Treximet (sumatriptan succinate/naproxen sodium)

It isessential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Administer orally, with or without food. Tablets should not be split, crushed, or chewed.

*Recommended dosage in pediatric patients 12 to 17 years of age: 1 tablet containing 10 mg sumatriptan and 60 mg naproxen sodium.

*The maximum recommended dosage in a 24-hour period is 1 tablet containing 85 of sumatriptan and 500 mg of naproxen sodium.

*The safety of treating an average of more than 2 migraine headaches in pediatric patients in a 30-day period has not been established. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.

*See Full Prescribing Information for additional instructions on dosage and administration.

*Recommended dosage in adults: 1 tablet containing 85 mg of sumatriptan and 500 mg of naproxen sodium. The fixed-combination 85/500 mg tablet contains a dose of sumatriptan higher than the lowest effective dose. The choice of the dose of sumatriptan, and of the use of the fixed-combination preparation should be made on an individual basis, weighing the possible benefit of a higher dose of sumatriptan with the potential for a greater risk of adverse reactions.

*The maximum recommended dosage in a 24-hour period is 2 tablets containing 85 mg of sumatriptan and 500 mg of naproxen sodium, taken at least 2 hours apart.

*The safety of treating an average of more than 5 migraine headaches in adults in a 30-day period has not been established. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.

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.

5-Ht1d Agonists/Ergot Alkaloids

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

MECHANISM OF ACTION: The 5-HT1D agonists and ergot alkaloids can produce vasospastic reactions.

CLINICAL EFFECTS: Concurrent therapy may produce additive vasospastic effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that sumatriptan should not be used within 24 hours of an ergotamine-containing or ergotamine-like medication (such as dihydroergotamine or methysergide).(1,2) The Australian(3) and UK(4,5) manufacturers state that 24 hours should elapse before sumatriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing preparation is administered following sumatriptan. The US manufacturer states that zolmitriptan should not be used within 24 hours of an ergotamine-containing or ergotamine-like medication.(6) The UK manufacturer states that zolmitriptan should not be used within 6 hours of an ergotamine-containing or ergotamine-like medication.(7) The The Australian manufacturer states that 24 hours should elapse before zolmitriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing medication is administered following zolmitriptan.(8) The US manufacturer states that the use of rizatriptan within 24 hours of an ergotamine-containing or ergot-type medication is contraindicated.(9) The US manufacturer states that the use of naratriptan within 24 hours of an ergotamine-containing or ergot-type medication is contraindicated.(10) The Australian manufacturer states that concurrent use of naratriptan and ergotamine or ergotamine derivatives is not recommended.(11) The US manufacturer states that the use of eletriptan within 24 hours of an ergotamine-containing or ergot-type medication is contraindicated.(12) The UK manufacturer states that the use of eletriptan within 24 hours of an ergotamine-containing or ergot-type medication is not recommended.(13)

DISCUSSION: Because of the theoretical risk of additive vasospastic effects, the US manufacturer states that the use of sumatriptan within 24 hours of an ergotamine-containing or ergotamine-like medication is contraindicated.(1,2) The Australian(3) and UK(4,5) manufacturer states that 24 hours should elapse before sumatriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing medication is administered following sumatriptan. Although the pharmacokinetics of zolmitriptan were not affected by ergotamine, the UK manufacturer of zolmitriptan recommends that 6 hours should elapse between the administration of zolmitriptan and an ergotamine preparation.(7) The US manufacturer of zolmitriptan states under contraindications that zolmitriptan should not be used within 24 hours of an ergotamine-containing or ergot-type medication.(6) The Australian manufacturer states that 24 hours should elapse before zolmitriptan is administered following an ergotamine-containing preparation and 6 hours should elapse before an ergotamine-containing medication is administered following zolmitriptan.(8) Because of the additive risk of prolonged vasospastic reactions, the manufacturers of rizatriptan(9) and naratriptan(10) in the US state that the use of ergotamine-containing or ergot-type medications and these agents is contraindicated. The Australian manufacturer states that concurrent use of naratriptan and ergotamine or ergotamine derivatives is not recommended.(11) Administration of oral ergotamine one and two hours after eletriptan resulted in additive increases in blood pressure.(13)

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 5-Ht1d Agonists/Mao Inhibitors

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: MAOIs inhibit the metabolism of rizatriptan,(1) sumatriptan,(2-9) and zolmitriptan.(10-11)

CLINICAL EFFECTS: Concurrent use of MAOIs may result in increased levels and effects of rizatriptan, sumatriptan or zolmitriptan.(1-11)

PREDISPOSING FACTORS: Patients with a history of cardiovascular disease, e.g., coronary artery disease (CAD), transient ischemic attack (TIA), stroke, cardiac conduction disorders or poorly controlled hypertension are not considered candidates for 5-HT1D agonist therapy and would be at greater risk for toxicity due to this interaction.

