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Interactions with Ibuprofen

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If you are currently being treated with any of the following medications, you should not use Ibuprofen without reading these interactions.

Pemetrexed

ADJUST DOSING INTERVAL: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the plasma concentrations of pemetrexed. The mechanism has not been described but may be related to NSAID inhibition of renal prostaglandins. Use of NSAIDs has been associated with nephropathy manifested as elevations in serum creatinine and BUN, tubular necrosis, glomerulitis, renal papillary necrosis, acute interstitial nephritis, nephrotic syndrome, and renal failure. Since pemetrexed is primarily eliminated unchanged by renal excretion, coadministration with NSAIDs may result in delayed and/or decreased clearance. Daily ibuprofen dosage of 400 mg four times a day has been shown to reduce pemetrexed clearance by about 20% in patients with normal renal function, whereas aspirin at 325 mg every 6 hours did not. The effect of higher dosages of ibuprofen or aspirin is unknown.

MANAGEMENT: Ibuprofen at 400 mg and aspirin at 325 mg four times a day, or less, may be used with pemetrexed in patients with normal renal function. However, caution is advised in patients with mild to moderate renal insufficiency (creatinine clearance 45 to 79 mL/min). These patients should avoid taking NSAIDs with short elimination half-lives (e.g., diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid, sulindac, tolmetin, low dosages of salicylates) 2 days before to 2 days after pemetrexed administration. If concomitant administration is necessary, patients should be monitored closely for toxicity, especially myelosuppression, nephrotoxicity, and gastrointestinal toxicity. In the absence of data regarding use with NSAIDs with longer half-lives, withholding NSAID dosing for at least 5 days before to 2 days after pemetrexed administration is recommended.

Tacrine

An isolated case has been reported in which delirium was associated with the combined use of tacrine and ibuprofen. The mechanism of this interaction has not been determined. When tacrine and ibuprofen are used together, clinical monitoring for evidence of delirium may be warranted.

Cidofovir

CONTRAINDICATED: Coadministration of cidofovir with other nephrotoxic agents may potentiate the risk of renal impairment. Dose-related nephrotoxicity is the major toxicity of cidofovir. Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with as few as one or two doses of cidofovir.

MANAGEMENT: The use of cidofovir in combination with other potentially nephrotoxic agents (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents) is considered contraindicated. Such agents should be discontinued for at least seven days prior to starting therapy with cidofovir. Initiation of cidofovir is also contraindicated in patients with a serum creatinine greater than 1.5 mg/dL, a calculated creatinine clearance at or below 55 mL/min, or a urine protein greater than or equal to 100 mg/dL.

Ketorolac

CONTRAINDICATED: The use of ketorolac in combination with other nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of serious NSAID adverse effects including renal failure and gastrointestinal inflammation, hemorrhage, ulceration, and perforation.

MANAGEMENT: Concurrent use of ketorolac with other NSAIDs or aspirin is considered contraindicated.

Donepezil (oral)

Donepezil may increase gastric acid secretion by increasing cholinergic activity. The risk for gastrointestinal bleeding is, therefore, theoretically increased in patients receiving donepezil in combination with a nonsteroidal anti-inflammatory agent. Caution is recommended when this combination is used.

Clofarabine

GENERALLY AVOID: Coadministration with drugs that are nephrotoxic may reduce the clearance of clofarabine, which is primarily eliminated by renal excretion.

MANAGEMENT: Drugs that are potentially nephrotoxic (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents) should be avoided during the 5 days of clofarabine administration if possible. Renal function should be evaluated prior to and during therapy, and administration discontinued immediately if substantial increases in creatinine is noted. Clofarabine therapy should be reinstated when the patient is stable and renal function has returned to baseline, possibly at a lower dosage.

Fondaparinux (injectable)

GENERALLY AVOID: In patients receiving neuraxial anesthesia or spinal puncture, the risk of developing an epidural or spinal hematoma during LMWH, heparinoid, or fondaparinux therapy may be increased by the concomitant use of other drugs that affect coagulation, including nonsteroidal anti-inflammatory drugs (NSAIDs). The development of epidural and spinal hematoma can lead to long-term or permanent paralysis.

GENERALLY AVOID: Theoretically, NSAIDs may potentiate the risk of bleeding complications associated with the use of fondaparinux. NSAIDs interfere with platelet adhesion and aggregation and may prolong bleeding time in healthy individuals. While these effects are generally slight and of relatively short duration with most NSAIDs (except aspirin) at recommended dosages, they may be of pronounced clinical significance when combined with the inhibitory effects of fondaparinux on the clotting cascade. In addition, NSAIDs are known to cause dose-related gastrointestinal bleeding, which may be complicated by anticoagulant therapy.

MANAGEMENT: Products containing NSAIDs, especially if given chronically or in high dosages, should preferably be discontinued prior to initiation of fondaparinux therapy. Close clinical and laboratory observation for bleeding complications is recommended if concurrent therapy is necessary. In patients undergoing neuraxial intervention, coadministration of these agents should be approached with caution and only after thorough assessment of risks and benefits. Besides bleeding complications, patients should also be monitored frequently for signs and symptoms of neurologic impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), and bowel or bladder dysfunction.

Enoxaparin, Dalteparin, Danaparoid, Ardeparin, Tinzaparin

GENERALLY AVOID: In patients receiving neuraxial anesthesia or spinal puncture, the risk of developing an epidural or spinal hematoma during low molecular weight heparin (LMWH) or heparinoid therapy may be increased by the concomitant use of other drugs that affect coagulation, including nonsteroidal anti-inflammatory drugs (NSAIDs). The development of epidural and spinal hematoma can lead to long-term or permanent paralysis.

GENERALLY AVOID: Theoretically, NSAIDs may potentiate the risk of bleeding complications associated with LMWH or heparinoid therapy. NSAIDs interfere with platelet adhesion and aggregation and may prolong bleeding time in healthy individuals. While these effects are generally slight and of relatively short duration with most NSAIDs (except aspirin) at recommended dosages, they may be of pronounced clinical significance when combined with the inhibitory effects of LMWHs or heparinoids on the clotting cascade. However, little clinical data exist regarding an actual interaction. In a controlled, randomized prospective study, 60 patients undergoing total hip replacement received enoxaparin (40 mg subcutaneously 12 hours pre- and every 24 hours postoperatively for 10 days) and analgesia with either ketorolac (30 mg IM on induction of anesthesia and every 24 hours postoperatively for 4 days) or an opioid plus acetaminophen. The authors reported no significant differences between the two groups for intraoperative blood loss, postoperative drainage, transfusion requirements, bruising, wound oozing, and leg swelling. However, there have been anecdotal reports of hemorrhagic complications in surgical patients treated with NSAIDs alone and in combination with a LMWH. In addition, NSAIDs are known to cause dose-related gastrointestinal bleeding, which may be complicated by anticoagulant therapy.

