Zynrelef (bupivacaine/meloxicam)

No dosing information is available for this tab.

Bupivacaine/meloxicam is a sterile extended-release solution that is administered by soft tissue or periarticular instillation; the drug should not be administered via epidural, intrathecal, intravascular, or intra-articular routes, or used in regional nerve block, or pre-incisional or pre-procedural locoregional anesthetic techniques. Limit exposure to articular cartilage due to the potential risk of chondrolysis. Bupivacaine/meloxicam extended-release solution is intended for single-dose administration only.

Bupivacaine/meloxicam solution should only be prepared and administered using the components provided in the Zynrelef(R) kit.

Allow the site to dry after application of a topical antiseptic such as povidone and iodine before administering bupivacaine/meloxicam.

Attach vented vial spike to vial. Fill syringe with air and attach to vial spike. Invert, inject air, then withdraw the required volume. Solution is very thick; may take a few minutes to withdraw.

Apply without a needle into the surgical site using the manufacturer-supplied Luer Lock syringe and applicator tip following final irrigation and suctioning and prior to suturing of each layer when multiple tissue layers are involved. When the solution comes in contact with moisture in the tissues, it becomes more viscous, allowing it to stay in place.

The size of provided syringe to be used (3 mL or 12 mL) will depend on the required dose; consult prescribing information for additional details. Prepare product immediately prior to use and apply syringe tip cap until product delivery.

Only apply to tissue layers below the skin incision and not directly onto the subdermal layer or the skin. Minimize administration near the incision line. Wipe off excess drug from the skin prior to suturing to prevent loosening of sutures. The viscosity of bupivacaine/meloxicam may result in loosening or untying of knots; consult prescribing information for additional details regarding surgical technique.

Bupivacaine/meloxicam solution for soft tissue or periarticular instillation is commercially available in the following strengths of bupivacaine/meloxicam: 400 mg/12 mg in 14 mL, 300 mg/9 mg in 10.5 mL, 200 mg/6 mg in 7 mL, and 60 mg/1.8 mg in 2.3 mL. The solution is a sterile, clear, pale-yellow to yellow viscous liquid. Do not use if particulate matter or discoloration is present.

Do not mix bupivacaine/meloxicam with water, saline, or other local anesthetics as the product will become more viscous and difficult to administer. Avoid additional use of local anesthetics within 96 hours following administration.

Store vials at 20-25degreesC (excursions permitted between 15-30degreesC). Protect from moisture and light. If vials are removed from the kit, store at controlled room temperature protected from light.

No dosing information is available for this tab.

No dosing information is available for this tab.

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)

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.

Selected Nephrotoxic Agents/Bacitracin

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: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3)

CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3)

PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1)

PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3)

DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3)

Selected Nephrotoxic Agents/Cidofovir

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: Cidofovir is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-3)

CLINICAL EFFECTS: Concurrent use of cidofovir with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian,(1) UK,(2) and US(3) manufacturers of cidofovir state that concurrent administration of potentially nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin. These agents should be discontinued at least 7 days before the administration of cidofovir.

DISCUSSION: The safety of cidofovir has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of cidofovir.(1-3)

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

Acetaminophen; Nsaids/Alprostadil

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

MECHANISM OF ACTION: Alprostadil is a prostaglandin E1 product used to maintain patency of a patent ductus arteriosus (PDA).(1) Acetaminophen and nonsteroidal anti-inflammatory (NSAID) agents inhibit prostaglandins and may be used for PDA closure in addition to pain/fever management.(2-4)

CLINICAL EFFECTS: Simultaneous administration of acetaminophen or NSAIDs may result in decreased clinical effects from alprostadil, including reduction in PDA.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent administration of acetaminophen or NSAIDs in patients on alprostadil for maintaining patency of a patent ductus arteriosus (PDA).(1)

DISCUSSION: NSAIDs and acetaminophen are used as management for patent ductus arteriosus (PDA) closure.(2-4) Alprostadil is used to maintain patency of a PDA.(1) In a case report, a 37-week gestational age neonate with cardiac defects required alprostadil therapy for PDA patency. After multiple doses of acetaminophen for pain, an echocardiogram showed reduction of the PDA requiring increased doses of alprostadil. Additional acetaminophen was discontinued. Follow up echocardiogram showed successful reversal of PDA reduction and alprostadil dose was reduced.(5)

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)

Long-Acting Bupivacaine/Local Anesthetics

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

MECHANISM OF ACTION: Concurrent use of other local anesthetics or use of other local anesthetics within 96 hours following long-acting bupivacaine may result in additive neurologic and cardiovascular effects. Use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine may also increase the risk of methemoglobinemia.(1,2) Non-liposomal bupivacaine may impact the pharmacokinetic and/or physicochemical properties of the liposomal formulation when administered in the same syringe or used simultaneously unless the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Local anesthetics other than bupivacaine may trigger the immediate release of bupivacaine from the liposomal formulation when administered together locally.(1)

