the formation of prostaglandins. Concurrent use of everolimus, sirolimus or tacrolimus with NSAIDs or salicylates may result in additive nephrotoxicity.

CLINICAL EFFECTS: Concurrent administration of cyclosporine, everolimus, sirolimus, or tacrolimus and a NSAID or salicylate may result in a decrease in renal function, with or without an alteration in immunosuppressant levels.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid the concurrent use of NSAIDs or salicylates in patients maintained on cyclosporine, everolimus, sirolimus, or tacrolimus. If concurrent therapy is warranted, patients should be monitored for a decrease in renal function. The NSAID or salicylate may need to be discontinued.

DISCUSSION: A decrease in renal function has been reported with concurrent cyclosporine and diclofenac, sulindac, mefenamic acid, ketoprofen, piroxicam, and naproxen. Decreasing the cyclosporine dose without discontinuing the NSAID does not appear to improve renal function. The use of agents which decrease renal function concurrently with everolimus, sirolimus or tacrolimus should be approached with caution. An observational study of 63 inpatient encounters for 57 transplant patients evaluated concurrent use between calcineurin inhibitor (CNI) therapy and NSAID use. Patients were matched to 126 transplant patients on CNI therapy without NSAID use. Patients who received at least one dose of NSAID had a 12.2% rate of treatment emergent acute kidney injury (AKI). The relative risk ratio for AKI in patient exposed to NSAID therapy was 2.20 (95% CI 0.74-6.54). An increase in 48 hour post NSAID exposure serum creatinine above baseline was documented in 65.9% of patients compared to 46% in the non NSAID group (p=0.016). Multivariate analysis revealed changes in serum creatinine at 48 hours after admission were independently associated with age (p=0.008) and NSAID use (p=0.026).(12)

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)

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 Salicylates/Methotrexate (Low Strength Inj, Oral)

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

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 salicylates 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 salicylates and low dose 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 in patients with renal impairment or near the time of methotrexate dosage (in patients receiving weekly therapy). The Australian prescribing information for aspirin DL-lysine states coadministration with methotrexate at doses of 15 mg/week or greater is contraindicated.

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 not linked to this interaction. Other lower-strength aspirin formulations (e.g. headache, cough & cold, opioid combinations) which could be consumed multiple times a day remain linked to this interaction.

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)

Selected Cyp1a2 Substrates/Viloxazine

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

MECHANISM OF ACTION: Viloxazine is a strong inhibitor of CYP1A2 and may increase the total exposure of sensitive CYP1A2 substrates.(1) The FDA defines strong inhibition as an increase in drug area-under-curve (AUC) greater than 5-fold.(2)

CLINICAL EFFECTS: Concurrent use of viloxazine with drugs primarily metabolized by CYP1A2 may lead to elevated drug levels and increase the risk of adverse reactions associated with the CYP1A2 substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Drugs linked to this monograph are moderately sensitive to CYP1A2 inhibition. Coadministration of viloxazine with moderately sensitive CYP1A2 substrates is not recommended. If coadministered, dose reduction of the CYP1A2 substrate may be warranted.(1)

DISCUSSION: Concomitant use of viloxazine significantly increases the total exposure, but not peak exposure, of sensitive CYP1A2 substrates, which may increase the risk of adverse reactions associated with these CYP1A2 substrates. In a study, viloxazine increased the AUC of caffeine by almost 6-fold.(1) Though not designed to evaluate drug interactions, the open-label portion of a pediatric randomized controlled trial looking at the association of riluzole concentrations with efficacy and adverse effects found that fluvoxamine (a strong CYP1A2 inhibitor) increased riluzole concentrations by about 2-fold.(3) CYP1A2 substrates linked to this monograph include: caffeine and riluzole.(2,4)

Selected Moderate And Weak Cyp1a2 Inhibitors/Tizanidine

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

MECHANISM OF ACTION: Moderate and weak CYP1A2 inhibitors may inhibit the metabolism of tizanidine by CYP1A2.(1)

CLINICAL EFFECTS: Concurrent use of moderate and weak CYP1A2 inhibitors may result in elevated levels of and effects from tizanidine, including hypotension, bradycardia, drowsiness, sedation, and decreased psychomotor function.

PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: The US manufacturer of tizanidine states that concurrent use of tizanidine with inhibitors of CYP1A2 should be avoided.(3) If adverse reactions such as hypotension, bradycardia or excessive drowsiness occur, reduce tizanidine dosage or discontinue tizanidine therapy.(3)

DISCUSSION: In a study, cannabidiol 750 mg twice daily (a weak CYP1A2 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a 200 mg single dose of caffeine (a sensitive CYP1A2 substrate) by 15% and 95%, respectively.(1) In a study in 10 healthy subjects, concurrent fluvoxamine, a strong inhibitor of CYP1A2, increased tizanidine Cmax, AUC, and half-life (T1/2) by 12-fold, 33-fold, and 3-fold, respectively. Significant decreases in blood pressure and increases in drowsiness and psychomotor impairment occurred.(3) In a study in 10 healthy subjects, concurrent ciprofloxacin, a strong inhibitor of CYP1A2, increased tizanidine Cmax and AUC by 7-fold and 10-fold, respectively. Significant decreases in blood pressure and increases in drowsiness and psychomotor impairment occurred.(3) Moderate CYP1A2 inhibitors linked to this monograph include: centanafadine, dipyrone, fexinidazole, genistein, methoxsalen, phenylpropanolamine, pipemidic acid, propranolol, rucaparib, and troleandomycin. Weak CYP1A2 inhibitors linked to this monograph include: allopurinol, artemisinin, belumosudil, caffeine, cannabidiol, curcumin, dan-shen, disulfiram, Echinacea, ginseng, parsley, piperine, ribociclib, simeprevir, thiabendazole, and triclabendazole.(4)

Selected Muscle Relaxants/Methadone (Cough And Cold)

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

MECHANISM OF ACTION: Concurrent use of methadone and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of methadone and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Avoid prescribing methadone-including cough and cold medications for patients taking CNS depressants such as muscle relaxants.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Selected Nsaids; Aspirin (>325 Mg)/Pemetrexed

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

MECHANISM OF ACTION: NSAIDs may decrease the clearance of pemetrexed.(1) This decreased clearance may be the result of chronic renal toxicity from NSAIDs or NSAIDs may compete with pemetrexed for tubular secretion.(2)

CLINICAL EFFECTS: Concurrent use of pemetrexed and NSAIDs 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 (creatinine clearance (CrCl) of 45 ml/min to 79 ml/min) and/or patients taking long acting NSAIDs. (1)

PATIENT MANAGEMENT: In patients with normal renal function (CrCl equal to or greater than 80 ml/min), ibuprofen (400 mg 4 times daily) can be administered with pemetrexed. Aspirin in low to moderate doses (325 mg every 6 hours) does not affect the pharmacokinetics of pemetrexed.(1) 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. Ibuprofen should be administered with caution in these patients.(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) If NSAIDs are required, patients should be monitored for pemetrexed toxicity, especially myelosuppression, renal toxicity, and gastrointestinal toxicity.(1)

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 products with greater than 325 mg strength, and aspirin combination products (e.g. opioid-aspirin or cough/cold/allergy products) with a reasonable likelihood of a total daily aspirin dose > or = 1,300 mg per day.

Selected Salicylates/Methotrexate (Oncology-Injection)

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

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 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 in patients with renal impairment or near the time of methotrexate dosage (in patients receiving weekly therapy). The Australian prescribing information for aspirin DL-lysine states coadministration with methotrexate at doses of 15 mg/week or greater is contraindicated.

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 not linked to this interaction. Other lower-strength aspirin formulations (e.g. headache, cough & cold, opioid combinations) which could be consumed multiple times a day remain linked to this interaction.