MANAGEMENT: Products containing NSAIDs, especially if given chronically and in high dosages, should preferably be avoided in patients receiving LMWHs or heparinoids. Close clinical and laboratory observation for bleeding complications is recommended if concurrent therapy is necessary. In patients undergoing neuraxial intervention, coadministration of these agents should be approached with caution and only after thorough assessment of risks and benefits. Besides bleeding complications, patients should also be monitored frequently for signs and symptoms of neurologic impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), and bowel or bladder dysfunction.

Desirudin

GENERALLY AVOID: In patients receiving neuraxial anesthesia or spinal puncture, the risk of developing an epidural or spinal hematoma during selective thrombin inhibitor therapy may be increased by the concomitant use of other drugs that affect coagulation, including nonsteroidal anti-inflammatory drugs (NSAIDs) and platelet inhibitors. The development of epidural and spinal hematoma can lead to long-term or permanent paralysis.

MONITOR: Theoretically, coadministration of selective thrombin inhibitors with drugs that affect platelet function may potentiate the risk of bleeding due to additive or synergistic effects on hemostasis.

MANAGEMENT: Close clinical and laboratory observation for bleeding complications is recommended if selective thrombin inhibitors are used with drugs that interfere with platelet function. In patients undergoing neuraxial intervention, coadministration of these agents should be approached with caution and only after thorough assessment of risks and benefits. Besides bleeding complications, patients should also be monitored frequently for signs and symptoms of neurologic impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), and bowel or bladder dysfunction.

Warfarin

GENERALLY AVOID: Nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the hypoprothrombinemic effect and bleeding risk associated with oral anticoagulants. In a one-year observational study of a population of coumarin users, the relative risk of bleeding complications due to concomitant NSAID use was 5.8 compared to coumarin use alone. Some investigators suggest that the risk of hemorrhagic peptic ulcers in particular may be substantially increased, especially in elderly or debilitated patients. A retrospective epidemiologic study of patients aged 65 years or older reported a nearly 13-fold increase in the risk of developing hemorrhagic peptic ulcer disease in concurrent users of oral anticoagulants and NSAIDs compared with nonusers of either drug. Fatalities have been reported. The pharmacologic effects of NSAIDs that contribute to this interaction include gastrointestinal irritation, prolongation of prothrombin time, and inhibition of platelet adhesion and aggregation. In addition, various NSAIDs have also been shown to alter the pharmacokinetics of warfarin and other oral anticoagulants, resulting in increased INR or prothrombin time. However, some studies failed to demonstrate any evidence of an interaction.

MANAGEMENT: NSAIDs should be administered with oral anticoagulants only if benefit outweighs risk. The INR should be checked frequently and oral anticoagulant dosage adjusted accordingly, particularly following initiation or discontinuation of NSAIDs in patients who are stabilized on their anticoagulant regimen. Patients should be advised to promptly report any signs of unusual bleeding or bruising to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, red or brown urine, or red or black stools. Salicylates (except aspirin) appear to have less effect on coagulation and may be preferable in patients treated with oral anticoagulants. Nevertheless, caution is advised and close monitoring for gastrointestinal bleeding is recommended, particularly in elderly or debilitated patients.

Aspirin (oral), Aspirin (rectal)

GENERALLY AVOID: The anti-platelet and cardioprotective effect of low-dose aspirin may be antagonized by prior administration (within 2 hours) or multiple daily doses of some nonsteroidal anti-inflammatory drugs (NSAIDs). Ibuprofen has been specifically implicated, and there is evidence that indomethacin may also. The mechanism of interaction is competitive inhibition of platelet cyclooxygenase by certain NSAIDs, which, unlike aspirin, bind reversibly at the active site of the enzyme and cause a temporary rather than sustained depression of thromboxane formation and thromboxane-dependent platelet function. A retrospective study of 7107 heart patients discharged from hospitals between 1989 and 1997 with aspirin prescriptions found that those also taking ibuprofen were twice as likely to die during the study period as those taking aspirin alone or with other NSAIDs or acetaminophen. That translates to 12 extra deaths (3 heart-related deaths) a year for every 1000 patients treated. The combined use of aspirin with NSAIDs in general may also increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. Pharmacokinetically, aspirin at anti-inflammatory dosages or higher has been shown to decrease the plasma concentrations of many NSAIDs. However, the therapeutic response does not appear to be affected.

MANAGEMENT: Patients receiving low-dose aspirin for cardioprotective effects should avoid the regular use of ibuprofen and possibly indomethacin. Occasional, single doses of these agents may be given but should not be administered simultaneously or within 2 hours prior to the aspirin dose. If routine NSAID therapy is necessary, diclofenac may be a viable alternative. In the study implicating ibuprofen, 75 mg twice daily of delayed-release diclofenac did not interfere with the anti-platelet activity of aspirin. In any case, caution is advised whenever aspirin is combined with a NSAID due to the potential for additive GI toxicity. Patients should be advised to take the medications with food and to immediately report signs and symptoms of GI ulceration and bleeding such as severe abdominal pain, dizziness, lightheadedness, and the appearance of black, tarry stools.

Heparin

GENERALLY AVOID: Theoretically, the coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs) and heparin or low molecular weight heparin (LMWH) may potentiate the risk of bleeding. NSAIDs interfere with platelet adhesion and aggregation and may prolong bleeding time in healthy individuals. While these effects are generally slight and of relatively short duration for most NSAIDs (except aspirin) at recommended dosages, they may be of pronounced clinical significance when combined with the inhibitory effects of heparin on the clotting cascade. However, little clinical data exist regarding an actual interaction. In a controlled, randomized prospective study, 60 patients undergoing total hip replacement received enoxaparin (40 mg subcutaneously 12 hours pre- and every 24 hours postoperatively for 10 days) and analgesia with either ketorolac tromethamine (30 mg IM on induction of anesthesia and every 24 hours postoperatively for 4 days) or an opioid plus acetaminophen. The authors reported no significant differences between the two groups for intraoperative blood loss, postoperative drainage, transfusion requirements, bruising, wound oozing, and leg swelling. However, there have been anecdotal reports of hemorrhagic complications in surgical patients treated with NSAIDs alone and in combination with a LMWH. In addition, NSAIDs are known to cause dose-related gastrointestinal bleeding, which may be complicated by anticoagulant therapy.

MANAGEMENT: Until further data are available, products containing NSAIDs, especially if given chronically or in high dosages, should preferably be avoided in patients receiving heparin or LMWH. Close clinical and laboratory observation for bleeding complications is recommended if concurrent therapy is necessary.