CLINICAL EFFECTS: Concurrent or use of local anesthetics with 96 hours of use of long-acting bupivacaine may result in neurologic and cardiovascular toxicity. Use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine may also result in methemoglobinemia.(1,2) Non-liposomal bupivacaine may impact the pharmacokinetic and/or physicochemical properties of the liposomal formulation when administered in the same syringe or used simultaneously unless the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Local anesthetics other than bupivacaine may trigger the immediate release of bupivacaine from the liposomal formulation when administered together locally.(1)

PREDISPOSING FACTORS: Use of additional agents that are associated with methemoglobinemia may further increase the risk of methemoglobinemia.(1) Patients who are at increased risk of developing methemoglobinemia include those with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.(1)

PATIENT MANAGEMENT: Avoid the use of other local anesthetics within 96 hours following the administration of long-acting bupivacaine. In patients for whom use is required, monitor for neurologic and cardiovascular effects. Also monitor for methemoglobinemia with use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine.(1,2) Non-liposomal bupivacaine may be administered in the same syringe as bupivacaine liposomal or injected immediately before bupivacaine liposomal as long as the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Lidocaine may be administered 20 minutes or more prior to bupivacaine. It is unknown if other local anesthetics may be used without compromising the release characteristic of bupivacaine liposomal.(1)

DISCUSSION: Concurrent use of other local anesthetics or use of other local anesthetics within 96 hours following long-acting bupivacaine may result in additive neurologic and cardiovascular effects. Use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine may also increase the risk of methemoglobinemia.(1,2) Non-liposome bupivacaine may impact the pharmacokinetic and/or physicochemical properties of the liposomal formulation when administered in the same syringe or used simultaneously unless the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Local anesthetics other than bupivacaine may trigger the immediate release of bupivacaine from the liposomal formulation when administered together locally. Lidocaine may be administered 20 minutes or more prior to bupivacaine. It is unknown if other local anesthetics may be used without compromising the release characteristic of bupivacaine liposomal.(1)

Non-Steroidal Anti-Inflammatory Drugs/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. Inotersen can also cause glomerulonephritis and renal toxicity. NSAIDs can impair thromboxane-dependent platelet aggregation by blocking the formation of thromboxane A2. Concurrent administration with NSAIDs may also result in additive or synergistic effects on renal function.(1)

CLINICAL EFFECTS: Concurrent use of inotersen with NSAIDs may result in additive or synergistic effects, including fatal and non-fatal intracranial hemorrhage, or renal toxicity.(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. Patients with pre-existing renal impairment.

PATIENT MANAGEMENT: Inotersen should be administered with caution in patients receiving NSAIDs. 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 NSAID. 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. Monitor renal function closely.

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) The safety of inotersen has not been studied in patients receiving other known potentially nephrotoxic agents.(1) Inotersen is only available through a Tegsedi REMS program because of the risk of severe thrombocytopenia and the risk of glomerulonephritis.(1)

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/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 and/or other clotting factors increased bleeding episodes can occur.(1,2)

CLINICAL EFFECTS: Concurrent use of dabigatran with NSAIDs or salicylates may result in additive or synergistic effects resulting in unwanted bleeding episodes.(1)

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-glycoprotein inhibitors, patient older than 74 years, coexisting conditions (e.g. recent trauma, thrombocytopenia, advanced liver disease), use of drugs associated with bleeding risk (e.g. other anticoagulants, antiplatelets, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)), and patient weight less than 50 kg. (1-3) Risk of GI bleed may be increased in patients who are of older age, in poor health status, who use alcohol or smoke, with longer duration of NSAID use, and with prior history of peptic ulcer disease and/or GI bleeding.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy for signs of blood loss and promptly evaluate patients with any symptoms. Discontinue dabigatran in patients with active pathological 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 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: 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) A post hoc analysis of nonselective NSAIDs in the RE-LY study (compared dabigatran 150 and 110 mg twice daily with warfarin in atrial fibrillation) assessed clinical outcomes by comparing nonselective NSAID use (at least once during trial) with no NSAID use in 2279 patients. The use of NSAIDs was associated an increased risk of major bleeding (hazard ratio (HR) 1.68), gastrointestinal major bleeding (HR 1.81), stroke or systemic embolism (HR 1.50), and hospitalization (HR 1.64).(22)

Nsaids; Salicylates/Selected Platelet Aggregation Inhibitors

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

MECHANISM OF ACTION: Abciximab, cangrelor, cilostazol, clopidogrel, dipyridamole, eptifibatide, prasugrel, ticagrelor, vorapaxar and NSAIDs or salicylates inhibit platelet aggregation.