Theophylline Derivatives/Cimetidine

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

MECHANISM OF ACTION: Cimetidine inhibits the metabolism of theophylline by CYP1A2.(1-10) The duration of cimetidine's inhibitory action is uncertain. Short-term cimetidine therapy appears to reverse rapidly(2) but may persist in prolonged therapy. Increased pentoxifylline serum levels may be the result of an increase in the oral bioavailability of pentoxifylline.(11)

CLINICAL EFFECTS: Concurrent cimetidine and theophylline derivative therapy may result in elevated theophylline derivative concentration levels, prolonged elimination half-life, and decreased clearance.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Theophylline derivative blood levels should be very closely monitored if cimetidine therapy is to be initiated, changed, or discontinued. Theophylline has a narrow therapeutic range; therefore, dosage reductions up to 30-50%(4) should be considered to prevent intoxication when cimetidine therapy is started. Antacids, famotidine, or possibly ranitidine might be more judicious choices than cimetidine in patients receiving theophylline derivatives.

DISCUSSION: It is well documented that cimetidine impairs the elimination of theophylline when the two agents are co-administered to patients.(1-10, 12-22) This interaction has been noted by a variety of routes including continuous intravenous infusion.(22) Reports indicate that with concurrent cimetidine, theophylline plasma concentrations increase, theophylline half-life is prolonged from 29% to 73%(1-3;9,12-14) and theophylline clearance is decreased by 18.5% to 46%.(1-3,9,13,23) Age and smoking do not appear to affect the magnitude of the interaction.(17,18,20) Significant changes can be seen within 24 hours(3,5) and may progress as co-therapy continues.(3) A study involving ten healthy patients demonstrated that concomitant administration of cimetidine significantly decreased the plasma clearance of oxtriphylline.(24) Aminophylline is involved in a similar interaction as theophylline as seen in one case report.(25) In one report cimetidine also decreased the clearance and prolonged the half-life of caffeine.(26,27) A study demonstrated that cimetidine caused a significant increase in plasma levels of pentoxifylline.(11) Information on ranitidine is conflicting. Several studies have shown that ranitidine does not influence theophylline.(9,15,16,19,28,29) One case report noted toxic theophylline levels after ranitidine;(30) however, this case report has been challenged.(31) In another case report, theophylline levels rose from 16.6 mcg/ml to 39.7 mcg/ml(32) when the patient was given ranitidine. Other reports have also noted a reduction in theophylline elimination by ranitidine.(33,34) Famotidine has shown to have no effect on theophylline metabolism in a clinical trial;(35) however, there is one case report of decreased theophylline clearance during famotidine therapy.(36) Dyphylline, a theophylline derivative that is not converted to theophylline in vivo, is not to be expected to interact with cimetidine. A study showed that cimetidine increased the average steady state plasma concentration of pentoxifylline and its metabolite by 25% and 30%, respectively.(37)

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

Anticholinergics/Select Antipsychotics;Select Phenothiazines

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

MECHANISM OF ACTION: Multiple mechanisms may be involved: 1. additive peripheral and CNS blockade of muscarinic receptors. 2. anticholinergic-induced inhibition of gastrointestinal absorption of phenothiazines. 3. antagonism of the dopamine blocking effects of selected antipsychotics and phenothiazines.

CLINICAL EFFECTS: The dopamine blocking effects of selected antipsychotic agents or phenothiazines may be decreased while anticholinergic adverse effects may be increased.

PREDISPOSING FACTORS: The risk for severe anticholinergic toxicities, e.g. delirium, hyperthermia, paralytic ileus is increased in the elderly and in patients on multiple anticholinergic agents.

PATIENT MANAGEMENT: Anticholinergic agents may be required to treat or prevent antipsychotic induced extrapyramidal symptoms. When other indications lead to co-prescribing of the combination, assess patient response to the combination. Review patient medication list for other anticholinergic agents. When needed, decrease the dosage or number of prescribed anticholinergic agents, particularly in the elderly.