Lepirudin

GENERALLY AVOID: Theoretically, the coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs) and thrombin inhibitors may potentiate the risk of bleeding. NSAIDs interfere with platelet adhesion and aggregation and may prolong bleeding time in healthy individuals. While these effects are generally slight and of relatively short duration for most NSAIDs (except aspirin) at recommended dosages, they may be of pronounced clinical significance when combined with the effects of thrombin inhibitors on the clotting cascade. NSAIDs are also known to cause dose-related gastrointestinal bleeding, which may be complicated by anticoagulant therapy. However, little clinical data exist regarding an actual interaction.

MANAGEMENT: Until further data are available, products containing NSAIDs, especially if given chronically or in high dosages, should preferably be avoided in patients receiving thrombin inhibitors. Close clinical and laboratory observation for bleeding complications is recommended if concurrent therapy is necessary.

Tirofiban, Eptifibatide

GENERALLY AVOID: The risk of bleeding associated with glycoprotein IIb/IIIa inhibitors is increased in the presence of nonsteroidal anti-inflammatory agents due to additive inhibitory effects on platelet function. Arterial puncture sites may be most problematic. Data are available for abciximab.

MANAGEMENT: It is recommended that these drugs be used together only when indicated by skilled personnel who are qualified and equipped to detect and treat bleeding complications.

Ranitidine, Cimetidine, Famotidine, Nizatidine, Ranitidine bismuth citrate

H2 antagonists may alter the disposition of nonsteroidal anti-inflammatory drugs (NSAIDs), resulting in increased or decreased plasma concentrations. Data are varied, even for the same NSAID. The mechanism may be related to inhibition of metabolism, changes in gastric pH that decrease absorption, and/or reduced urinary elimination. Statistically significant changes have been small and of limited clinical significance. Clinical monitoring of patient response and tolerance is recommended.

Valproic acid

High doses of ibuprofen (greater than 400 mg/day) may displace valproic acid from protein binding sites in vitro. This interaction may be more significant in uremic patients. Free valproic acid concentrations should be measured if toxicity is suspected.

Modafinil

MONITOR: Based on in vitro inhibition data, coadministration with modafinil may increase the plasma concentrations of drugs that are substrates of the CYP450 2C9 and/or 2C19 isoenzymes. The mechanism is decreased clearance due to inhibition of CYP450 2C9/2C19 activities by modafinil. Pharmacologic response to these drugs may be altered, particularly if they have a narrow therapeutic range. For example, modafinil was implicated in a case of clozapine toxicity, characterized by dizziness, ataxia, and tachycardia. Clozapine serum levels increased from 761 ng/mL to 1400 ng/mL several weeks after concurrent modafinil therapy was initiated.

MANAGEMENT: Patients should be monitored for altered efficacy and safety whenever modafinil is added to or withdrawn from therapy. Dosage adjustments may be required if an interaction is suspected.

Entecavir

MONITOR: Because entecavir is primarily eliminated by renal excretion, coadministration with drugs that affect renal function may alter the plasma concentrations of entecavir and/or the coadministered drug. In patients with renal impairment, the apparent oral clearance of entecavir has been shown to decrease as the creatinine clearance decreases. In a small pilot study consisting of nine liver transplant recipients on a stable dose of cyclosporine or tacrolimus, entecavir exposure was approximately 2-fold that in healthy subjects with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these patients.

MANAGEMENT: Caution is advised if entecavir is prescribed in combination with potentially nephrotoxic drugs (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). Renal function should be evaluated prior to and during therapy with entecavir. Dosage adjustment is required in patients with renal insufficiency (creatinine clearance below 50 mL/min) at baseline or during treatment in accordance with the manufacturer's product labeling.

Telbivudine

MONITOR: Because telbivudine is primarily eliminated by renal excretion, coadministration with drugs that affect renal function may alter the plasma concentrations of telbivudine and/or the coadministered drug.

MANAGEMENT: Caution is advised if telbivudine is prescribed in combination with potentially nephrotoxic drugs (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). Renal function should be evaluated prior to and during therapy with telbivudine. Adjustment of dosing interval is required in patients with renal insufficiency (creatinine clearance below 50 mL/min) at baseline or during treatment in accordance with the manufacturer's product labeling.

Labetalol, Nadolol, Propranolol, Acebutolol, Metoprolol, Pindolol, Timolol, Carteolol, Bisoprolol, Carvedilol, Betaxolol, Penbutolol, Sotalol, Sotalol AF

MONITOR: Chronic (longer than 1 week) nonsteroidal anti-inflammatory drug (NSAID) administration may attenuate the antihypertensive effects of beta blockers. The proposed mechanism is NSAID-induced inhibition of renal prostaglandin synthesis, which results in unopposed pressor activity producing hypertension.

MANAGEMENT: Patients who require concomitant therapy should be monitored for altered antihypertensive response whenever an NSAID is introduced or discontinued, or when its dosage is modified.

Adefovir

MONITOR CLOSELY: Coadministration of adefovir dipivoxil with other nephrotoxic agents may increase the risk and severity of nephrotoxicity due to additive effects on the kidney. Additionally, renal impairment secondary to the use of these agents may reduce the clearance of adefovir, which is primarily eliminated by renal excretion. The use of adefovir dipivoxil has been associated with dose-related nephrotoxicity characterized by a delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus. Generally, the risk is low in patients with adequate renal function receiving 10 mg/day but increases with increasing dosage and in patients with underlying renal impairment.

MANAGEMENT: Caution is advised if adefovir dipivoxil must be used in patients who have recently received or are receiving treatment with other potentially nephrotoxic agents (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, cidofovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). Renal function should be evaluated prior to and during therapy with adefovir dipivoxil. Patients with renal insufficiency at baseline or during treatment may require dosage adjustment in accordance with the manufacturer's product labeling.

Dasatinib

MONITOR CLOSELY: Coadministration of dasatinib and drugs that interfere with platelet function or coagulation may potentiate the risk of bleeding complications. Treatment with dasatinib is associated with severe thrombocytopenia. In addition, dasatinib has been shown to induce platelet dysfunction in vitro. Severe central nervous system hemorrhages, including fatalities, occurred in 1% of patients receiving dasatinib in clinical trials. Severe gastrointestinal hemorrhage occurred in 7% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 4% of patients. Most bleeding events were associated with severe thrombocytopenia.

MANAGEMENT: Concomitant use of other medications that interfere with platelet function or coagulation should be considered cautiously in patients treated with dasatinib. Close clinical and laboratory observation for bleeding complications is recommended during therapy. A complete blood count (CBC) with differential and platelet count should be obtained prior to and at least weekly for the first 2 months, then monthly thereafter or as clinically indicated. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

Ibritumomab

MONITOR CLOSELY: Coadministration of ibritumomab and drugs that interfere with platelet function or coagulation may potentiate the risk of bleeding complications. Ibritumomab commonly causes severe and prolonged thrombocytopenia, and the risk is increased further in patients with mild thrombocytopenia at the initiation of therapy. Hemorrhage, including fatal cerebral hemorrhage, has occurred in a minority of patients in clinical studies. The median time to thrombocyte nadir was 7 to 9 weeks, and the median duration of thrombocytopenia was 22 to 35 days. However, in less than 5% of the cases, patients experienced severe cytopenia that extended beyond 12 weeks following administration of the ibritumomab therapeutic regimen. Platelet transfusions were given to 22% of patients in clinical trials.