CLINICAL EFFECTS: Concurrent use of platelet aggregation inhibitors and NSAIDs or salicylates may increase the risk of 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, other 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. Risk increases as the number of risk factors increases.

PATIENT MANAGEMENT: Use caution when administering platelet aggregation inhibitors with NSAIDs or salicylates.(1-5) It would be prudent to monitor patients more closely during concurrent therapy and to use the lowest NSAID or salicylate dose possible. If concurrent therapy is warranted, 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. 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 2010 ACCF/ACG/AHA Consensus guidelines recommend the use of proton pump inhibitors (PPIs) in patients with multiple risk factors for GI bleeding who require antiplatelet therapy. However, esomeprazole and omeprazole should be avoided with clopidogrel as they are expected to reduce the effectiveness of clopidogrel. Use of other PPIs should be approached with caution, as they may reduce the effectiveness of clopidogrel.

DISCUSSION: Because of the increased risk of bleeding, caution is warranted when using this combination. In a nationwide cohort study, patients were evaluated for thromboembolic cardiovascular and clinically relevant bleeding events with concurrent antithrombotic and ongoing NSAID treatment. A total of 108,232 patients were followed for a mean of 2.3 +/- 1.8 years after diagnosis of myocardial infarction. Concomitant NSAID treatment significantly increased the risk for cardiovascular events (hazard ratio (HR) 6.96; 95% CI 6.24 - 6.77; p<0.001) and bleeding events (HR 4.08; 95% CI 3.51 - 4.73; p<0.001) compared to no NSAID treatment. NSAIDs were further evaluated and revealed the use of celecoxib (HR: 4.65; 95% CI: 3.17 to 6.82; p < 0.001, and 3.44; 95% CI: 2.20 to 5.39; p < 0.001, respectively) and meloxicam (HR: 3.03; 95% CI: 1.68 to 5.47; p < 0.001, and 2.80; 95% CI: 1.40 to 5.60; p < 0.001, respectively) had the lowest risk for cardiovascular and bleeding events, receptively.

Nsaids;Salicylates/Apixaban;Betrixaban;Edoxaban;Rivaroxaban

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

MECHANISM OF ACTION: Concurrent use of apixaban(1-4), betrixaban(7), edoxaban(5), or rivaroxaban(6) and nonsteroidal antiinflammatory agents (NSAIDs) or salicylates may result in additive increased risk of bleeding.

CLINICAL EFFECTS: Concurrent use of apixaban(1), betrixaban(7), edoxaban(5), or rivaroxaban(2) with NSAIDs or salicylates may result in unwanted bleeding episodes.

PREDISPOSING FACTORS: Bleeding risk may be increased in patients with renal impairment and in patients older than 75 years. 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., other 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: Approach concurrent therapy with apixaban(1-4), betrixaban(7), edoxaban(5), or rivaroxaban(6) with caution. 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: In a study, naproxen (500 mg) increased apixaban (10 mg) area-under-curve (AUC) and maximum concentration (Cmax) by 1.5-fold an 1.6-fold, respectively, with corresponding increases in clotting tests. There were no changes in the effect of naproxen on arachidonic acid-induced platelet aggregation, no clinically relevant changes in bleeding times, or naproxen pharmacokinetics.(1) In a single dose study, there were no pharmacokinetic or pharmacodynamic interactions between rivaroxaban and naproxen.(6) Although effects seen in the above studies were limited, NSAIDs are known to increase bleeding and may further increase the risk of bleeding with these agents.(1-6) In edoxaban clinical studies, concomitant use of low-dose aspirin (less than or equal to 100 mg/day) or thienopyridines, and NSAIDs was permitted and resulted in increased rates of clinically relevant bleeding.(5) In a study of 34 healthy subjects administered edoxaban 60 mg daily and naproxen 500 mg daily, bleeding time increased by 2.08-fold from baseline on the combination, compared to a 1.23-fold increase with naproxen alone and 1.7-fold increase on edoxaban alone.(8) 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 ibuprofen resulted in a ratio of rate ratios (RR) (95% CI) of 5.16 (3.0-8.85); apixaban and celecoxib ratio of RR 1.8 (1.06-3.06); rivaroxaban and etodolac ratio of RR 2.47 (1.18-4.22); rivaroxaban and naproxen ratio of RR 1.89 (1.12-1.43); and rivaroxaban and ibuprofen ratio of RR 1.68 (1.29-4.44).(9)

Selected Nephrotoxic Agents/Colistimethate

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

MECHANISM OF ACTION: Colistimethate can cause nephrotoxicity.(1,2) Concurrent administration of other nephrotoxic agents may result in an increased risk of nephrotoxicity.(1) It is suspected that cephalothin interferes with the excretion of colistimethate resulting in enhanced nephrotoxicity.(2,3)

CLINICAL EFFECTS: Concurrent use of colistimethate with other nephrotoxic agents may result in additive nephrotoxic effects.

PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include higher cumulative doses of colistimethate, longer treatment duration, hypovolemia, and critical illness.

PATIENT MANAGEMENT: Concurrent use of potentially nephrotoxic agents with colistimethate should be avoided.(1,2) If concurrent use is necessary, it should be undertaken with great caution.(1)

DISCUSSION: In a case control study of 42 patients on intravenous colistimethate sodium, NSAIDs were identified as an independent risk factor for nephrotoxicity (OR 40.105, p=0.044).(4) In 4 case reports, patients developed elevated serum creatinine and blood urea nitrogen following concurrent colistimethate and cephalothin (3 patients) or when colistimethate followed cephalothin therapy (1 patient).(3) A literature review found that individual nephrotoxic agents, including aminoglycosides, vancomycin, amphotericin, IV contrast, diuretics, ACE inhibitors, ARBs, NSAIDs, and calcineurin inhibitors, were not consistently associated with additive nephrotoxicity when used with colistimethate. However, when multiple agents (at least 2 additional potential nephrotoxins) were used concurrently, there was a significant correlation to colistimethate nephrotoxicity.(5)

Selected Nephrotoxic Agents/Foscarnet

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

MECHANISM OF ACTION: Foscarnet is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1) Concurrent intravenous pentamidine may also result in hypocalcemia.(1)

CLINICAL EFFECTS: Concurrent use of foscarnet with nephrotoxic agents such as acyclovir, adefovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, non-steroidal anti-inflammatory agents, intravenous pentamidine, tacrolimus, tenofovir, vancomycin and voclosporin may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of foscarnet state that concurrent administration of potentially nephrotoxic agents such as acyclovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, tacrolimus, and intravenous pentamidine should be avoided.(1) Other nephrotoxic agents include adefovir, capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, non-steroidal anti-inflammatory agents, streptozocin, tenofovir, vancomycin and voclosporin. If concurrent therapy is warranted, monitor renal function closely. In patients receiving concurrent foscarnet and pentamidine, also monitor serum calcium levels and instruct patients to report severe muscle spasms, mental/mood changes, and/or seizures.(1)

DISCUSSION: The safety of foscarnet has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of foscarnet.(1)

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.

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

Agents With Hyponatremia Risk/Desmopressin

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

MECHANISM OF ACTION: Carbamazepine, chlorpromazine, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants increase the risk of hyponatremia.(1-3)

CLINICAL EFFECTS: Concurrent use may increase the risk of hyponatremia with desmopressin.(1-3)

PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (glucocorticoids, loop diuretics).

PATIENT MANAGEMENT: The concurrent use of agents with a risk of hyponatremia with desmopressin may increase the risk of hyponatremia. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1)

DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4)

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/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)

Nsaids/Erlotinib

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: Concurrent use of NSAIDs may increase the risk of gastrointestinal bleeding and/or perforation in patients receiving erlotinib. Fatalities have been reported.(1)

PREDISPOSING FACTORS: Patients with a history of peptic ulceration or diverticular disease or who are receiving concomitant anti-angiogenic, corticosteroids, and/or taxane-based chemotherapy may be an increased risk of gastrointestinal perforation.(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.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy for signs of gastrointestinal bleeding and/or perforation. Discontinue erlotinib in patients who develop gastrointestinal perforation.(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. 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: Infrequent cases of gastrointestinal bleeding were reported during erlotinib trials. Some cases were associated with NSAID administration.(1) In a phase II trial of concurrent bevacizumab plus erlotinib, 2 of 13 patients suffered fatal gastrointestinal perforations.(2) In another phase II trial of concurrent bevacizumab with erlotinib, 1 of 104 patients died of gastrointestinal perforation.(3)

Nsaids/Heparins

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

MECHANISM OF ACTION: Heparin inhibits thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin.(1) NSAIDs inhibit coagulation by interfering with platelet-aggregation, while inhibition of prostaglandin synthesis increases the risk for gastrointestinal bleeding.

CLINICAL EFFECTS: Concurrent use of heparin and an NSAID may increase the risk for bleeding.(1,2)

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., other 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 recommend caution and monitoring when using this combination of drugs.(1,2) 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 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: Based upon drug mechanisms of action, careful monitoring would be prudent.