DISCUSSION: Although numerous studies have been published regarding a possible interaction between phenothiazines and anticholinergics, the earlier reports were not double-blind or placebo controlled and patients may have received other drugs concomitantly. These earlier investigations reported increased side effects as well as increased, decreased and no effect on the therapeutic outcome. Double-blind studies have also reported conflicting results. Anticholinergic therapy varied from having no effect on phenothiazine concentration or patient outcome, to increasing phenothiazine levels. The discrepancies reported may be due to interpatient variability including age of the patient, type and duration of illness and treatment setting.

Anticholinergics/Topiramate

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

MECHANISM OF ACTION: Topiramate can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2)

CLINICAL EFFECTS: Concurrent use of topiramate with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The manufacturer of topiramate states that caution should be used when topiramate is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered.

DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment.(1) A 64-year old woman developed non-exertional hyperthemia while taking multiple psychiatric medications with topiramate.(2)

Anticholinergics/Zonisamide

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

MECHANISM OF ACTION: Zonisamide can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2)

CLINICAL EFFECTS: Concurrent use of zonisamide with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The UK and US manufacturers of zonisamide state that caution should be used in adults when zonisamide is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity.(1-2) Pediatric and adolescent patients must not take anticholinergic agents (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered.

DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment and resulted in death.(1)

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 (> 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 (>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.

Caffeine-Containing Products/Migalastat

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 unknown.

CLINICAL EFFECTS: Concurrent use of a caffeine-containing product may result in decreased levels and effectiveness of migalastat.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid coadministration of migalastat with caffeine-containing products. Do not administer caffeine-containing products within 2 hours before and 2 hours after taking migalastat.(1)

DISCUSSION: Coadministration of migalastat with caffeine 190 mg decreased the migalastat maximum concentration (Cmax) by 60% and area-under-curve (AUC) by 55%.(1)

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)

Muscle Relaxants/Buprenorphine For Mat

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

MECHANISM OF ACTION: Concurrent use of buprenorphine and muscle relaxants may result in additive CNS depression.(1,2)

CLINICAL EFFECTS: Concurrent use of buprenorphine and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1,2)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Medication assisted treatment (MAT) with buprenorphine is not contraindicated in patients taking CNS depressants; however, discontinuation of CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering may be appropriate. In others, gradual tapering or decreasing to the lowest effective dose of the CNS depressant is appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(3) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing opioid reversal agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(4)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(6) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(7) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(8) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(9) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(10) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(11) While concomitant use of MAT with CNS depressants increases the risk of adverse reactions, barriers to MAT can pose a greater risk of morbidity and mortality due to opioid use disorder.(2)

Muscle Relaxants/Gabapentinoids

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

MECHANISM OF ACTION: Concurrent use of gabapentinoids and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of gabapentinoids and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing muscle relaxants and gabapentinoids to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a gabapentinoid with a muscle relaxant, prescribe a lower initial dose of the gabapentinoid than indicated in the absence of a muscle relaxant and titrate based upon clinical response. If a muscle relaxant is indicated in a patient already taking a gabapentinoid, prescribe a lower dose of the muscle relaxant and titrate based upon clinical response.(1) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1)

DISCUSSION: Clinical trials have shown no pharmacokinetic interaction between pregabalin and muscle relaxants.(2) Among 49 case reports submitted to FDA over a 5 year period (2012-2017), 12 people died from respiratory depression with gabapentinoids. Two randomized, double-blind, placebo-controlled clinical trials in healthy people, three observational studies, and several studies in animals were reviewed. A trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function. Three observational studies showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after surgery. Several animal studies also showed that pregabalin plus opioids can depress respiratory function. Muscle relaxants are expected to have a similar effect when used with gabapentinoids.(1)

Muscle Relaxants/Opioids (Extended Release)

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

MECHANISM OF ACTION: Concurrent use of opioids and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Muscle Relaxants/Opioids (Immediate Release)

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

MECHANISM OF ACTION: Concurrent use of opioids and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Nsaids; Aspirin (Non-Cardioprotective)/Beta-Blockers

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

MECHANISM OF ACTION: Unknown; however, possibly related to inhibition of prostaglandin by NSAIDs.

CLINICAL EFFECTS: The antihypertensive action of beta-blockers may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patient's blood pressure and adjust the dose of the beta-blocker as needed.