MANAGEMENT: Caution is advised if ibritumomab is used in combination with drugs that interfere with platelet function or coagulation. Close clinical and laboratory observation for bleeding complications is recommended during and after ibritumomab therapy.

Tacrolimus (oral), Sirolimus

MONITOR CLOSELY: Coadministration of macrolide immunosuppressants with other nephrotoxic agents may increase the risk and severity of renal impairment due to additive effects on the kidney. No formal interaction studies have been performed. However, clinical experience in coadministration with cyclosporine indicates increased renal toxicity as evidenced by increased serum creatinine and decreased glomerular filtration rate. An interaction with ibuprofen resulting in acute renal failure was suspected in two liver transplant patients who had been stabilized on tacrolimus.

MANAGEMENT: Caution is advised if macrolide immunosuppressants must be used in patients who have recently received or are receiving treatment with other potentially nephrotoxic drugs (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, tenofovir, foscarnet, cisplatin, cyclosporine, gallium nitrate, lithium, mesalamine, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). Renal function should be closely monitored both during and after discontinuation of therapy.

Methotrexate

MONITOR CLOSELY: Nonsteroidal anti-inflammatory agents (NSAIDs) may interfere with the renal elimination of methotrexate. Pharmacologic effect and toxicity of methotrexate may be increased. Patients who are receiving high doses of methotrexate or who have renal impairment are at greater risk of developing toxicity. Fatalities have been reported. Weekly low-dose methotrexate has been used in combination with NSAIDs to treat rheumatic inflammatory diseases.

MANAGEMENT: Caution should be exercised with concomitant use of these agents, and the patient should be monitored closely for signs and symptoms of bone marrow suppression and nephrotoxicity. Patients should be advised to report possible symptoms of toxicity including nausea, vomiting, diarrhea, stomatitis, sore throat, chills, fever, rash, unusual bruising or bleeding, jaundice, dark urine, swelling of the extremities, or shortness of breath to their physician. Patients should also be counseled to avoid any other over-the-counter NSAID products.

Sulfasalazine, Mesalamine (oral), Olsalazine, Mesalamine (rectal), Balsalazide

MONITOR: Coadministration of 5-aminosalicylate with other nephrotoxic agents may increase the risk and severity of nephrotoxicity due to additive effects on the kidney. The use of 5-aminosalicylate or its prodrugs has been associated with rare reports of renal impairment including minimal change nephropathy and acute or chronic interstitial nephritis. Animal studies have also shown the kidney to be the major target organ of 5-aminosalicylate toxicity. Renal lesions including granular and hyaline casts, tubular degeneration, tubular dilation, renal infarct, papillary edema, papillary necrosis, tubular necrosis, interstitial fibrosis, and interstitial nephritis have been observed with large doses.

MANAGEMENT: Caution is advised if 5-aminosalicylate preparations must be used in patients who have recently received or are receiving treatment with other potentially nephrotoxic agents (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, foscarnet, cisplatin, gallium nitrate, lithium, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). Renal function should be evaluated prior to and during 5-aminosalicylate therapy.

Etidronate, Pamidronate, Zoledronic acid, Ibandronate

MONITOR: Coadministration of bisphosphonates with other nephrotoxic agents may increase the risk and severity of renal impairment due to additive effects on the kidney. The use of bisphosphonates has been associated with nephrotoxicity manifested as deterioration of renal function and renal failure. Cases have primarily involved intravenous formulations of the drugs such as pamidronate and zoledronic acid, especially when they are administered too rapidly. The risk of hypocalcemia may also be increased, as drug-induced renal tubular damage can lead to renal loss of calcium and other electrolytes such as magnesium. Bisphosphonates alone often cause mild, asymptomatic hypocalcemia via inhibitive effects on bone resorption and possibly chelation of blood calcium.

MANAGEMENT: Caution is advised if pamidronate, zoledronic acid, or other intravenous formulations of bisphosphonates must be used in patients who have recently received or are receiving treatment with other potentially nephrotoxic agents (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). Renal function and serum electrolytes should be monitored. Patients should have serum creatinine assessed prior to each treatment, and treatment should be withheld for renal deterioration. In those treated for bone metastases, treatment should not be resumed until renal function returns to baseline.

Leflunomide (oral)

MONITOR: Coadministration of leflunomide with nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of hepatotoxicity. The mechanism of interaction is unknown. Pharmacokinetically, the active metabolite of leflunomide has been shown to cause increases of 13% to 50% in the free fraction of diclofenac and ibuprofen. Additionally, in vitro studies indicate that the metabolite inhibits hepatic microsomal enzyme CYP450 2C9, which participates in the metabolism of many NSAIDs. No differential effects were observed with the concomitant use of NSAIDs in clinical studies of leflunomide. However, serious hepatic reactions have been reported in patients concurrently treated with leflunomide and other hepatotoxic agents, including NSAIDs.

MANAGEMENT: Patients being treated with leflunomide and NSAIDs should be closely monitored for hepatotoxicity. Liver enzyme levels should be obtained prior to initiating leflunomide and monthly during therapy. If ALT increases to 2 to 3 times normal, the leflunomide dose should be reduced and liver enzymes monitored weekly. If ALT increases to more than 3 times normal, leflunomide should be discontinued and the washout procedure instituted.

Aprepitant

MONITOR: Coadministration with aprepitant may decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 2C9. The mechanism is accelerated clearance due to induction of CYP450 2C9 activity by aprepitant. According to the manufacturer, coadministration of aprepitant (125 mg single dose on day 1 and 80 mg/day on days 2 and 3) and the 2C9 substrate tolbutamide (500 mg orally prior to initiation of aprepitant and on days 4, 8 and 15) resulted in a reduction in the area under the plasma concentration-time curve (AUC) of tolbutamide by 23% on day 4, 28% on day 8, and 15% on day 15. Similarly, healthy subjects stabilized on chronic warfarin therapy given the same regimen of aprepitant had a 34% decrease in S(-) warfarin trough concentration accompanied by a 14% decrease in the INR five days after completion of aprepitant dosing. However, there was no effect on the systemic exposure (AUC) of R(+) and S(-) warfarin determined on day 3.

MANAGEMENT: Caution is advised if aprepitant must be used concomitantly with medications that undergo metabolism by CYP450 2C9, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever aprepitant is added to or withdrawn from therapy.

Bosentan

MONITOR: Coadministration with bosentan may decrease the plasma concentrations of drugs that are substrates of the CYP450 2C9 and/or 3A4 isoenzymes. The mechanism is accelerated clearance due to induction of those isoenzymes by bosentan.

