Celebrex (Celecoxib) Interactions
Aminoglycosides
- Amiodarone
- Amphotericin B
Anticoagulants
Antihypertensive Agents
Antineoplastic Agents
- Antithymocyte Globulin
- Aspirin, ASA
- Bosentan
- Cidofovir
- Cimetidine
Corticosteroids
- Cyclosporine
- Delavirdine
- Dextromethorphan
Diuretics
- Donepezil
- Drospirenone; Ethinyl Estradiol
- Entecavir
- Ethanol
- Feverfew, Tanacetum parthenium
- Fluconazole
- Fluoxetine
- Fluvoxamine
- food
- Foscarnet
- Galantamine
- Ganciclovir
- Garlic, Allium sativum
- Ginger, Zingiber officinale
- Ginkgo, Ginkgo biloba
- Imatinib, STI-571
Immunosuppressives
Nonsteroidal antiinflammatory drugs (NSAIDs)
- Pamidronate
- Pemetrexed
- Pentamidine
Photosensitizing Agents
Platelet Inhibitors
Radiopaque Contrast Agents
- Rifampin
- Risedronate
- Rivastigmine
Salicylates
Selective serotonin reuptake inhibitors (SSRIs)
- Strontium-89 Chloride
- Sulfinpyrazone
- Tacrine
Thrombolytic Agents
- Vancomycin
- Voriconazole
- Zafirlukast
- Zoledronic Acid
Celebrex Celecoxib Interactions
NOTE: Celecoxib is a substrate of the hepatic cytochrome isoenzyme CYP2C9, and CYP2C9 inhibitors may significantly increase plasma concentrations of celecoxib. In vitro studies indicate that celecoxib is an inhibitor of CYP2D6; however the clinical relevance of the in vitro findings are not known. In vitro studies indicate that celecoxib is not an inhibitor of CYP2C9, 2C19, or 3A4 isoenzymes.
Because celecoxib exerts similar pharmacologic characteristics to other systemic nonsteroidal antiinflammatory drugs (NSAIDs), including COX-2 inhibitors, additive pharmacodynamic effects, including a potential increase for additive adverse gastrointestinal (GI) effects, may be seen if celecoxib is used with other NSAIDs. The drugs may represent duplicative therapies and generally concurrent use should be avoided.
Celecoxib is a substrate of the cytochrome P450 (CYP) 2C9 isoenzyme. Fluconazole significantly inhibits the metabolism of celecoxib via CYP2C9. Fluconazole at 200 mg per day resulted in a 2-fold increase in celecoxib plasma concentration after a single 200 mg dose of celecoxib. Celecoxib should be introduced at the lowest recommended dose in patients receiving fluconazole. In a crossover study, ketoconazole 200 mg daily did not alter the pharmacokinetics of celecoxib; however, abnormally high celecoxib plasma concentrations were noted in one of about 45 subjects. Theoretically, a similar interaction could occur with voriconazole, a known 2C9 inhibitor. Coadministration of celecoxib with other drugs that are known to inhibit CYP2C9 such as amiodarone, cimetidine, delavirdine, fluoxetine, fluvoxamine, imatinib, STI-571, metronidazole, or zafirlukast should be done with caution. The pharmacokinetics and/or pharmacodynamics of celecoxib on other CYP2C9 substrates including glyburide, phenytoin, and tolbutamide have been studied. Glycemic control with glyburide was not altered; no clinically important pharmacokinetic interactions were found.
Rifampin has been reported to induce the hepatic metabolism of celecoxib via cytochrome P450 2C9. In a pharmacokinetic study, patients were given celecoxib 200 mg twice daily and rifampin 600 mg daily or placebo for 11 days. The AUC of celecoxib was reduced by about 50% with concurrent rifampin administration as compared to placebo. Although analgesic efficacy was not evaluated in this study, it is possible that patients treated with celecoxib and rifampin may have a reduced response to celecoxib. Other rifamycins (e.g., rifabutin or rifapentine) are not as potent inducers and would be less likely to produce clinically significant decreases in celecoxib concentrations.