PATIENT MANAGEMENT: Concurrent administration of rizatriptan and a MAOI or administration of rizatriptan within two weeks of the discontinuation of a MAOI is contraindicated according to product labeling for rizatriptan.(1) Concurrent administration of sumatriptan and a MAOI or administration of sumatriptan within two weeks of the discontinuation of a MAOI is contraindicated according to the Australian, Canada, UK, and US product labeling for these agents.(2-9) Concurrent administration of zolmitriptan and a MAO-A inhibitor or the administration of zolmitriptan within two weeks of discontinuation of a MAO-A inhibitor is contraindicated according to US labeling.(10) The UK manufacturer states that a maximum of 7.5 mg of zolmitriptan should be administered within 24 hours of a MAO-A inhibitor.(11) Eletriptan and frovatriptan are not metabolized by MAO-A(12, 13) and may be an alternative in patients who require treatment with an MAO-A inhibitor.

DISCUSSION: Rizatriptan is metabolized by the 'A' subtype of monoamine oxidase. In a study with 12 subjects, the concurrent administration of rizatriptan (10 mg) with moclobemide (450 mg daily, a selective, reversible MAO-A inhibitor) resulted in increases in the rizatriptan area-under-curve (AUC) and maximum concentration (Cmax) by 119% and 41%, respectively. The AUC of the active metabolite, N-monodesmethyl rizatriptan, increased over 400%. Plasma concentrations of rizatriptan may be increased by selective MAO-A inhibitors or by nonselective MAO-A and MAO-B inhibitors, although the interaction is expected to be greater with selective MAO-A inhibitors. The manufacturer also states that no interaction is expected with selective MAO-B inhibitors.(1) Sumatriptan oral bioavailability is approximately 15%, primarily due to presystemic clearance by MAO-A in the gut and liver. A small study found an approximately 7-fold increase in systemic sumatriptan exposure when an MAO-A inhibitor was given prior to a 25 mg oral dose of sumatriptan.(4) In another study, pretreatment with an MAO-A inhibitor prior to administration of injectable sumatriptan resulted in a 2-fold increase in sumatriptan AUC and a 40% increase in elimination half-life.(8) Pretreatment with a MAO-B inhibitor did not produce any significant changes in sumatriptan pharmacokinetics. The effect of a MAOI on nasal sumatriptan systemic absorption is expected to be less than that seen with oral sumatriptan but greater than that seen with injectable sumatriptan.(6) Administration of moclobemide, a MAO-A inhibitor, for one week (150 mg twice daily) resulted in a 25% increase in zolmitriptan AUC and a three-fold increase in Cmax and AUC for zolmitriptan's active N-desmethyl metabolite.(10,11) Administration of selegiline for one week at a dosage of 10 mg daily had no effect on the pharmacokinetics of zolmitriptan or its metabolite.(10) At daily doses of 10 mg, selegiline is primarily a selective MAO-B inhibitor; however, at higher doses, selegiline is capable of inhibiting MAO-A. Hypertensive reactions to the addition of either tyramine or a sympathomimetic to recommended dosages of selegiline have been reported.(14) Therefore, patients receiving selegiline at dosages of greater than 10 mg daily should be considered to be receiving a MAO-A inhibitor. It would also be prudent to monitor patients receiving selegiline at recommended dosages for this interaction. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(15) Metaxalone is a weak inhibitor of MAO.(17,18) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

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)

Selected Photosensitizers/Tretinoin-Mequinol

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: Tretinoin, anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are all known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of tretinoin in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that tretinoin-mequinol should not be administered to patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides.(1)

DISCUSSION: Because of the risk of increased photosensitivity, the US manufacturer states that tretinoin-mequinol should not be administered to patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), methotrexate, phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides.(1)

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 Half-Life Nsaids; Diflunisal/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: 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) 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.(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)

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)

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/Methotrexate; Pralatrexate

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

MECHANISM OF ACTION: The exact mechanism is unknown. NSAID-induced inhibition of prostaglandin synthesis may decrease renal perfusion rate and therefore inhibit methotrexate and pralatrexate clearance. NSAIDs may also compete for renal secretion with methotrexate and pralatrexate. Since methotrexate is not extensively protein bound, displacement of methotrexate by NSAIDs is unlikely to have altered methotrexate kinetics.

CLINICAL EFFECTS: Increased levels of methotrexate and pralatrexate, with increased effects, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.