MANAGEMENT: When drugs that are known substrates of CYP450 2C9 and/or 3A4 are coadministered with bosentan, the possibility of a diminished therapeutic response to those drugs should be considered. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs, particularly those with a narrow therapeutic range, whenever bosentan is added to or withdrawn from therapy.

Imatinib (oral)

MONITOR: Coadministration with imatinib may increase the plasma concentrations of drugs that are substrates of CYP450 2C9, 2D6 and/or 3A4. The mechanism is decreased clearance due to inhibition of these isoenzymes by imatinib. According to the manufacturer, imatinib increased the mean peak plasma concentration and area under the concentration-time curve of simvastatin (a CYP450 3A4 substrate) by 2- and 3.5-fold, respectively. Data for other substrates are not currently available, although human liver microsome studies indicate that imatinib is a potent competitive inhibitor of all three isoenzymes.

MANAGEMENT: Caution is advised if imatinib must be used concomitantly with medications that undergo metabolism by CYP450 2C9, 2D6 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever imatinib is added to or withdrawn from therapy.

Enoxacin, Lomefloxacin, Norfloxacin, Ofloxacin, Sparfloxacin, Levofloxacin, Grepafloxacin, Trovafloxacin, Moxifloxacin, Gatifloxacin

MONITOR: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the risk of central nervous system toxicity sometimes associated with fluoroquinolone use. The interaction has been reported most often with enoxacin. It may occur with other fluoroquinolones as well, but is poorly documented. The exact mechanism of interaction is unknown. Some investigators suggest that the piperazine ring of fluoroquinolones may inhibit the binding of gamma-aminobutyric acid (GABA) to brain receptors and that NSAIDs may synergistically add to this effect. Patients with a history of seizures may be at greater risk.

MANAGEMENT: Clinical monitoring for signs of CNS stimulation such as tremors, involuntary muscle movements, hallucinations, or seizures is recommended if fluoroquinolone antibiotics are prescribed in combination with NSAIDs.

Rifapentine

MONITOR: Coadministration with rifapentine may decrease the plasma concentrations of drugs that are substrates of the CYP450 2C8, 2C9, and/or 3A4 isoenzymes. The mechanism is accelerated clearance due to induction of those isoenzymes by rifapentine. Enzyme activities may be induced within 4 days of the first dose and return to normal 14 days after discontinuation of rifapentine. In vitro and in vivo enzyme studies have suggested rifapentine induction potential to be less than that of rifampin but greater than that of rifabutin. In addition, the magnitude of induction is dependent on dose and dosing frequency.

MANAGEMENT: When drugs that are known substrates of CYP450 2C8, 2C9, and/or 3A4 are coadministered with rifapentine, the possibility of a diminished therapeutic response to those drugs should be considered. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs, particularly those with a narrow therapeutic range, whenever rifapentine is added to or withdrawn from therapy.

Voriconazole

MONITOR: Coadministration with voriconazole may increase the plasma concentrations of drugs that are substrates of CYP450 2C19, 2C9, and/or 3A4. The mechanism is decreased clearance due to inhibition of those isoenzymes by voriconazole. Increased plasma levels and/or pharmacologic effects of drugs such as cyclosporine, sirolimus, tacrolimus (3A4 substrates), and warfarin (2C9 substrate) have been reported during coadministration with voriconazole.

MANAGEMENT: Caution is advised if voriconazole must be used concomitantly with medications that undergo metabolism by CYP450 2C19, 2C9 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever voriconazole is added to or withdrawn from therapy. The manufacturer specifically recommends that a dosage reduction be considered for benzodiazepines, HMG-CoA reductase inhibitors (i.e. statins), and vinca alkaloids that are metabolized by the affected isoenzymes when used with voriconazole.

Furosemide, Amiloride, Bumetanide, Chlorothiazide, Chlorthalidone, Hydrochlorothiazide, Indapamide, Metolazone, Spironolactone, Triamterene, Ethacrynic acid, Torsemide

MONITOR: Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics may adversely affect renal function due to NSAID inhibition of the renal synthesis of prostaglandins that help maintain renal perfusion in dehydrated states. The risk may be increased in patients on dietary sodium restriction. At the same time, hypotensive effect of the diuretics may be reduced because inhibition of prostaglandins can lead to unopposed pressor activity and, consequently, elevation in blood pressure. Natriuretic and diuretic effects may also be reduced, as NSAIDs have been reported to cause sodium and water retention, which may account for the increased risk of congestive heart failure associated with the combination. One study showed an increase in the incidence density of congestive heart failure (in patients over 55 years of age) from 9.3 per 1,000 person-years in patients on diuretics to 23.3 per 1,000 person-years in patients on both diuretic and NSAID therapy. NSAIDs may also increase the risk of hyperkalemia associated with potassium-sparing diuretics.

MANAGEMENT: In patients receiving both diuretic and NSAID therapy, management consists of avoiding dehydration and carefully monitoring the patient's renal function and blood pressure. If renal insufficiency or hyperkalemia develops, both drugs should be discontinued until the condition is corrected.

Flucytosine

MONITOR: Drugs that impair glomerular filtration may prolong the half-life of flucytosine and lead to accumulation. Prolonged flucytosine serum concentrations of greater than 100 mcg/mL may increase the risk of gastrointestinal, hepatic, and hematologic toxicity.

MANAGEMENT: Caution is advised if flucytosine is used in patients who have recently received or are receiving treatment with potentially nephrotoxic drugs (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). Renal function and flucytosine blood levels should be closely monitored during therapy, and the dose or dosing interval should be adjusted to maintain flucytosine concentrations below 100 mcg/mL.

Diltiazem, Verapamil (oral), Nifedipine, Felodipine, Isradipine, Nicardipine, Bepridil, Amlodipine, Nimodipine, Nisoldipine (oral)

MONITOR: Limited data indicate that some cyclooxygenase inhibitors may attenuate the antihypertensive effects of some calcium channel blockers. The mechanism appears to be related to an alteration of vascular tone, which is dependent on prostacyclins and other vasodilatory prostanoids. When a nonsteroidal anti-inflammatory drug (NSAID) is added to the regimen of a patient who is already taking a calcium channel blocker, increased blood pressure may result. Also, the clinician should be aware that the risk of hypotension is increased when NSAIDs are withdrawn from the regimen.

MANAGEMENT: Monitoring for altered blood pressure control is recommended.

Eplerenone

MONITOR: Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effect of eplerenone. The proposed mechanism is NSAID-induced inhibition of renal prostaglandin synthesis, which results in unopposed pressor activity producing hypertension. In addition, NSAIDs can cause fluid retention, which also affects blood pressure. Although the interaction has not specifically been studied with eplerenone, it has been reported with other potassium-sparing antihypertensive drugs such as ACE inhibitors. In patients with renal impairment receiving these antihypertensive agents, concomitant use of NSAIDs has also resulted in severe hyperkalemia.