DISCUSSION: Concurrent administration of beta-blockers and NSAIDs has been associated with a clinically significant loss in antihypertensive response. The magnitude of the effect of NSAIDs on control of blood pressure by beta-blockers needs to be determined for each anti-inflammatory agent. 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.

Nsaids; Aspirin (Non-Cardioprotective)/Metoprolol

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

MECHANISM OF ACTION: Unknown; however, possibly related to inhibition of prostaglandin by NSAIDs.

CLINICAL EFFECTS: The antihypertensive action of metoprolol may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patient's blood pressure and adjust the dose of metoprolol as needed.

DISCUSSION: Concurrent administration of metoprolol and NSAIDs has been associated with a clinically significant loss in antihypertensive response. The magnitude of the effect of NSAIDs on control of blood pressure by beta-blockers needs to be determined for each anti-inflammatory agent. 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.

Nsaids; Salicylates/Aldosterone Receptor Antag; Baxdrostat

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

MECHANISM OF ACTION: The exact mechanism is unknown; however, nonsteroidal anti-inflammatory (NSAID) inhibition of prostaglandins may allow baxdrostat, eplerenone, finerenone, or spironolactone-induced nephrotoxicity or hyperkalemia to occur in some patients.(1-4) In some patients, NSAIDs may reduce the diuretic, natriuretic and antihypertensive effects of baxdrostat, eplerenone, finerenone, or spironolactone.(1-4)

CLINICAL EFFECTS: Concurrent use of baxdrostat, eplerenone, finerenone, or spironolactone with NSAIDs may result in renal failure or hyperkalemia. The effects of the diuretic, natriuretic, or antihypertensive effects of baxdrostat, eplerenone, finerenone, or spironolactone may be decreased.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, avoid concurrent therapy with baxdrostat, eplerenone, finerenone, or spironolactone with NSAIDs. If these agents are used concurrently, monitor renal function and serum electrolytes. If decreased renal function or hyperkalemia develops, discontinue both agents. The manufacturer of eplerenone recommends checking serum potassium and serum creatinine within 3-7 days of concurrent therapy with NSAIDs.(1) The manufacturer of spironolactone states concurrent use with NSAIDs may lead to severe hyperkalemia and extreme caution should be used during concurrent therapy.(2)

DISCUSSION: Although acute renal failure and hyperkalemia have only been reported in studies and case reports involving indomethacin, diclofenac, flurbiprofen, and ibuprofen with either triamterene or amiloride, the proposed mechanism suggests that all nonsteroidal anti-inflammatory agents may be capable of this interaction with all potassium-sparing diuretics. Patients receiving diuretics are at an increased risk of NSAID-induced renal failure.

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/Drospirenone

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

MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. NSAIDs may also increase potassium levels.(1)

CLINICAL EFFECTS: Concurrent use of drospirenone and NSAIDs may result in hyperkalemia.(1)

PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium supplements, ACE inhibitors, angiotensin II receptor antagonists, heparin, and potassium-sparing diuretics may increase potassium levels.(1)

PATIENT MANAGEMENT: Patients receiving drospirenone with a NSAID should have their serum potassium level checked during the first treatment cycle.(1)

DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of NSAIDs may also increase potassium levels.(1) Occasional or chronic use of NSAIDs was not restricted in clinical trials of drospirenone.(1)

Nsaids; Salicylates/Lithium

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

MECHANISM OF ACTION: Decreased renal excretion of lithium, possibly resulting from NSAID-induced prostaglandin inhibition.

CLINICAL EFFECTS: May observe increased lithium toxicity.