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

PATIENT MANAGEMENT: Avoid the use of NSAIDs with high dose methotrexate therapy.(1) If both drugs must be given, monitor methotrexate levels and patient response carefully. Consider extending leucovorin rescue duration. Use caution when administering NSAIDs with low dose methotrexate therapy. (1) Administration of NSAIDs with pralatrexate requires close monitoring for toxicity.(2)

DISCUSSION: A retrospective review documented four cases of methotrexate toxicity during concurrent administration of ketoprofen and methotrexate in 36 patients. Three cases were fatalities.(3) In contrast, a four-way cross-over study in ten subjects found no effect on methotrexate oral or renal clearance by ketoprofen, piroxicam, or flurbiprofen.(4) In a study in 19 subjects, the concurrent administration of methotrexate and piroxicam resulted in a decrease in methotrexate maximum concentration (Cmax) but no other changes in methotrexate kinetics.(5) Another three-way cross-over study in six patients showed no effect by flurbiprofen or ibuprofen on methotrexate kinetics.(6) In contrast, administration of ibuprofen to nine patients resulted in a 39% decrease in methotrexate total clearance and a 40% decrease in methotrexate renal clearance.(7) Information on naproxen is also conflicting. In another arm of the earlier study (7), the administration of naproxen in nine patients decreased methotrexate total clearance by 22%, but had no significant effects on methotrexate renal clearance. In another study in nine subjects, methotrexate altered naproxen kinetics by greater than 30% in six subjects, although these changes were not statistically significant. Naproxen altered methotrexate kinetics by greater than 30% in four subjects, although these changes were also not statistically significant.(8) In contrast, the administration of naproxen with methotrexate in 15 subjects showed no significant effects on methotrexate oral or renal clearance.(9) A study in 19 subjects found that the concurrent administration of etodolac and methotrexate decreased methotrexate Cmax and increased methotrexate mean residence time. There were no changes in methotrexate clearance or area-under-curve (AUC) and no toxicity was observed.(10) A study in 12 patients showed no significant effects of sulindac on methotrexate kinetics unless one patient who had low baseline clearance of methotrexate was excluded from analysis.(11) A study in seven children examined the effects of the children's usual NSAID on methotrexate kinetics. NSAIDs were naproxen, tolmetin, and indomethacin. Methotrexate half-life increased during NSAID administration. There were no significant changes in methotrexate clearance, AUC or volume of distribution. There was inter-subject variably in response. In six of seven patients, NSAID administration increased methotrexate AUC 19-140%.(12) Case reports have documented an interaction between methotrexate and phenylbutazone (13), indomethacin (14), flurbiprofen (15), and naproxen (16,17); however, one naproxen report (16) is complicated by the fact that the patient took 27.5 mg methotrexate in one week instead of 2.5 mg three times weekly. Because of the conflicting data and wide patient variability, caution is warranted during concurrent administration of methotrexate and any NSAID.

Nsaids/Selected Anticoagulants (Vit K Antagonists)

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

MECHANISM OF ACTION: The exact mechanism is unknown. Some NSAIDs may displace anticoagulants from plasma protein binding sites. NSAIDs also have the potential to produce gastrointestinal ulceration and bleeding. Some NSAIDs may impair platelet function and prolong bleeding times.

CLINICAL EFFECTS: Concurrent use of anticoagulants and NSAIDs may increase the risk for bleeding.

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

DISCUSSION: The effects of NSAIDs on the hypoprothrombinemic response to anticoagulants appears to vary between patients as well as with different NSAIDs. Documentation is frequently contradictory - while studies have shown several NSAIDs to have no effect on the pharmacokinetics of warfarin, case reports have documented increased effects with and without bleeding when these same NSAIDs were administered concurrently with warfarin. While celecoxib has been shown not to affect platelet aggregation or bleeding times and had no effects on the anticoagulant effect of warfarin in healthy subjects, increased prothrombin times and bleeding episodes, some of which were fatal, have been reported, predominantly in the elderly, in patients receiving concurrent therapy with celecoxib and warfarin. Rofecoxib has been shown to increase prothrombin times in subjects who received concurrent warfarin therapy. 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) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and sulindac resulted in a ratio of rate ratios (RR) (95% CI) of 3.7 (1.79-7.62); warfarin and etodolac ratio of RR 2.61 (1.6-4.25); warfarin and ibuprofen ratio of RR 1.94 (1.5-2.5); warfarin and naproxen ratio of RR 1.72 (1.35-2.19); warfarin and indomethacin ratio of RR 1.62 (1.03-2.55); warfarin and diclofenac ratio of RR 1.43 (1.07-1.92; warfarin and celecoxib ratio of RR 1.24 (1.02-1.53); and warfarin and meloxicam ratio of RR 1.23 (1.02-1.47).(23) 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. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 8 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and NSAIDs (OR=1.83; 95% CI 1.29-2.59). Increased bleeding risk was seen in subgroup analyses with non-selective NSAIDs (OR=1.86; 95% CI 1.10-3.17) and COX-2 inhibitors (OR=1.81; 95% CI 1.3-2.52).(24) If concurrent therapy with anticoagulants and NSAIDs is warranted, it would be prudent to monitor patients closely for increased anticoagulant effects.