MANAGEMENT: Patients receiving eplerenone who require prolonged (greater than 1 week) concomitant therapy with an NSAID should have blood pressure monitored more closely following initiation, discontinuation, or change of dosage of the NSAID. The interaction is not expected to occur with low doses (e.g., low-dose aspirin) or intermittent short-term administration of NSAIDs.

Hydralazine

MONITOR: Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effect of hydralazine and dihydralazine. This interaction suggests that prostaglandins play a pivotal role in the vasodilatory effects of hydralazine. However, data have been conflicting.

MANAGEMENT: Recommended management consists of monitoring the antihypertensive effectiveness of hydralazine or dihydralazine during therapy, increasing the dosage as necessary, or decreasing or substituting another drug for the NSAID.

Fosinopril, Quinapril, Ramipril, Benazepril, Lisinopril, Moexipril, Trandolapril, Perindopril

MONITOR: Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effects of ACE inhibitors. The proposed mechanism is NSAID-induced inhibition of renal prostaglandin synthesis, which results in unopposed pressor activity producing hypertension. In addition, NSAIDs can cause fluid retention, which also affects blood pressure. Some NSAIDs may also alter the pharmacokinetics of certain ACE inhibitors. For example, oxaprozin has been shown to reduce the systemic exposure (AUC) of enalapril and its active metabolite, enalaprilat.

MANAGEMENT: Patients receiving ACE inhibitors who require prolonged (greater than 1 week) concomitant therapy with an NSAID should have blood pressure monitored more closely following initiation, discontinuation, or change of dosage of the NSAID. The interaction is not expected to occur with low doses (e.g., low-dose aspirin) or intermittent short-term administration of NSAIDs.

Losartan, Valsartan, Irbesartan, Eprosartan, Candesartan, Telmisartan, Olmesartan

MONITOR: Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effects of angiotensin II receptor antagonists. The proposed mechanism is NSAID-induced inhibition of renal prostaglandin synthesis, which results in unopposed pressor activity producing hypertension. In addition, NSAIDs can cause fluid retention, which also affects blood pressure. Clinical data are limited.

MANAGEMENT: Patients receiving angiotensin II receptor antagonists who require prolonged (greater than 1 week) concomitant therapy with an NSAID should have blood pressure monitored more closely following initiation, discontinuation, or change of dosage of the NSAID. The interaction is not expected to occur with low doses (e.g., low-dose aspirin) or intermittent short-term administration of NSAIDs.

Prazosin

MONITOR: Nonsteroidal anti-inflammatory drugs (NSAIDs) may decrease the antihypertensive effect of prazosin. The proposed mechanism is NSAID-induced inhibition of prostaglandin synthesis. Data are available for indomethacin. A similar interaction is expected with other NSAIDs.

MANAGEMENT: The patient's blood pressure should be monitored during coadministration, and the dosage adjusted as necessary.

Digoxin (oral)

MONITOR: Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase plasma digoxin concentrations and half-life. The exact mechanism is unknown, but may be related to reduced renal clearance of digoxin. Data have been conflicting. The interaction has been reported with indomethacin and ibuprofen, but data for other NSAIDs are not available.

MANAGEMENT: Patients who require concomitant therapy should be monitored for altered pharmacologic effects of digoxin and for increased plasma levels. The digoxin dosage may require adjustment. Patients should be advised to notify their physician if they experience nausea, anorexia, visual changes, slow pulse, or irregular heartbeats.

Cyclosporine

MONITOR: Nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the nephrotoxic effects of cyclosporine, especially if dehydration is present. The exact mechanism is unknown but is apparently unrelated to plasma cyclosporine levels. The interaction has been reported with diclofenac and sulindac. Data for other NSAIDs are not available, but a similar effect may be expected based on their common pharmacologic action.

MANAGEMENT: Renal function should be closely monitored in patients receiving concomitant therapy with cyclosporine and NSAIDs.

Pegaspargase

MONITOR: Pegaspargase may lead to imbalances in coagulation factors predisposing the patient to bleeding or thrombosis.

MANAGEMENT: The clinician should exercise caution when coadministering any nonsteroidal anti-inflammatory agent or anticoagulant therapy with pegaspargase. Patients should be closely monitored for signs of bleeding during coadministration.

Fluoxetine, Clomipramine, Sertraline, Paroxetine, Fluvoxamine, Sibutramine (oral), Citalopram (oral), Escitalopram

MONITOR: Serotonin reuptake inhibitors (SRIs) may potentiate the risk of bleeding in patients treated with agents that affect hemostasis such as anticoagulants, platelet inhibitors, thrombin inhibitors, thrombolytic agents, or agents that commonly cause thrombocytopenia. The tricyclic antidepressant, clomipramine, is also a strong SRI and may interact similarly. Serotonin release by platelets plays an important role in hemostasis, thus SRIs may alter platelet function and induce bleeding. Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic agents that interfere with serotonin reuptake. Additional epidemiological studies have confirmed the association between use of these agents and the occurrence of upper gastrointestinal bleeding, and concurrent use of NSAIDs or aspirin was found to potentiate the risk. Preliminary data also suggest that there may be a pharmacodynamic interaction between SSRIs and oral anticoagulants that can cause an increased bleeding diathesis. Concomitant administration of paroxetine and warfarin, specifically, has been associated with an increased frequency of bleeding without apparent changes in the disposition of either drug or changes in the prothrombin time. Bleeding has also been reported with fluoxetine and warfarin, while citalopram and sertraline have been reported to prolong the prothrombin time of patients taking warfarin by about 5% to 8%.

MANAGEMENT: Caution is advised if SRIs or clomipramine are used in combination with other drugs that affect hemostasis. Close clinical and laboratory observation for hematologic complications is recommended. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

Lithium

MONITOR: Several case reports and small studies suggest that some nonsteroidal anti-inflammatory drugs (NSAIDs) may increase serum lithium levels and increase the risk of toxicity. The exact mechanism is unknown but may involve inhibition of renal prostaglandin synthesis by NSAIDs. Lithium toxicity has been reported during concomitant use of indomethacin, ketorolac, mefenamic acid, and piroxicam. Lithium plasma concentrations have been shown to increase in healthy subjects or patients taking various NSAIDs including celecoxib, diflunisal, flurbiprofen, meloxicam, naproxen, and valdecoxib. Limited data suggest that sulindac may participate in the interaction to a lesser extent than do other NSAIDs. Aspirin and other salicylates do not appear to interact with lithium.

MANAGEMENT: Patients who must take lithium in combination with NSAIDs should be monitored for evidence of lithium toxicity, although clinically significant interactions are thought to be rare. More frequent monitoring of lithium levels is recommended. Patients should be advised to notify their physician if they experience potential signs and symptoms of lithium toxicity such as drowsiness, dizziness, confusion, weakness, ataxia, tremor, tinnitus, blurred vision, vomiting, diarrhea, thirst, and increased urination.