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: renal impairment or worsening of existing renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics). Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: The magnitude of this interaction is highly variable. Patients with predisposing factors, e.g. dehydration, renal impairment, or concurrent use of other agents which may impair lithium elimination, are expected to have a higher risk for lithium toxicity. If both drugs are administered, monitor plasma lithium levels and observe the patient for signs and symptoms of lithium toxicity or changes in renal function. Full effects of the addition or an increase in NSAID dose may not be seen for one to two weeks. Adjust the dose of lithium accordingly. If lithium is to be started in a patient stabilized on chronic NSAID therapy, consider starting with a lower lithium dose and titrate slowly as half-life may be prolonged. Monitor lithium concentrations until stabilized on the combination. Counsel the patient to contact their prescriber before starting an OTC NSAID. Assure that patients are familiar with signs and symptoms of lithium toxicity (e.g. new or worsening tremor, nausea/vomiting, diarrhea, ataxia, or altered mental status) and to report signs and symptoms of toxicity.

DISCUSSION: Numerous studies and case reports have been documented that administration of a NSAID to a patient stabilized on lithium therapy may result in increased serum lithium levels and possible toxicity. Full effects may take 1 to 2 weeks to develop and may persist for a week after the NSAID is discontinued.

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)

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)

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 Muscle Relaxants/Levomethadyl

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

MECHANISM OF ACTION: Concurrent use of levomethadyl and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of levomethadyl and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics ho are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Selected Muscle Relaxants/Methadone (Immediate Release)

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

MECHANISM OF ACTION: Concurrent use of methadone and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of methadone and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing methadone with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Selected Muscle Relaxants/Selected Opioids For Mat

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

MECHANISM OF ACTION: Concurrent use of diacetylmorphine or methadone and muscle relaxants may result in additive CNS depression.(1-3) Levomethadone is an enantiomer of methadone.(4)

CLINICAL EFFECTS: Concurrent use of diacetylmorphine or methadone and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1-3)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Medication assisted treatment (MAT) with diacetylmorphine or methadone is not contraindicated in patients taking CNS depressants; however, discontinuation of CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering may be appropriate. In others, gradual tapering or decreasing to the lowest effective dose of the CNS depressant is appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's diacetylmorphine or methadone treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(5) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(6)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(7) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(8) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(9) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(10) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(11) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(12) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(13) While concomitant use of MAT with CNS depressants increases the risk of adverse reactions, barriers to MAT can pose a greater risk of morbidity and mortality due to opioid use disorder.(2)

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 Nsaids; Salicylates/Triamterene; Amiloride

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

MECHANISM OF ACTION: The exact mechanism is unknown; however, nonsteroidal anti-inflammatory (NSAID) inhibition of prostaglandins may allow triamterene or amiloride- induced nephrotoxicity or hyperkalemia to occur in some patients.

CLINICAL EFFECTS: Possible renal failure or hyperkalemia.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, avoid concurrent therapy with triamterene or amiloride with NSAIDs. If these agents are used concurrently, monitor renal function and serum electrolytes. If decreased renal function or hyperkalemia develops, discontinue both agents.

DISCUSSION: Although acute renal failure and hyperkalemia have only been reported in studies and case reports involving indomethacin, diclofenac, flurbiprofen, and ibuprofen with either triamterene or amiloride, the proposed mechanism suggests that all nonsteroidal anti-inflammatory agents may be capable of this interaction. Patients receiving diuretics are at an increased risk of NSAID-induced renal failure.

Selected Salicylates/Heparin

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

MECHANISM OF ACTION: Additive prolongation of bleeding time.

CLINICAL EFFECTS: Increased risk of bleeding which may extend for several days beyond discontinuation of salicylates.

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. If this combination is used, monitor patients 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. A non-acetylated salicylate may be used to avoid antiplatelet activity. 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. Single ingredient aspirin or buffered aspirin products with strengths < or = 325 mg and combination aspirin products which are used to treat cardiovascular disease (e.g. aspirin+statins, aspirin+dipyridamole) are not included in this interaction.

DISCUSSION: This interaction is likely to occur.