In vitro studies indicate that celecoxib is an inhibitor of cytochrome P450 (CYP) 2D6. There is a potential for drug interaction between celecoxib and drugs that are metabolized by CYP2D6. More than 30 drugs are metabolized by CYP2D6, which include codeine, desipramine, dextromethorphan, encainide, flecainide, haloperidol, meperidine, methadone, morphine, oxycodone, propafenone, and propranolol. In a small pharmacokinetic study, patients were given celecoxib 200 mg twice daily or placebo and dextromethorphan 60 mg and desipramine 100 mg on days 6 and 9, respectively. Results indicated no change in desipramine metabolism but a modest inhibitory effect on dextromethorphan metabolism. In vitro studies indicate that celecoxib is not an inhibitor of CYP2C9, 2C19, or 3A4 isoenzymes.
The addition of celecoxib to systemic salicylates therapy may represent a duplication of therapy and should be approached with caution. In addition, additive GI effects may be seen in patients receiving salicylates or platelet inhibitors concurrently with celecoxib. The concurrent use of aspirin and celecoxib does increase the risk of serious gastrointestinal events. For example, over a 6-month period, 6 ulcer complications (i.e., GI bleeding, perforation, or obstruction) occurred in 833 patients that took aspirin up to 325 mg daily and celecoxib 400 mg twice daily as compared with 5 events in 3154 patients only taking celecoxib. Furthermore, the annualized incidences of ulcer complications and symptomatic ulcers (endoscopic or x-ray evidence of a gastric or duodenal ulcer) were similar for patients taking aspirin and celecoxib (14 events for 298 patient-years of exposure) or aspirin and ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily (17 events for 283 patient-years of exposure). Because of its lack of platelet effects, celecoxib is not a substitute for aspirin, ASA for cardiovascular prophylaxis. According to information in the prescribing information, celecoxib may be given with low-dose aspirin. The difference between the antiplatelet effects and the antagonism of aspirin by a nonsteroidal anti-inflammatory drug needs to be appreciated. Ibuprofen, but not rofecoxib, has been shown to interfere with the antiplatelet effects of aspirin. As determined by an in vitro study, the rank order of potencies for reducing the antagonism of COX-1 by aspirin is ibuprofen > celecoxib > valdecoxib > rofecoxib. In vitro, the blockage of aspirin inactivation of platelet COX-1 can occur at much lower concentrations of celecoxib than inhibition of platelet COX-1 activity. Receipt of aspirin at the same time as celecoxib 200 mg by 8 adults did not affect the platelet inhibitory effect of aspirin in one study; patients received celecoxib 200 mg twice daily for 4 days before the single dose of aspirin 325 mg given with the morning celecoxib dose on day 5. Until further data are available to support or refute the hypothesis that celecoxib does not antagonize the antiplatelet effects of aspirin, cautious use of celecoxib for patients taking low-dose (i.e., < 325 mg/day) aspirin for cardiovascular prophylaxis appears to be warranted.
Drug interactions might be seen in patients receiving anticoagulants or thrombolytic agents concurrently with celecoxib. Although celecoxib lacks platelet inhibitory effects, GI adverse events or bleeding side effects are possible. In an observational study, patients older than 66 years who continuously received warfarin and were hospitalized with an upper GI hemorrhage were significantly more likely to be taking nonselective NSAIDs, celecoxib, or rofecoxib as compared with a similar group of patients who did not have the adverse event. Furthermore, the risk of hospitalization for upper GI hemorrhage was similar for patients who took warfarin and celecoxib, rofecoxib, or nonselective NSAIDs. There have been post-marketing reports of serious bleeding events, some of which were fatal, in predominantly elderly patients receiving concomitant warfarin and celecoxib. The events were in association with increases in the INR. In a group of healthy subjects receiving warfarin doses of 2—5 mg daily, the INR was unaffected by the addition of celecoxib. Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing celecoxib therapy in patients receiving warfarin or similar agents.
Additive GI effects may be seen in patients receiving corticosteroids along with NSAIDs, including celecoxib. Although some patients may need to be given corticosteroids and NSAIDs concomitantly, which can be done successfully for short periods of time without sequelae, prolonged concomitant administration should be avoided.
Ethanol can be irritating to the gastric mucosa and additive GI effects may be seen in patients who ingest ethanol along with NSAIDs, including celecoxib. It is advisable to limit intake of alcoholic beverages during celecoxib therapy. Prolonged concomitant administration should be avoided.