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 Immunosuppressants

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Nsaids; Salicylates/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/Sodium Phosphate Bowel Cleanser

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

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

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

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

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

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

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 5-Ht1d Agonists/Linezolid

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

MECHANISM OF ACTION: Monoamine oxidase inhibitors (MAOIs) inhibit the metabolism of rizatriptan,(1) sumatriptan,(2-9) and zolmitriptan.(10) Linezolid is a weak, reversible, nonselective MAOI.(12)

CLINICAL EFFECTS: Concurrent use of linezolid may result in increased levels and effects of rizatriptan, sumatriptan or zolmitriptan.(1-11)

PREDISPOSING FACTORS: Patients with a history of cardiovascular disease, e.g. coronary artery disease (CAD), transient ischemic attack (TIA), stroke, cardiac conduction disorders or poorly controlled hypertension, are not considered candidates for 5-HT1D agonist therapy and would be at greater risk for toxicity due to this interaction.

PATIENT MANAGEMENT: Concurrent administration of rizatriptan and a MAOI or administration of rizatriptan within two weeks of the discontinuation of a MAOI is contraindicated according to product labeling for rizatriptan.(1) Concurrent administration of sumatriptan and a MAOI within two weeks of the discontinuation of a MAOI is contraindicated according to the Australian, Canada, UK, and US product labeling for these agents.(2-9) Concurrent administration of zolmitriptan and a MAO-A Inhibitor or the administration of zolmitriptan within two weeks of discontinuation of a MAO-A Inhibitor is contraindicated according to US labeling.(10) The UK manufacturer states that a maximum of 7.5 mg of zolmitriptan should be administered within 24 hours of a MAO-A inhibitor.(11) The manufacturer of linezolid does not contraindicated the use of 5-HT1D agonists but states that they should not be coadministered unless clinically appropriate and patients are carefully observed for signs and symptoms of serotonin syndrome.(12) Eletriptan and frovatriptan are not metabolized by MAO-A(13,14) and may be an alternative in patients who require treatment with linezolid.

DISCUSSION: The combination of linezolid and 5-HT1D agonists has not been studied. Other MAOIs have been reported to interact with 5-HT1D agonists. Rizatriptan is metabolized by the 'A' subtype of monoamine oxidase. In a study with 12 subjects, the concurrent administration of rizatriptan (10 mg) with moclobemide (450 mg daily, a selective, reversible MAO-A inhibitor) resulted in increases in the rizatriptan area-under-curve (AUC) and maximum concentration (Cmax) by 119% and 41%, respectively. The AUC of the active metabolite, N-monodesmethyl rizatriptan, increased over 400%. Plasma concentrations of rizatriptan may be increased by selective MAO-A inhibitors or by nonselective MAO-A&B inhibitors, although the interaction is expected to be greater with selective MAO-A inhibitors. The manufacturer also states that no interaction is expected with selective MAO-B inhibitors.(1) Sumatriptan oral bioavailability is approximately 15%, primarily due to presystemic clearance by MAO-A in the gut and liver. A small study found an approximately 7-fold increase in systemic sumatriptan exposure when an MAO-A inhibitor was given prior to a 25 mg oral dose of sumatriptan.(4) In another study, pretreatment with an MAO-A inhibitor prior to administration of injectable sumatriptan resulted in a 2-fold increase in sumatriptan AUC and a 40% increase in elimination half-life.(8) Pretreatment with a MAO-B inhibitor did not produce any significant changes in sumatriptan pharmacokinetics. The effect of a MAOI on nasal sumatriptan systemic absorption is expected to be less than that seen with oral sumatriptan but greater than that seen with injectable sumatriptan.(6) Administration of moclobemide, a MAO-A inhibitor, for one week (150 mg twice daily) resulted in a 25% increase in zolmitriptan AUC and a three-fold increase in Cmax and AUC for zolmitriptan's active N-desmethyl metabolite.(10,11)

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 Photosensitizers/Aminolevulinic Acid

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

MECHANISM OF ACTION: Aminolevulinic acid, anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are all known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of aminolevulinic acid in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that aminolevulinic acid should be avoided in patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides for 24 hours before and after administration of aminolevulinic acid.(1)

DISCUSSION: Because of the risk of increased photosensitivity, the US manufacturer states that aminolevulinic acid should be avoided in patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides for 24 hours before and after administration of aminolevulinic acid.(1)

Selected Photosensitizers/Methoxsalen

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

MECHANISM OF ACTION: Methoxsalen causes photosensitivity due to residual drug which is present in all parts of the skin from photopheresis. Anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are other known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of methoxsalen in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of methoxsalen states that concurrent use of methoxsalen with anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides should be avoided.(1)

DISCUSSION: All patients who have received methoxsalen become photosensitive. It is unknown what the risk of photosensitivity reactions is when methoxsalen is used concurrently with other photosensitizing agents.(1)

Selected Photosensitizers/Porfimer

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

MECHANISM OF ACTION: Porfimer causes photosensitivity due to residual drug which is present in all parts of the skin. Anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are other known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of porfimer in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: Patients with any hepatic impairment and patients with severe renal impairment have reduced drug elimination and may remain photosensitive for 90 days or longer.(1)

PATIENT MANAGEMENT: The US manufacturer of porfimer states that concurrent use of porfimer with photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides should be avoided.(1) Since the photosensitive effect of porfimer may persist for at least 30 days (and for 90 days in some patients), it would be prudent to avoid other photosensitizing agents for at least 30 days after administration of porfimer.