Selected Xanthine Derivatives/Fluvoxamine

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

MECHANISM OF ACTION: Fluvoxamine may inhibit the metabolism of the xanthine derivatives by CYP1A2.(1,2)

CLINICAL EFFECTS: Concurrent use of fluvoxamine and xanthine derivatives may result in elevated levels of the xanthine derivative and toxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of fluvoxamine recommends that the dose of theophylline be decreased to one-third of the usual daily dose in patients receiving concurrent therapy. Theophylline levels should be closely monitored and patients should be observed for signs of theophylline toxicity.(3) The dosage of theophylline may need to be adjusted if fluvoxamine is discontinued. Patients receiving fluvoxamine should be instructed to consume caffeine containing beverages and/or medications with caution.

DISCUSSION: In a study in 12 healthy subjects, the administration of a single dose of theophylline ethylenediamine (300 mg) on Day 4 of fluvoxamine (50 mg Day 1, 100 mg daily Days 2-6) decreased theophylline total clearance by 70%. The half-life of theophylline increased 2.3-fold (from 6.6 hours to 22 hours).(1) In a study in 12 healthy males, the administration of a single dose of theophylline (375 mg given as 442 mg aminophylline) with fluvoxamine (50 mg twice daily at steady state) decreased theophylline clearance by 3-fold.(3) Fluvoxamine has been shown to inhibit the metabolism of theophylline in vitro.(2) There are four case reports of theophylline toxicity during concurrent fluvoxamine therapy.(4-7) In a study in eight healthy subjects, the administration of a single dose of caffeine (200 mg) on Day 8 of fluvoxamine (50 mg daily Days 1-4, 100 mg daily Days 5-12) decreased caffeine clearance by 80%. The half-life of caffeine increased 5.2-fold (from 5 hours to 31 hours).(8) In a study, seven reports of impaired caffeine clearance were reported in patients whom received single 250mg doses of caffeine together with fluvoxamine (four doses of 100mg over two days). Fluvoxamine reduced the apparent oral clearance of caffeine by 91.3%, and prolonged its elimination half-life by 11.4-fold (from 4.9 hours to 56 hours). There were no changes in the pharmacodynamic effects of caffeine.(9)

Theophylline Derivatives/Lithium

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

MECHANISM OF ACTION: Theophylline derivatives increase the renal excretion of lithium.

CLINICAL EFFECTS: Decreased levels of lithium which may result in decreased clinical effectiveness.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lithium levels and response should be monitored in patients in whom theophylline therapy is initiated or withdrawn. Patients receiving concurrent therapy should be monitored for increased adverse effects.

DISCUSSION: In a study involving ten volunteers, the concurrent administration of lithium and theophylline resulted in a significant decrease in lithium serum levels. Upon discontinuation of theophylline, lithium levels and half-life increased, and the clearance of lithium decreased. Individual variability in these parameters was significant. The overall incidence of adverse effects was significantly greater with concurrent therapy including restlessness, tremor, and anorexia. In another study in ten normal subjects, lithium (1200 mg/day for seven days) was administered and it was reported that theophylline infusion (dosed to achieve a plasma level of 14 mcg/ml) increased lithium clearances by 51%. In a case report, reduced lithium levels as well as worsening of manic symptoms occurred after increasing doses of theophylline were administered. It has been shown that aminophylline increases the lithium/creatinine clearance ratio, which may result in decreased serum lithium below the therapeutic level. Caffeine withdrawal has been reported to increase lithium levels in several case reports. This interaction is most important to consider in patients who have been previously sensitive to relapse with decreased lithium levels and in whom levels are maintained at the therapeutic/prophylactic borderline.

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• Achalasia of esophagus
• Aspirin exacerbated respiratory disease
• Benign prostatic hyperplasia
• Bladder outflow obstruction
• Duodenal obstruction
• Gastrointestinal hemorrhage
• Glaucoma
• Hemolytic anemia from pyruvate kinase and g6PD deficiencies
• Hemorrhage
• Increased risk of bleeding due to coagulation disorder
• Lactation
• Myasthenia gravis
• Pregnancy
• Pyloroduodenal obstruction
• Reye's syndrome
• Stenosing peptic ulcer