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)

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 Nephrotoxic Agents/Adefovir

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

MECHANISM OF ACTION: Recommended doses of adefovir have been associated with delayed nephrotoxicity.(1-4) Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1)

CLINICAL EFFECTS: Concurrent use of adefovir with nephrotoxic agents such as intravenous aminoglycosides, amphotericin B, cyclosporine, tacrolimus,tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, intravenous pentamidine, and streptozocin.

PREDISPOSING FACTORS: Patients with pre-existing renal impairment(1,2) or receiving multiple nephrotoxic agents appear to be at greater risk for nephrotoxicity.

PATIENT MANAGEMENT: Evaluate renal function prior to initiation of concurrent therapy and continue renal function monitoring during therapy. Dose adjustments may be required for impaired renal function. Weigh the risks and benefits of concurrent therapy in patients with treatment-emergent nephrotoxicity.

DISCUSSION: Because of the known risks for adefovir nephrotoxicity, particularly at higher than recommended doses, the safety of adefovir has not been studied in patients receiving other known potentially nephrotoxic agents.

Selected Nephrotoxic Agents/Cisplatin

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

MECHANISM OF ACTION: The nephrotoxic effects of aminoglycosides or non-steroidal anti-inflammatory drugs (NSAIDs) may be additive to those of cisplatin.

CLINICAL EFFECTS: The concurrent administration of amikacin, gentamicin, tobramycin, or NSAIDs with cisplatin may result in additive nephrotoxic effects.(1,2,5,6)

PREDISPOSING FACTORS: Pre-existing renal insufficiency, advanced age, dehydration may increase the risk of nephrotoxicity.(1,5,6)

PATIENT MANAGEMENT: The US labeling for aminoglycosides and cisplatin states that the concurrent use of aminoglycosides and cisplatin should be avoided.(1,3,4,6) Inform patients that concurrent cisplatin and aminoglycosides or NSAIDs can cause nephrotoxicity and that renal function and electrolyte monitoring during treatment is necessary.(2)

DISCUSSION: The US manufacturers of amikacin, gentamicin and tobramycin state that since the nephrotoxic effects of these medications may be additive, avoid concurrent or sequential use of other neurotoxic and/or nephrotoxic agents including cisplatin.(1,3,6)

Selected Nephrotoxic Agents/Immune Globulin Iv (Igiv)

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

MECHANISM OF ACTION: Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, can cause renal dysfunction, acute renal failure, osmotic nephrosis, and/or death. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-4)

CLINICAL EFFECTS: Concurrent use of Immune Globulin Intravenous (IGIV) products with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, non-steroidal anti-inflammatory agents, tenofovir, and vancomycin may result in renal toxicity.(1-4) Other nephrotoxic agents include capreomycin, gallium nitrate, and streptozocin.

PREDISPOSING FACTORS: Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs.(1-4) Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose.(3-4)

PATIENT MANAGEMENT: For patients at risk of renal dysfunction or renal failure, the US manufacturers of Immune Globulin Intravenous (IGIV) products recommends administration at the minimum dose and infusion rate practicable; ensure adequate hydration in patients before administration; and monitor renal function and urine output with assessment of blood urea nitrogen (BUN) and serum creatinine before initial infusion and at regular intervals during therapy.(1-3) Concurrent administration of potentially nephrotoxic agents should be avoided.(1) Review prescribing information for IGIV product to be administered for sucrose content. If concurrent therapy is warranted, monitor renal function closely. In high risk patients, consider selecting an IGIV product that does not contain sucrose.

DISCUSSION: The safety of Immune Globulin Intravenous (IGIV) has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is a major toxicity of IGIV products.(1-3) A review of the FDA renal adverse events (RAEs) (i.e. acute renal failure or insufficiency) from June 1985 to November 1998 identified 120 reports worldwide associated with IGIV administration. In the US, the FDA received 88 reports of cases with clinical and/or laboratory findings consistent with RAE (i.e. increased serum creatinine, oliguria, and acute renal failure). Patient cases involved a median age of 60.5 years and 55% were male. Of the 54 patients who developed acute renal failure, 65% were greater than 65 years, 56% had diabetes, and 26% had prior renal insufficiency; 59% had one, 35% had two, and 6% had three of these conditions. Upon review of the IGIV product received, 90% of cases received sucrose-containing IGIV products with the remaining patients receiving either maltose- or glucose-containing products. Approximately 40% of affected patients required dialysis and RAE may have contributed to death in 15% of patients.(4)

Selected Nephrotoxic Agents/Tenofovir

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

MECHANISM OF ACTION: Tenofovir and other nephrotoxic agents may result in additive or synergistic effects on renal function and increase nephrotoxicity risk.(1)