DISCUSSION: All patients who have received porfimer become photosensitive. It is unknown what the risk of photosensitivity reactions is when porfimer is used concurrently with other photosensitizing agents. When porfimer was used in clinical trials, photosensitivity reactions occurred in about 20% of cancer patients and in 69% of high-grade dysplasia in Barretts esophagus patients. Most of the reactions were mild to moderate erythema, but they also included swelling, pruritus, burning sensation, feeling hot, or blisters. The majority of reactions occurred within 90 days of porfimer administration.(1)

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/Corticosteroids

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

MECHANISM OF ACTION: Concurrent use of NSAIDs and corticosteroids result in additive risk of GI ulceration.

CLINICAL EFFECTS: Concurrent use of NSAIDs and corticosteroids may increase the incidence and/or severity of GI irritation or ulceration, including increasing the risk for bleeding.

PREDISPOSING FACTORS: 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 by concurrent use of anticoagulants, antiplatelets, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs); with longer duration of NSAID use; and with prior history of peptic ulcer disease and/or GI bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia, advanced liver disease).

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy carefully for signs of gastrointestinal ulceration. Use the lowest effective NSAID dose for the shortest duration possible. 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 signs of GI bleeding such as black, tarry stools; "coffee ground" vomit; nausea; or stomach/abdominal pain.

DISCUSSION: Concurrent use of NSAIDs and corticosteroids increase the risk of GI bleeding.

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/Angiotensin Ii Receptor Blocker (Arb)

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

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

CLINICAL EFFECTS: Concurrent use of ARBs 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 ARBs 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 use of diuretics can lead to hypovolemia and increased risk of AKI.

PATIENT MANAGEMENT: Patients maintained on ARBs 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 ARBs. 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 ARB therapy. Concurrent use of ARBs with NSAIDs and diuretics should be used with caution and monitored 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.(22,23) 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).(24) In a population based cohort study, the concurrent use of NSAIDs with renin-angiotensin system (RAS) inhibitors in 5,710 hypertensive patients stabilized on antihypertensive therapy required hypertension treatment intensification. Adjusted hazard ratios (HR) for hypertension treatment intensification were 1.34 [95% CI 1.05-1.71] for NSAIDs in general, 1.79 (95% CI 1.15-2.78) for diclofenac and 2.02 (95% CI 1.09-3.77) for piroxicam. There were significant interactions between NSAIDs and angiotensin converting enzyme inhibitors (ACE inhibitors; HR 4.09, 95% CI 2.02-8.27) or angiotensin receptor blockers (ARBs; HR 3.62, 95% CI 1.80-7.31), but not with other antihypertensive drugs.

Nsaids; Salicylates/Drospirenone

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

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

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

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

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

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

Nsaids; Salicylates/Lithium

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

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

CLINICAL EFFECTS: May observe increased lithium toxicity.

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

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

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

Nsaids; Salicylates/Loop Diuretics

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

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

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

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

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

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

Nsaids; Salicylates/Minoxidil

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

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

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

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

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

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

Nsaids; Salicylates/Sparsentan

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

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

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

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

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

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

Nsaids; Salicylates/T Cell Immunotherapies

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Selected 5-Ht1d Agonists/Rasagiline

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

MECHANISM OF ACTION: Rasagiline may inhibit the monamine oxidase-A (MAO-A) mediated metabolism of rizatriptan,(2) sumatriptan,(3-10) and zolmitriptan.(11-12) At concentrations associated with recommended doses of 0.5 mg to 1 mg daily, rasagiline has a high specificity for MAO-B. Mild hepatic impairment, concomitant use of strong CYP1A2 inhibitors, or use of higher than recommended doses may substantially increase rasagiline systemic exposure and could result in MAO-A inhibition.

CLINICAL EFFECTS: Systemic concentrations of rizatriptan, sumatriptan or zolmitriptan may be increased.(2-12)

PREDISPOSING FACTORS: Rasagiline concentration may be increased 2-fold or more in patients also receiving a strong CYP1A2 inhibitor (e.g. ciprofloxacin, fluvoxamine).(1) Rasagiline plasma concentrations are higher in patients with any degree of hepatic impairment. Rasagiline should not be used in patients with moderate or severe hepatic impairment.(1) Patients with a history of cardiovascular disease, e.g. coronary artery disease (CAD), transient ischemic attack (TIA), stroke, cardiac conduction disorders or poorly controlled hypertension, are not considered candidates for 5-HT1D agonist therapy and would be at greater risk for toxicity due to this interaction.