NSAIDs interfere with lithium excretion and may lead to elevated lithium serum concentrations. Clinically significant interactions rarely occur, but lithium toxicity has been reported. It is thought that prostaglandins are involved in the renal clearance of lithium and that NSAIDs interfere with this process. Increased lithium levels develop over 5—10 days after adding a NSAID and return to pretreatment levels within 7 days of stopping the NSAID. Lithium plasma concentrations were increased approximately 17% in subjects receiving lithium 450 mg twice daily and celecoxib 200 mg twice daily compared to subjects receiving lithium alone. If NSAID therapy is started or stopped in a patient stabilized on lithium, monitor for evidence of lithium toxicity or decreased clinical effects, respectively.
In general, NSAID therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate levels. Nonsteroidal antiinflammatory drugs (NSAIDs) should not be administered prior to, concomitantly, or following intermediate or high doses of methotrexate. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs are administered concurrently with lower doses of methotrexate. In patients with rheumatoid arthritis, methotrexate has been given concurrently with NSAIDs without apparent problems. The pharmacokinetics of methotrexate was not affected by celecoxib 200 mg twice daily for one week in a study including 14 rheumatoid arthritis patients receiving maintenance doses of methotrexate (5—20 mg once weekly for at least 3 months). It should be noted that the doses of methotrexate used in rheumatoid arthritis are lower than those used in psoriasis or malignant disease; these higher doses may lead to unexpected toxicity in combination with NSAIDs. Concurrent use of NSAIDs may lead to an increased risk of GI bleeding in patients with methotrexate-induced thrombocytopenia or mask fever, pain, swelling and other signs and symptoms of an infection.
Clinical status and serum creatinine and potassium levels should be closely monitored when cyclosporine is given with salicylates or other nonsteroidal antiinflammatory drugs (NSAIDs). Pharmacodynamic interactions have been reported between cyclosporine and NSAIDs, consisting of additive decreases in renal function with concomitant use. NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
The concomitant administration of cidofovir and NSAIDs is contraindicated due to the potential for increased nephrotoxicity. NSAIDs should be discontinued 7 days prior to beginning cidofovir.
The manufacturer reported that coadministration of celecoxib with an aluminum- and magnesium-containing antacid decreased plasma celecoxib concentrations by 37%; but minimally decreased celecoxib AUC by 10%. This interaction was not considered to be clinically significant.
Garlic, Allium sativum, ginger, Zingiber officinale and ginkgo, Ginkgo biloba, have clinically significant effects on platelet aggregation leading to a theoretical increased risk of bleeding when used with NSAIDs. An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia due to decreases in platelet aggregation. Notable interactions may occur with myelosuppressive antineoplastic agents, antithymocyte globulin, and strontium-89 chloride . It is unclear if celecoxib is associated with less risk than other NSAIDs due to its lack of platelet inhibitory effects and minimal gastric ulceration or hemorrhagic potential.
In a retrospective study, those women taking an NSAID concomitantly with alendronate had a 70% increased risk of developing a GI adverse event, such as gastric ulceration. The use of celecoxib may be an alternative to a traditional NSAID in these patients, but the incidence of GI effects has not been evaluated with the combination of celecoxib and alendronate.
Preclinical data suggest agents that inhibit prostaglandin synthesis such as NSAIDs could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Since the use of NSAIDs and aspirin, ASA, is associated with GI irritation, exercise caution when administering these agents with risedronate due to the potential for additive GI toxicity. During clinical trials for osteoporosis, the majority of patients took either NSAIDs or aspirin and the incidence of adverse upper GI reactions was similar between risedronate-treated (24.5%) and placebo-treated patients (24.8%).
NSAIDs, to varying degrees, have been associated with an elevation in blood pressure (approximately 5 mm Hg) when given over a period of weeks. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs, including selective COX-2 inhibitors such as celecoxib, may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways. NSAIDs have been shown to attenuate the effects of diuretics, beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), vasodilators, central alpha-2 agonists, peripheral alpha-1 blockers, and angiotensin II blockers. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
It is possible that additive nephrotoxicity may occur in patients who receive NSAIDs concurrently with other nephrotoxic agent. These include aminoglycosides, amphotericin B , cisplatin , foscarnet , ganciclovir , pamidronate , pentamidine , IV vancomycin, and zoledronic acid.