CLINICAL EFFECTS: Concurrent use of tenofovir and other nephrotoxic agents may result in renal toxicity and acute renal failure.(1) Reports of acute renal failure and Fanconi syndrome have been reported with tenofovir use.(2,3) However, this has been reported in 3 case reports and the renal failure may have been complicated by other pre-existing conditions.(2)

PREDISPOSING FACTORS: Pre-existing renal dysfunction, long duration of use, low body weight, concomitant use of drugs that may increase tenofovir levels may increase the risk of nephrotoxicity.(1)

PATIENT MANAGEMENT: The US prescribing information for tenofovir recommends avoiding concurrent or recent use of a nephrotoxic agent.(3) Evaluate renal function prior to initiation of concurrent therapy and continue renal function monitoring during therapy. Dose adjustments may be required for impaired renal function. Tenofovir should be avoided with high-dose or multiple NSAIDs. Alternatives to NSAIDs should be considered in patients at risk for renal dysfunction.(3) Patients receiving concurrent NSAIDs with tenofovir should be monitored for possible renal toxicity.(1,2) The dosing interval should be adjusted in patients with a baseline creatinine clearance of less than 50 ml/min.(1-3)

DISCUSSION: From March 18, 2003 to December 1, 2005, Health Canada received 10 reports of nephrotoxic reactions with tenofovir. Three of these occurred following the addition of a NSAID to tenofovir therapy. In the first report, a patient maintained on tenofovir for 29 months developed acute renal failure and acute tubular necrosis requiring dialysis 5 days after beginning indomethacin (100 mg rectally twice daily). In the second report, a patient maintained on tenofovir for 7 months developed acute renal failure and acute tubular necrosis after taking 90 tablets of naproxen (375 mg) over 2 months. The patient died. In the third report, a patient maintained on tenofovir for over a year developed acute renal failure and nephrotic syndrome after 2 months of valdecoxib (20 mg daily) therapy. Symptoms subsided following discontinuation of valdecoxib.(1)

Selected Nsaids/Selected Cyp2c9 Inhibitors

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

MECHANISM OF ACTION: The major metabolic pathway for many non-steroidal anti-inflammatory agents (NSAIDs) is CYP2C9. Inhibitors of CYP2C9 include: amiodarone, asciminib, diosmin, fluconazole, ketoconazole, miconazole, nitisinone, oxandrolone, piperine, voriconazole, and zafirlukast.(1,2)

CLINICAL EFFECTS: Concurrent use of NSAIDs with inhibitors of CYP2C9 may result in increased levels of and adverse effects from NSAIDs, including increased risk for bleeding. NSAIDs linked to this monograph are celecoxib, diclofenac, flurbiprofen, ibuprofen, meloxicam, naproxen, parecoxib, piroxicam and valdecoxib.

PREDISPOSING FACTORS: Higher doses of either agent would be expected to increase the risk for serious adverse effects such as gastrointestinal bleeding (GIB) or renal failure. Patients who smoke, are elderly, debilitated, dehydrated, have renal impairment, or who have a history of GIB due to NSAIDs are also at increased risk for serious adverse events.(3-7) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients on routine NSAID therapy when an inhibitor of CYP2C9 is started should be evaluated for patient-specific risk factors for NSAID toxicity. Based upon this risk assessment, consider dose reduction of the NSAID or close monitoring for adverse effects. For a patient already receiving a CYP2C9 inhibitor when an NSAID is started, consider initiating the NSAID at a lower than usual dose, particularly when predisposing risk factors for harm are present. The manufacturer of celecoxib recommends that celecoxib be introduced at the lowest recommended dose in patients receiving fluconazole therapy.(3) The manufacturer of fluconazole states that half the dose of celecoxib may be necessary when fluconazole is added.(4) It would be prudent to follow this recommendation with other CYP2C9 inhibitors and to decrease the dose of celecoxib in patients in whom CYP2C9 inhibitors are added to celecoxib therapy. The manufacturer of diclofenac-misoprostol states that the total daily dose of diclofenac should not exceed the lowest recommended dose of 50 mg twice daily in patients taking CYP2C9 inhibitors.(5) It would be prudent to use the lowest recommended dose of other diclofenac formulations in patients taking CYP2C9 inhibitors. The manufacturer of parecoxib states that the dose of parecoxib should be reduced in those patients who are receiving fluconazole therapy.(6) It would be prudent to follow this recommendation with other CYP2C9 inhibitors. The manufacturer of nitisinone recommends reducing the dosage of a CYP2C9 substrate by one-half.(7) 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: The concomitant administration of celecoxib and fluconazole (200 mg daily) resulted in a 2-fold increase in celecoxib plasma concentration.(3) In vitro studies in human hepatocytes found that amiodarone inhibited diclofenac metabolism.(8) In two separate studies, single doses of diclofenac (50 mg) or ibuprofen (400 mg) were coadministered with the last dose of voriconazole (400 mg q12h on Day 1, followed by 200 mg q12h on Day 2). Voriconazole increased the mean AUC of diclofenac by 78% and increased the AUC of the active isomer of ibuprofen by 100%.(9-11) Coadministration of diosmin increased diclofenac levels by 63%.(2) Coadministration of flurbiprofen or ibuprofen with fluconazole increased the AUC of flurbiprofen by 81% and of the active ibuprofen by 82% compared with either agent alone.(4) Concurrent voriconazole increased meloxicam AUC by 47%.(12,13) The concurrent administration of fluconazole and parecoxib resulted in increases in the area-under-curve (AUC) and maximum concentration (Cmax) of valdecoxib (the active metabolite of parecoxib) by 62% and 19%, respectively.(6) In a study, single dose diclofenac (50mg) given concurrently with the last dose of voriconazole (400 mg every 12 hours on Day 1, 200 mg every 12 hours on Day 2) increased Cmax and AUC by 2.1-fold and 1.8-fold, respectively. (5) Inhibitors of CYP2C9 include: amiodarone, asciminib, camizestrant, diosmin, fluconazole, ketoconazole, miconazole, nitisinone, oxandrolone, piperine, voriconazole, and zafirlukast.(1,2)