• Alcohol use disorder
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Gastrointestinal ulcer
• Hypoprothrombinemia
• Necrotizing enterocolitis
• Peptic ulcer
• Salicylate intoxication
• Severe hepatic disease
• Systemic mastocytosis
• Thrombocytopenic disorder
• Thrombotic thrombocytopenic purpura

• Acute decompensated heart failure
• Anemia
• Cardiac arrhythmia
• Chronic myocardial ischemia
• Disease of liver
• Gout
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Nasal polyp
• Seizure disorder
• Tachyarrhythmia
• Vitamin K deficiency

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Less Frequent

• Ocular hypertension
• Palpitations
• Syncope
• Tachycardia

Rare or Very Rare

• Acute eruptions of skin
• Allergic dermatitis
• Anaphylaxis
• Anemia
• Angioedema
• Aplastic anemia
• Blistering skin
• Bronchospastic pulmonary disease
• Bullous dermatitis
• DRESS syndrome
• Drug-induced hepatitis
• Dyspnea
• Exfoliative dermatitis
• Extrasystoles
• Gastrointestinal hemorrhage
• Gastrointestinal perforation
• Gastrointestinal ulcer
• Hallucinations
• Hemolytic anemia
• Hemorrhage
• Interstitial nephritis
• Intracranial bleeding
• Leukopenia
• Pancytopenia
• Platelet aggregation inhibition
• Purpura
• Rectal bleeding
• Renal papillary necrosis
• Seizure disorder
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Urticaria
• Wheezing

More Frequent

• Abdominal pain with cramps
• Gastric acid hypersecretory conditions
• Gastrointestinal irritation
• Gastrointestinal irritation
• Heartburn
• Insomnia
• Nausea
• Nervousness
• Vomiting

Less Frequent

• Abdominal pain with cramps
• Acute cognitive impairment
• Blurred vision
• Constipation
• Diplopia
• Dizziness
• Drowsy
• Dysuria
• Excitement
• Headache disorder
• Insomnia
• Nausea
• Nervousness
• Tremor
• Visual changes
• Vomiting
• Xerostomia

Rare or Very Rare

• Abnormal hepatic function tests
• Accidental fall
• Agitation
• Anorexia
• Anticholinergic toxicity
• Black tarry stools
• Drowsy
• Dyspepsia
• Ecchymosis
• Epistaxis
• Erythema
• Gastritis
• Gingival bleeding
• Hematoma
• Hyperesthesia
• Hyperglycemia
• Irritability
• Muscle weakness
• Nausea
• Pruritus of skin
• Scotomata
• Skin rash
• Symptoms of anxiety
• Tachycardia
• Tinnitus
• Tinnitus
• Tremor
• Vomiting

No enhanced messaging available.

No enhanced messaging available.

Safe use of orphenadrine during pregnancy has not been established. The drug has caused adverse effects in animals at high doses. In one reproduction study in rats receiving 5 times the human daily dose, degenerative changes in the urinary bladder occurred in 5% of the offspring; in a subsequent study using 12 times the human daily dose, this abnormality was not observed. Orphenadrine should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

There are no adequate and well-controlled studies in pregnant women. In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained-release pellets at 50 mg/kg (less than the maximum IV loading dose for neonates on a mg/m2 basis) during the period of organogenesis caused a low incidence of cleft palate and exencephaly in fetuses. Based on data from a large retrospective epidemiologic study and from a large retrospective case-control study in humans, it appears that use of caffeine during pregnancy has little, if any, effect on the outcome of pregnancy. Although caffeine use during pregnancy does not appear to be associated with substantial risk, most clinicians recommend that pregnant women avoid or limit their consumption of foods, beverages, and drugs containing caffeine, since caffeine crosses the placenta.

Since it is not known if orphenadrine is distributed into milk, the drug should be used with caution in nursing women.

Caffeine is distributed into the milk of nursing women. Milk-to-plasma ratios of 0.5-0.76 have been reported. The amount of caffeine ingested from usual quantities of caffeinated beverages is considered compatible with breast-feeding; however, caffeine may accumulate in nursing infants following moderate to heavy maternal consumption of caffeine, resulting in irritability and poor sleeping patterns.

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