Dipyridamole, Sulfinpyrazone, Epoprostenol, Anagrelide, Cilostazol

MONITOR: Systemically and topically administered nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the risk of bleeding in patients treated with anticoagulants and other drugs that affect hemostasis such as platelet inhibitors, thrombin inhibitors, thrombolytic agents, or agents that commonly cause thrombocytopenia. The pharmacologic effects of NSAIDs that contribute to this interaction include prolongation of prothrombin time and inhibition of platelet adhesion and aggregation.

MANAGEMENT: Caution is advised if NSAIDs are used in combination with other drugs that affect hemostasis. Close clinical and laboratory observation for hematologic complications is recommended. Patients should be advised to promptly report any signs of bleeding to their doctor, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

Clopidogrel

MONITOR: The coadministration of clopidogrel with naproxen resulted in occult gastrointestinal blood loss in healthy volunteers. The mechanism has not been described, but may be due to additive platelet inhibition. The coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs) and clopidogrel should be undertaken with extreme caution. Additionally, some NSAIDs are substrates for the CYP450 isoenzyme 2C9. Clopidogrel inhibits this isoenzyme and therefore may lead to decreased metabolism of these NSAIDs. The clinical magnitude of this interaction is not known.

MANAGEMENT: Close observation for increased NSAID toxicity is recommended if these agents are coadministered with clopidogrel. Patients should also be advised to promptly report any signs of GI bleeding to their caregiver, including pain, swelling, dizziness, weakness, bloody or coffee-ground emesis, or red or black stools, and to avoid any over-the-counter NSAID products.

Alendronate

MONITOR: The combined use of alendronate with naproxen may synergistically increase the potential for gastrointestinal (GI) toxicity, including severe gastric mucosal damage and ulceration. A blinded, randomized, crossover study with healthy volunteers (n=26) demonstrated a significantly higher incidence of gastric ulcers (38%) in subjects receiving the combination for 10 days, compared to subjects receiving naproxen alone (12%) or alendronate alone (8%). This effect is also possible when alendronate is given concomitantly with other nonsteroidal anti-inflammatory drugs (NSAIDs).

MANAGEMENT: Until more information is available, caution is advised if alendronate is used with other NSAIDs. During concomitant therapy, patients should be closely monitored for symptoms of gastric ulcers and should be advised to immediately report signs and symptoms such as severe abdominal pain, nausea, loss of appetite, diarrhea, dizziness, lightheadedness, or the appearance of black, tarry stools.

Prednisolone, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisone, Cortisone, Triamcinolone (oral and injectable), Triamcinolone inhalation, Betamethasone, Fludrocortisone, Triamcinolone acetonide injection, Budesonide inhalation, Budesonide (oral)

MONITOR: The combined use of oral corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. In a large, case-control study of elderly patients, those who used corticosteroids and NSAIDs concurrently had an estimated relative risk (RR) for peptic ulcer disease and GI hemorrhage of 14.6 compared to those who used neither. Oral corticosteroid use was associated with a doubling of the risk (estimated RR = 2.0), but the risk was confined to those who also used NSAIDs. It is possible that both categories of agents are ulcerogenic and have additive effects on the GI mucosa during coadministration. Some investigators have also suggested that the primary effect of corticosteroids in this interaction is to delay healing of erosions caused by NSAIDs rather than cause de novo ulcerations.

MANAGEMENT: Caution is advised if oral corticosteroids and NSAIDs are used together, especially in patients with a prior history of peptic ulcer disease or GI bleeding and in elderly and debilitated patients. During concomitant therapy, patients should be advised to take the medications with food and to immediately report signs and symptoms of GI ulceration and bleeding such as severe abdominal pain, dizziness, lightheadedness, and the appearance of black, tarry stools. The selective use of prophylactic anti-ulcer therapy (e.g., antacids, H2-antagonists) may be considered.

Daptomycin

MONITOR: The concomitant administration of daptomycin and other nephrotoxic drugs or drugs that reduce renal filtration may result in additive renal effects and/or increased plasma levels of daptomycin. Daptomycin has been associated with renal impairment, although causality has not been determined. Increased plasma concentrations of daptomycin may increase the risk of myopathy. The risk may be increased in patients with pre-existing renal dysfunction.

MANAGEMENT: Serum drug concentrations and renal function, including serum creatinine, should be carefully monitored during concurrent administration. In addition, all patients receiving daptomycin should be monitored for the development of muscle pain or weakness, particularly of the distal extremities. CPK levels should be monitored weekly, and patients who develop unexplained elevations in CPK should be monitored more frequently. Daptomycin should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK levels exceeding 1000 U/L (approximately 5 times the upper limit of normal), or in patients without reported symptoms who have marked elevations in CPK (10 times the upper limit of normal, or more).

Chlorpropamide, Acetohexamide, Glipizide, Glyburide, Tolazamide, Tolbutamide, Glimepiride, Repaglinide (oral), Nateglinide (oral)

MONITOR: The hypoglycemic effect of insulin secretagogues (e.g., sulfonylureas, meglitinides) may be potentiated by certain drugs, including ACE inhibitors, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs), nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinine, and quinidine. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, fibrates); stimulating insulin secretion (salicylates, NSAIDs, disopyramide, quinine, quinidine, MAOIs); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); and/or inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor). Or, they may increase plasma concentration of insulin secretagogues by displacing them from plasma protein binding sites and/or inhibiting their metabolism (fibrates, NSAIDs, salicylates, sulfonamides). Clinical hypoglycemia has been reported during use of these agents alone or with insulin and/or sulfonylureas. Use of SSRIs has also been associated with loss of awareness of hypoglycemia in isolated cases.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin secretagogues, particularly in patients with advanced age and/or renal impairment. The oral antidiabetic dosage(s) may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their doctor if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.

Tobramycin (inhalation), Tobramycin (injection), Amikacin

MONITOR: The nephrotoxic effect of aminoglycosides may be potentiated by nonsteroidal anti-inflammatory drugs (NSAIDs), particularly if the latter had been given in high dosages for prolonged periods. Four children with cystic fibrosis who had been receiving chronic ibuprofen developed acute renal insufficiency shortly after initiation of IV aminoglycoside therapy for pulmonary exacerbations. An adolescent with CF who received intermittent, standard-dose ibuprofen during treatment with IV gentamicin also developed renal failure in addition to severe vestibular toxicity. Animal models suggest that renal prostaglandins may play a role in maintaining normal renal blood flow and glomerular filtration rate during the development of aminoglycoside nephrotoxicity, thus inhibition of their production by NSAIDs may worsen the renal damage.

MANAGEMENT: Whenever feasible, NSAID use should preferably be discontinued prior to initiating IV aminoglycoside therapy. If concomitant administration is necessary, hydration status as well as renal and vestibular functions should be closely monitored.