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/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 ACE inhibitors 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. Concurrent use of ACE inhibitors with NSAIDs 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 renal impairment may increase an individuals susceptibility to AKI.

PATIENT MANAGEMENT: Patients maintained on ACE inhibitors 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 ACE inhibitors. 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 ACE inhibitor therapy. Concurrent use of ACE inhibitors with NSAIDs and diuretics should be used with caution and monitored closely for signs of AKI.

DISCUSSION: 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.(30,31) 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).(32) 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. 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.

*Patients with known hypersensitivity (e.g., anaphylactic reactions, serious skin reactions) to any local anesthetic agent of the amide-type, nonsteroidal anti-inflammatory agents (NSAIAs), or to any of the other components of bupivacaine/meloxicam.

*Patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIAs. Severe, sometimes fatal, anaphylactic reactions to NSAIAs have been reported in such patients.

*Patients undergoing obstetrical paracervical block anesthesia.

*Patients undergoing coronary artery bypass graft (CABG) surgery.

• Aspirin exacerbated respiratory disease
• Cerebrovascular accident
• History of roux-en-Y gastric bypass
• Post-operative from CABG surgery
• Pregnancy
• Renal transplant

• Acute myocardial infarction
• Alcohol use disorder
• Chronic heart failure
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Gastrointestinal perforation
• Gastrointestinal ulcer
• Hemorrhage
• History of kidney donation
• Increased risk of bleeding
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Nephrectomy
• Systemic mastocytosis
• Thrombotic disorder
• Tobacco smoker

• Anemia
• Disease of liver
• Edema
• Hypertension

Most common adverse reactions (incidence >=10%) of bupivacaine/meloxicam are constipation, vomiting, and headache.

Less Frequent

• Edema
• Skin rash

Rare or Very Rare

• Abnormal hepatic function tests
• Acute eruptions of skin
• Acute myocardial infarction
• Acute respiratory failure
• Agranulocytosis
• Allergic dermatitis
• Anaphylaxis
• Anaphylaxis
• Anemia
• Angina
• Angioedema
• Angioedema
• Aphthous stomatitis
• Asthma
• Body fluid retention
• Bradycardia
• Bronchospastic pulmonary disease
• Bullous dermatitis
• Cerebrovascular accident
• Chest tightness
• CNS depression
• Colitis
• DRESS syndrome
• Drug-induced hepatitis
• Dyspnea
• Erythema multiforme
• Excitement
• Exfoliative dermatitis
• Facial edema
• Gastric ulcer
• Gastrointestinal hemorrhage
• Gastrointestinal perforation
• Gastrointestinal ulcer
• Heart block
• Hepatic failure
• Hyperkalemia
• Hypersensitivity drug reaction
• Hypertension
• Hypotension
• Hypotension
• Interstitial nephritis
• Jaundice
• Leukopenia
• Methemoglobinemia
• Muscle fasciculation
• Nephrotoxicity
• Pancreatitis
• Paralysis
• Pharyngitis
• Purpura
• Renal failure
• Renal papillary necrosis
• Seizure disorder
• Stevens-johnson syndrome
• Tachyarrhythmia
• Tachycardia
• Tachycardia
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Unconsciousness
• Urinary retention
• Urticaria
• Urticaria
• Vasculitis
• Vasodilation of blood vessels
• Ventricular arrhythmias
• Wheezing
• Worsening of chronic heart failure