PATIENT MANAGEMENT: Evaluate patient for predisposing risk factors, e.g. concomitant use with CYP1A2 inhibitors, cardiovascular disease, and hepatic impairment. Patients with mild hepatic impairment or receiving concurrent therapy with a CYP1A2 inhibitor (e.g. ciprofloxacin, fluvoxamine) should be receiving a maximum rasagiline dose of 0.5 mg daily.

DISCUSSION: Triptan interaction studies with other MAO inhibitors: Rizatriptan is metabolized by the 'A' subtype of monoamine oxidase. In a study with 12 subjects, the concurrent administration of rizatriptan (10 mg) with moclobemide (450 mg daily, a selective, reversible MAO-A inhibitor) resulted in increases in the rizatriptan area-under-curve (AUC) and maximum concentration (Cmax) by 119% and 41%, respectively. The AUC of the active metabolite, N-monodesmethyl rizatriptan, increased over 400%. Plasma concentrations of rizatriptan may be increased by selective MAO-A inhibitors or by nonselective MAO-A&B inhibitors, although the interaction is expected to be greater with selective MAO-A inhibitors. The manufacturer also states that no interaction is expected with selective MAO-B inhibitors.(2) Sumatriptan oral bioavailability is approximately 15%, primarily due to presystemic clearance by MAO-A in the gut and liver. A small study found an approximately 7-fold increase in systemic sumatriptan exposure when an MAO-A inhibitor was given prior to a 25 mg oral dose of sumatriptan.(5) In another study, pretreatment with an MAO-A inhibitor prior to administration of injectable sumatriptan resulted in a 2-fold increase in sumatriptan AUC and a 40% increase in elimination half-life.(9) Pretreatment with a MAO-B inhibitor did not produce any significant changes in sumatriptan pharmacokinetics. The effect of a MAOI on nasal sumatriptan systemic absorption is expected to be less than that seen with oral sumatriptan but greater than that seen with injectable sumatriptan.(6) Administration of moclobemide, a MAO-A inhibitor, for one week (150 mg twice daily) resulted in a 25% increase in zolmitriptan AUC and a three-fold increase in Cmax and AUC for zolmitriptan's active N-desmethyl metabolite.(11,12) Administration of selegiline for one week at a dosage of 10 mg daily had no effect on the pharmacokinetics of zolmitriptan or its metabolite.(11) At daily doses of 10 mg, selegiline is primarily a selective MAO-B inhibitor; however, at higher doses, selegiline is capable of inhibiting MAO-A. Hypertensive reactions to the addition of either tyramine or a sympathomimetic to recommended dosages of selegiline have been reported.(15) Therefore, patients receiving selegiline at dosages of greater than 10 mg daily should be considered to be receiving a MAO-A inhibitor. It would also be prudent to monitor patients receiving selegiline at recommended dosages for this interaction.

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/Aspirin (For Cardioprotection)

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

MECHANISM OF ACTION: Some non-steroidal anti-inflammatory agents (NSAIDs) are reversible inhibitors of cyclooxygenase and aspirin is an irreversible inhibitor. If these NSAIDs are given before aspirin, the aspirin will not be able to bind to the cyclooxygenase site, which will result in a lack of effect.

CLINICAL EFFECTS: The antiplatelet and cardioprotective effect of aspirin may be decreased with the concurrent use of some NSAIDs, particularly during the washout period of the NSAID.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consideration should be given to use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or a non-NSAID analgesic if appropriate. If an NSAID must be used, cardioprotective doses of aspirin should be administered before taking any NSAIDs. Single doses of ibuprofen should be given at least 8 hours before or at least 2 hours after immediate release aspirin. The administration of other NSAIDs should be separated from aspirin by at least 2 hours.

DISCUSSION: The cardioprotective effect from aspirin is based on the antiplatelet effects. The irreversible inhibition of cyclooxygenase mediates the antiplatelet effects. Administration of a reversible inhibitor or cyclooxygenase blocks the irreversible effect of aspirin on the platelets. This effect has been seen with celecoxib, flufenamic acid, ibuprofen, indomethacin, naproxen, nimesulide, oxaprozin, piroxicam, and tiaprofenic acid but not with diclofenac, etoricoxib, ketorolac, meloxicam, or sulindac. In a study of 80 healthy volunteers, aspirin antiplatelet activity, measured by % thromboxane B2 inhibition (TxB2), was decreased when naproxen 220 mg daily was given simultaneously with or 30 minutes before aspirin 81 mg daily for 10 days (98.7% aspirin alone vs 93.1% and 87.7% naproxen and aspirin). The interaction persisted at least 1 day following discontinuation of naproxen but was normalized by the 3rd day. 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.

Selected Nsaids/Probenecid

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

MECHANISM OF ACTION: Probenecid may inhibit the renal tubular secretion of some NSAIDs. Probenecid may also prevent biliary clearance of NSAIDs.