MONITOR: In premature infants, NSAIDs may increase the plasma concentrations of aminoglycosides. The proposed mechanism is decreased aminoglycoside clearance due to NSAID reduction of glomerular filtration rate, which is already low in premature infants. In a study of 20 preterm infants who had been given at least three days of amikacin or gentamicin therapy, mean peak plasma concentration increased by 17% and 33%, and mean trough concentration increased by 29% and 48%, respectively, on day 1 following administration of IV indomethacin for patent ductus arteriosus. Serum creatinine increased by 17%, while urine output and serum sodium decreased. Six patients developed hyponatremia.

MANAGEMENT: It may be advisable to consider reducing the dosage of aminoglycoside prior to initiation of NSAID therapy in infants. During coadministration, plasma antibiotic concentrations and renal function should be closely monitored, and the antibiotic dosage further adjusted as necessary.

Oxaliplatin

MONITOR: Theoretically, coadministration with drugs that are nephrotoxic may delay and/or decrease the clearance of oxaliplatin, which is primarily eliminated unchanged by the kidney. However, formal studies have not been conducted.

MANAGEMENT: Caution is advised if oxaliplatin is used in patients who have recently received or are receiving treatment with potentially nephrotoxic drugs (e.g., aminoglycosides, polypeptide and polymyxin antibiotics, vancomycin, amphotericin B, adefovir, cidofovir, tenofovir, foscarnet, cisplatin, gallium nitrate, lithium, mesalamine, certain immunosuppressants, intravenous bisphosphonates, intravenous pentamidine, high intravenous dosages of methotrexate, high dosages of nonsteroidal anti-inflammatory agents). The potential for increased toxicity of oxaliplatin such as peripheral sensory neuropathies and neutropenia should be considered. Renal function should be closely monitored during therapy.

Iloprost

MONITOR: Theoretically, iloprost may potentiate the risk of bleeding in patients treated with agents that affect hemostasis such as anticoagulants, platelet inhibitors, thrombin inhibitors, thrombolytic agents, or agents that commonly cause thrombocytopenia. Iloprost inhibits platelet aggregation. In clinical trials, hemoptysis occurred in 5% of the patients receiving iloprost compared to 2% of patients receiving placebo.

MANAGEMENT: Caution is advised if iloprost is used in combination with other drugs that affect hemostasis. Close clinical and laboratory observation for hematologic complications is recommended. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

Treprostinil

MONITOR: Theoretically, treprostinil may potentiate the risk of bleeding in patients treated with agents that affect hemostasis such as anticoagulants, platelet inhibitors, thrombin inhibitors, thrombolytic agents, or agents that commonly cause thrombocytopenia. Treprostinil inhibits platelet aggregation. However, patients received concomitant anticoagulants and nonsteroidal anti-inflammatory agents without increased bleeding in clinical trials.

MANAGEMENT: Caution is advised if treprostinil is used in combination with other drugs that affect hemostasis. Patients should be advised to promptly report any signs of bleeding to their doctor, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

Bivalirudin

MONITOR: The safety and efficacy of bivalirudin have not been established when used in conjunction with platelet inhibitors other than aspirin. Theoretically, the concomitant administration of bivalirudin (plus aspirin) and platelet inhibitors may increase the risk of bleeding complications due to additive or synergistic effects on the clotting cascade. However, limited data from drug interaction studies do not suggest pharmacodynamic interactions with the platelet inhibitors, ticlopidine and abciximab.

MANAGEMENT: Until further data are available, the coadministration of bivalirudin and antiplatelet agents, and possibly other agents with antiplatelet activity such as nonsteroidal anti-inflammatory drugs (NSAIDs), should probably be undertaken with caution. Close clinical and laboratory observation for bleeding complications is recommended.

Desmopressin oral and injectable, Desmopressin nasal

MONITOR: The use of selective serotonin reuptake inhibitors (SSRIs) has rarely been associated with hyponatremia, sometimes secondary to development of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). These events have generally been reversible following discontinuation of SSRI therapy and/or medical intervention. SSRI-related hyponatremia may be more common in elderly female patients and those who are volume-depleted or receiving concomitant diuretic therapy. Other drugs, including tricyclic antidepressants, chlorpromazine, chlorpropamide, carbamazepine, and nonsteroidal anti-inflammatory agents (NSAIDS), may also potentiate the effects of DDAVP and increase the risk of water intoxication and hyponatremia.

MANAGEMENT: Caution may be warranted during concomitant use. Serum electrolytes, especially sodium as well as BUN and plasma creatinine, should be monitored regularly.

Ticlopidine (oral)

MONITOR: Ticlopidine has been reported to potentiate the effect of nonsteroidal anti-inflammatory agents (NSAIDs) on platelet aggregation. The risk of bleeding may be increased, especially in patients with a history of gastrointestinal (GI) ulceration or bleeding. The safety of concomitant use has not been established.

MANAGEMENT: Patients should be monitored for signs and symptoms of bleeding, especially GI bleeding, if NSAIDs and ticlopidine are coadministered. They should be advised to promptly report any signs of bleeding to their physician, including abdominal pain, vomiting blood, red or black stools, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, nosebleeds, bleeding of gums from brushing, red or brown urine, or other unusual bleeding or bruising. Patients should also be counseled to avoid any other over-the-counter NSAID products.

Phenytoin (oral)

One case report has suggested that ibuprofen may cause phenytoin toxicity. However, data have been conflicting: one pharmacokinetic study did not demonstrate an effect and another study demonstrated that ibuprofen displaces phenytoin from protein binding sites in vitro. The clinical significance is unknown. Clinical and laboratory monitoring for altered phenytoin effect is recommended.

Magnesium hydroxide

One study has suggested that coadministration of magnesium hydroxide and ibuprofen may significantly increase the area under the plasma concentration-time curve for ibuprofen. This increase may be clinically beneficial in circumstances in which a rapid response to ibuprofen is desirable.

Probenecid

Probenecid may interfere with the plasma protein binding, metabolism, and/or renal elimination of nonsteroidal anti-inflammatory drugs (NSAIDs), resulting in increased NSAID plasma levels. The risk of NSAID toxicity may be increased. Although adverse effects from this interaction have not been reported, patients receiving this combination should be monitored for increased NSAID side effects. Patients should be advised to report possible signs of NSAID toxicity such as dizziness, drowsiness, headache, tinnitus, nausea, vomiting, dyspepsia, abdominal pain, diarrhea, or black tarry stools.

Ritonavir

Ritonavir has a moderate affinity for the CYP450 2C9 microsomal enzyme and may variably affect drugs that are substrates of this enzyme. The area under the plasma concentration-time curves for these drugs may increase or decrease. If concomitant therapy is necessary, close monitoring for therapeutic and adverse effects is strongly recommended. Dosage adjustments should be made as necessary.

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