More Frequent

• Acute abdominal pain
• Blurred vision
• Constipation
• Diarrhea
• Dysgeusia
• Fever
• Headache disorder
• Localized edema
• Postprocedural seroma
• Swelling of scrotum

Less Frequent

• Constipation
• Dizziness
• Dyspepsia
• Flatulence
• Flu-like symptoms
• Headache disorder
• Nausea
• Pain
• Upper respiratory infection
• Urinary tract infection

Rare or Very Rare

• Acute cognitive impairment
• Alopecia
• Black tarry stools
• Chills
• Cough
• Dizziness
• Drowsy
• Drowsy
• Dysgeusia
• Eructation
• Erythema
• Esophagitis
• Fatigue
• Fever
• Flushing
• Gastroesophageal reflux disease
• Hematuria
• Hyperhidrosis
• Increased urinary frequency
• Malaise
• Mood changes
• Muscle weakness
• Nausea
• Nervousness
• Nervousness
• Oral hypoesthesia
• Paresthesia
• Paresthesia
• Proteinuria
• Pruritus of skin
• Pruritus of skin
• Skin photosensitivity
• Sneezing
• Symptoms of anxiety
• Symptoms of anxiety
• Syncope
• Tinnitus
• Tinnitus
• Tremor
• Tremor
• Vertigo
• Visual changes
• Vomiting
• Vomiting
• Weight gain
• Weight loss
• Xerostomia

No enhanced messaging available.

Safety and effectiveness of bupivacaine/meloxicam in pediatric patients have not been established.

There are no available human data on use of bupivacaine/meloxicam in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, there are available data on the individual components.

Bupivacaine: The available data on bupivacaine use in pregnant women for epidural anesthesia (excluding paracervical block) are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are no adequate and well-controlled studies with bupivacaine in pregnant women. In animal studies, embryofetal lethality was noted when bupivacaine was administered subcutaneously to pregnant rabbits during organogenesis at a comparable bupivacaine dose level of 400 mg at the maximum recommended human dose (MRHD) of bupivacaine/meloxicam. Decreased pup survival was observed in a rat pre- and post-natal developmental study. Based on animal data, pregnant women should be advised of the potential risks to a fetus.

Meloxicam: Use of NSAIAs, including meloxicam, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of bupivacaine/meloxicam use between about 20 and 30 weeks of gestation, and avoid use at about 30 weeks of gestation and later in pregnancy. If an NSAIA is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. Because meloxicam can be detected in plasma beyond 48 hours after administration of bupivacaine/meloxicam, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, follow up according to clinical practice.

Published literature reports that the use of NSAIAs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Additionally, published studies and postmarketing reports describe maternal NSAIA use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAIA initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAIA use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Data from observational studies regarding other potential embryofetal risks of NSAIA use in women in the first or second trimesters of pregnancy are inconclusive.

Embryofetal death, septal heart defects, dystocia, delayed parturition, and decreased offspring survival were reported in animal studies of exposure to oral meloxicam at doses ranging from 0.1-97 times the MRHD; no malformations were reported.

Limited published literature reports that bupivacaine and its primary metabolite, pipecoloxylidine (PPX), are present in human milk at low levels. There are no human data available on whether meloxicam is present in human milk. There is no available information on effects of bupivacaine or meloxicam in the breastfed infant or effects of the drugs on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for bupivacaine/meloxicam and any potential adverse effects on the breastfed infant from the combination drug or from the underlying maternal condition.

Dose selection should be done carefully in geriatric patients due to a higher likelihood of renal impairment. Consider dosage reduction in geriatric patients and monitor renal function.

Of the total number of patients undergoing various surgical procedures who were exposed to bupivacaine/meloxicam in clinical studies, 136 patients (12.7%) were >=65 years of age, while 30 (2.8%) were >=75 years of age. No overall differences in safety or efficacy were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Elderly patients, compared to younger patients, are at greater risk for NSAIA-associated serious CV, GI, and/or renal adverse reactions, although the applicability of this to a single administration of low-dose meloxicam in bupivacaine/meloxicam is uncertain In clinical studies, differences in various pharmacokinetic parameters have been observed with bupivacaine hydrochloride between elderly and younger patients. Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to bupivacaine may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in bupivacaine/meloxicam dose selection, and it may be useful to monitor renal function. Consider reducing the dose of bupivacaine/meloxicam in elderly patients.