CLINICAL EFFECTS: The decreased clearance of NSAIDs may lead to increased blood levels and an increase in adverse effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for an increase in NSAID-related adverse effects, including renal insufficiency. The dose of the NSAID may need to be decreased or probenecid may need to be discontinued.

DISCUSSION: Probenecid has been reported to increase the blood levels of indomethacin by 2-fold to 6-fold.(1,2) Probenecid has been reported to increase levels of oral ketoprofen by 93%;(3) however, no effect was seen on intramuscular ketoprofen in another study.(4) Probenecid has also been shown to increase naproxen levels.(5) Probenecid has been shown to increase the maximum concentration (Cmax) of tenoxicam. No other pharmacokinetic parameters were affected.(6) This interaction may result in clinical benefits in some patients.

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.

Selected Nsaids; Salicylates/Triamterene; Amiloride

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

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

CLINICAL EFFECTS: Possible renal failure or hyperkalemia.

PREDISPOSING FACTORS: None determined.

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

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

*History of coronary artery disease or coronary vasospasm.

*In the setting of CABG surgery.

*Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders.

*History of stroke, transient ischemic attack, or hemiplegic or basilar migraine.

*Peripheral vascular disease.

*Ischemic bowel disease.

*Uncontrolled hypertension.

*Recent (within 24 hours) use of another 5-HT1 agonist (e.g., another triptan) or of ergotamine-containing medication.

*Concurrent or recent (past 2 weeks) use of monoamine oxidase (MAO)-A inhibitor.

*History of asthma, urticaria, other allergic type reactions, rhinitis, or nasal polyps syndrome after taking aspirin or other NSAIA/analgesic drugs.

*Known hypersensitivity to sumatriptan, naproxen, or any components of the fixed-combination preparation (angioedema and anaphylaxis seen).

*Severe hepatic impairment.

• Acute myocardial infarction
• Angina
• Aspirin exacerbated respiratory disease
• Cerebral ischemia
• Cerebrovascular accident
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Coronary artery disease
• Hemiplegic migraine
• History of roux-en-Y gastric bypass
• Ischemic bowel disease
• Myocardial ischemia
• Peripheral vascular disease
• Post-operative from CABG surgery
• Pregnancy
• Prinzmetal angina
• Renal transplant
• Serotonin syndrome
• Severe uncontrolled hypertension

• Acute myocardial infarction
• Alcohol use disorder
• Anemia
• Chronic heart failure
• Disease of liver
• Edema
• Esophageal dysmotility
• Gastrointestinal perforation
• Gastrointestinal ulcer
• Hemorrhage
• History of kidney donation
• Hypertension
• Increased risk of bleeding
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Nephrectomy
• Systemic mastocytosis
• Tachyarrhythmia
• Thrombotic disorder
• Tobacco smoker

• Seizure disorder

The most common adverse reactions (incidence >=2%) in adults: Dizziness, somnolence, nausea, chest discomfort/chest pain, neck/throat/jaw pain/tightness/pressure, paresthesia, dyspepsia, dry mouth.

The most common adverse reactions (incidence >=2%) in pediatric patients: Hot flush (i.e., hot flashes), muscle tightness.

More Frequent

• Abnormal hepatic function tests
• Body fluid retention
• Skin rash
• Tinnitus
• Urticaria

Less Frequent

• Blurred vision
• Bruising
• Ecchymosis
• Hemorrhage
• Polydipsia
• Purpura
• Visual changes

Rare or Very Rare

• Abdominal pain with cramps
• Acquired dystonia
• Acute cognitive impairment
• Acute eruptions of skin
• Acute myocardial infarction
• Acute myocardial infarction
• Acute pancreatitis
• Agranulocytosis
• Allergic dermatitis
• Anaphylaxis
• Anaphylaxis
• Anemia
• Angioedema
• Angioedema
• Aplastic anemia
• Bacterial sepsis
• Bloody vomit
• Bronchospastic pulmonary disease
• Bronchospastic pulmonary disease
• Bullous dermatitis
• Cardiac arrhythmia
• Cerebrovascular accident
• Cerebrovascular accident
• Chest pain
• Chest tightness
• Chest tightness
• Chronic heart failure
• Colitis
• Coma
• Corneal opacity
• Coronary artery spasm
• Cystitis
• Depression
• Dysphagia
• Dyspnea
• Eosinophilia
• Eosinophilic pneumonia
• Erythema multiforme
• Exfoliative dermatitis
• Fever
• Gastric ulcer
• Gastrointestinal hemorrhage
• Gastrointestinal obstruction
• Gastrointestinal perforation
• Gastrointestinal ulcer
• Glomerulonephritis
• Heart failure
• Hematuria
• Hemolytic anemia
• Hepatic failure
• Hepatitis
• Hyperglycemia
• Hyperkalemia
• Hypersensitivity drug reaction
• Hypertension
• Hypertension
• Hypoglycemic disorder
• Hypotension
• Hypotension
• Interstitial nephritis
• Intracerebral hemorrhage
• Ischemic bowel disease
• Jaundice
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Leukopenia
• Loffler syndrome
• Lupus-like syndrome
• Lymphadenopathy
• Myalgia
• Myocardial ischemia
• Nephrotic syndrome
• Non-infective meningitis
• Optic neuritis
• Pancytopenia
• Peptic ulcer
• Peripheral ischemia
• Pneumonia
• Polyuria
• Proteinuria
• Pruritus of skin
• Pulmonary edema
• Raynaud's phenomenon
• Rectal bleeding
• Renal failure
• Renal papillary necrosis
• Renal tubular necrosis
• Respiratory depression
• Seizure disorder
• Seizure disorder
• Serotonin syndrome
• Splenic infarction
• Stevens-johnson syndrome
• Subarachnoid intracranial hemorrhage
• Syncope
• Tachycardia
• Thrombocytopenic disorder
• Thrombotic disorder
• Toxic epidermal necrolysis
• Vasculitis
• Ventricular fibrillation
• Ventricular tachycardia
• Vision impairment
• Wheezing