In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of many NSAIDs. Leflunomide has inhibited the metabolism of diclofenac in vitro. Leflunomide also altered protein binding, increasing the free fraction of both ibuprofen and diclofenac by 13—50%. The clinical significance of these interactions with NSAIDs is unknown. There was extensive concomitant use of NSAIDs in phase III clinical studies of leflunomide in the treatment of rheumatoid arthritis and no clinical differential effects were observed. However, because some NSAIDs have been reported to cause hepatotoxic effects, some caution may be warranted in their use with leflunomide.
Nonsteroidal antiinflammatory drugs (NSAIDs) may cause additive pharmacodynamic GI effects with Alzheimer’s disease (AD) agents that inhibit cholinesterase (e.g., donepezil, galantamine , rivastigmine , or tacrine), leading to GI intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of AD , there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
Feverfew appears to inhibit prostaglandin synthesis, reportedly at a different step in the prostaglandin pathway than the NSAIDs, which inhibit cyclooxygenase. Theoretically, the NSAIDs might decrease the effectiveness of feverfew, Tanacetum parthenium. However, clinical interactions have not been reported.
Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Drugs that may have additive effects on serum potassium with drospirenone; ethinyl estradiol (Yasmin®) include chronic treatment with NSAIDs, and monitoring of serum potassium in the 1st month of concurrent therapy is recommended.
Bosentan is a significant inducer of CYP2C9 and CYP3A4 hepatic isoenzymes. Theoretically, bosentan can increase the hepatic clearance of celecoxib (CYP2C9 substrate); however, this interaction has not been studied.
Sulfinpyrazone is an inhibitor of CYP2C9 and may lead to increased plasma levels of some NSAIDs, including celecoxib. Sulfinpyrazone and its metabolites inhibit platelet cyclooxygenase leading to decreased platelet aggregation. Co-administration of sulfinpyrazone with NSAIDs may increase the risk of GI ulceration and/or bleeding.
Use of pemetrexed with celecoxib, a nonsteroidal anti-inflammatory drug (NSAID), may increase the systemic exposure to pemetrexed. The clearance of pemetrexed is reduced about 20% in patients with normal renal function that also take ibuprofen 400 mg four times daily. Patients with a creatinine clearance between 45 and 79 ml/minute should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days after pemetrexed administration. Due to an absence of data, NSAIDs with longer half-lives should not be taken by anyone (regardless of renal function status) for a period of 5 days before, the day of, and 2 days after pemetrexed administration. If use of a NSAID is unavoidable, monitor patients for myelosuppression, renal, and gastrointestinal adverse effects from pemetrexed.
When celecoxib was taken with a high fat meal, peak plasma levels were delayed 1—2 hours with an increase in total absorption of 10—20%. Under fasting conditions, at doses > 200 mg, there is a less than proportional increase in Cmax and AUC, which may be due to low solubility of the drug in aqueous media. It is recommended that celecoxib at doses up to 200 mg twice daily can be administered without regards to meals; however, higher doses (400 mg twice daily) should be administered with food to improve absorption.
Because the use of other nephrotoxic drugs including nonsteroidal anti-inflammatory drugs (NSAIDs) is an additive risk factor for nephrotoxicity in patients receiving radiopaque contrast agents, NSAID therapy should be withheld, when possible, during radiopaque contrast agent administration.
Because entecavir is primarily eliminated by the kidneys and nonsteroidal anti-inflammatory agents (NSAIDs) can affect renal function, concurrent administration with NSAIDs may increase the serum concentrations of entecavir and adverse events. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
The combined use of selective serotonin reuptake inhibitors (SSRIs) and either aspirin, ASA or nonsteroidal anti-inflammatory drugs (NSAIDs) may elevate the risk for an upper GI bleed. In a large cohort, the observed/expected risk ratio for GI bleeding when an SSRI was combined with a NSAID was 12.2 (CI 7.1—19.5) vs. 3.6 (CI 2.7—4.7) when a SSRI was used alone. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin or NSAIDs. Aspirin and NSAIDs also impair the gastric mucosa defenses by inhibiting prostaglandin formation. In the cohort study evaluating SSRIs and NSAIDs, COX-2 inhibitor use was not evaluated separately; the absolute risk of GI bleed when an SSRI is combined with a COX-2 selective agent is not known. In patients at risk for GI bleed, the combined use of COX-2 inhibitors and SSRIs should be approached cautiously.
[ Last revised: 8/3/2005 6:04:00 PM ]
Related entries
Syndicate
|