More Frequent

• Constipation
• Dizziness
• Dizziness
• Drowsy
• Dysgeusia
• Edema
• Flushing
• Headache disorder
• Heartburn
• Hypoesthesia
• Injection site sequelae
• Nasal passage irritation
• Nausea
• Nausea
• Paresthesia
• Sensation of warmth
• Stinging of skin
• Vertigo
• Vomiting

Less Frequent

• Diarrhea
• Drowsy
• Dysesthesia
• Dyspepsia
• Hearing loss
• Hyperhidrosis
• Hyperhidrosis
• Muscle weakness
• Myalgia
• Neck stiffness
• Palpitations
• Upper abdominal pain
• Vertigo

Rare or Very Rare

• Alopecia
• Anticholinergic toxicity
• Appetite changes
• Black tarry stools
• Concentration difficulty
• Conjunctivitis
• Cramps
• Dysuria
• Eructation
• Erythema nodosum
• Esophagitis
• Fatigue
• Fatigue
• Gastritis
• General weakness
• Glossitis
• Hallucinations
• Insomnia
• Jaw pain
• Lichen planus
• Medication overuse headache
• Menstrual disorder
• Mouth irritation
• Muscle rigidity
• Muscle weakness
• Nasal pain
• Nervousness
• Oliguria
• Palpitations
• Papilledema
• Paresthesia
• Sinusitis
• Skin photosensitivity
• Sore tongue
• Stomatitis
• Symptoms of anxiety
• Symptoms of anxiety
• Tremor
• Tremor
• Visual changes
• Vomiting
• Weight gain
• Weight loss
• Xerostomia

No enhanced messaging available.

Safety and effectiveness of sumatriptan/naproxen sodium in pediatric patients under 12 years of age have not been established.

The safety and efficacy of sumatriptan/naproxen sodium for the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in a double-blind, placebo-controlled trial.

Use of NSAIAs, including sumatriptan/naproxen sodium, 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 sumatriptan/naproxen sodium use between about 20 and 30 weeks of gestation, and avoid sumatriptan/naproxen sodium use at about 30 weeks of gestation and later in pregnancy.

Use of NSAIAs, including sumatriptan/naproxen sodium, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Use of NSAIAs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

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

Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population). In animal studies, administration of sumatriptan and naproxen, alone or in combination, during pregnancy resulted in developmental toxicity (increased incidences of fetal malformations, embryofetal and pup mortality, decreased embryofetal growth) at clinically relevant doses. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen sodium resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine.

Several studies have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.

Avoid use of NSAIAs in women at about 30 weeks gestation and later in pregnancy, because NSAIAs, including sumatriptan/naproxen sodium, can cause premature closure of the fetal ductus arteriosus.

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. If sumatriptan/naproxen sodium treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue the fixed-combination therapy and follow up according to clinical practice.

There are no studies on the effects of naproxen tablets during labor or delivery. In animal studies, NSAIAs, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. Sumatriptan is excreted in human milk following subcutaneous administration. There is no information regarding sumatriptan concentrations in milk from lactating women following administration of sumatriptan tablets.

There are no data on the effects of naproxen or sumatriptan on the breastfed infant or the effects of naproxen or sumatriptan on milk production.

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

Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with sumatriptan tablets.

Elderly patients, compared to younger patients, are at greater risk for NSAIA-associated serious cardiovascular, GI, and/or renal adverse reactions. Sumatriptan/naproxen sodium is not recommended for use in elderly patients who have decreased renal function, higher risk for unrecognized CAD, and increases in blood pressure that may be more pronounced in the elderly.

A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving sumatriptan/naproxen sodium.