Zoledronic Acid
Naproxen Interactions
NOTE: Naproxen is a substrate of the hepatic cytochrome isoenzyme CYP2C9.
Because naproxen 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 naproxen is used with other NSAIDs. In general, concurrent use of naproxen and another NSAID should be avoided. Concomitant use of ketorolac with naproxen is contraindicated.
Increased adverse gastrointestinal (GI) effects are possible if naproxen is used with ethanol. Patients with alcoholism may have an increased risk of GI bleeding with nonsteroidal anti-inflammatory drug usage. Patients using alcohol and naproxen concurrently should be monitored closely for bleeding.
Concomitant use of naproxen with tobacco may enhance the risk of gastrointestinal (GI) side effects. Patients with tobacco use may have an increased risk of GI bleeding with nonsteroidal anti-inflammatory drug usage. Patients using tobacco and naproxen concurrently should be monitored closely for bleeding.
Increased gastrointestinal (GI) effects are possible if naproxen is used with corticosteroids. 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. Concomitant use of corticosteroids appears to increase the risk of adverse GI events due to NSAIDs. Nonsteroidal anti-inflammatory drugs should be used cautiously in patients receiving corticosteroids.
The concomitant administration of ofloxacin or levofloxacin and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of CNS stimulation and convulsive seizures. Patients with CNS disorders that may predispose them to seizure development or patients taking drugs that lower the seizure threshold may not be appropriate candidates for naproxen or another NSAID usage if they are also taking levofloxacin or ofloxacin.
Aspirin, ASA displaces naproxen from binding to albumin and increases naproxen excretion. Due to an increased free fraction of naproxen, increased adverse gastrointestinal effects are possible if naproxen is used with aspirin. In addition, further benefit with use of the two drugs as compared with aspirin monotherapy is not apparent, and antagonism of the irreversible platelet effect of aspirin occurs with concurrent use. The interaction appears to be due to competition at the enzyme active site. Patients who take low-dose aspirin for cardiovascular health may have the beneficial effects of aspirin on platelet function counteracted by naproxen. Concomitant aspirin and naproxen use is not recommended.
Due to high protein binding, salicylates (e.g., salsalate) could be displaced from binding sites or could displace other highly protein-bound drugs such as naproxen. An enhanced effect of the displaced drug may occur. Because naproxen can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time, additive effects may be seen in patients receiving platelet inhibitors (e.g., aspirin), anticoagulants, or thrombolytic agents. Patients treated with anticoagulants may have an increased risk of gastrointestinal (GI) bleeding with nonsteroidal anti-inflammatory drug usage. A clinically significant interaction between naproxen and warfarin has not been observed; however, a prolongation of prothrombin time has been reported with concurrent administration of warfarin and other NSAIDs. Both naproxen and warfarin are highly protein bound. Therefore, close monitoring of the INR is recommended during and shortly after concurrent use of naproxen and warfarin. Patients receiving any anticoagulant or thrombolytic agent and naproxen concurrently should be monitored closely for bleeding.
The concomitant administration of cidofovir and nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen, is contraindicated due to the potential for increased nephrotoxicity. Naproxen should be discontinued 7 days prior to beginning cidofovir.
Chronic coadministration of adefovir with nephrotoxic drugs, such as nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. The use of adefovir with NSAIDs may be done cautiously. As stated in the current adefovir prescribing information, ‘Ibuprofen (800 mg PO three times daily), when given concomitantly with adefovir dipivoxil, increased the adefovir Cmax by 33% and AUC by 23%, as well as urinary recovery. The increase appears to be due to higher oral bioavailability, not a reduction in renal clearance of adefovir.’ In an in vitro investigation, the antiviral effect of adefovir was unaltered and the renal proximal tubule accumulation of adefovir was inhibited by the presence of a NSAID. Adefovir is efficiently transported by the human renal organic anion transporter 1, and the presence of this transporter appears to mediate the accumulation of the drug in renal proximal tubules. The in vitro study suggests that the use of a NSAID with adefovir may potentially reduce the nephrotoxic potential of adefovir. Of course, NSAIDs are associated with nephrotoxicity of their own; therefore, further data on the interaction between NSAIDs and adefovir in humans are needed.
Preclinical data suggest agents that inhibit prostaglandin synthesis such as naproxen could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Nonsteroidal anti-inflammatory drugs (NSAIDs) interfere with lithium excretion and may lead to elevated lithium serum concentrations. It is thought that prostaglandins are involved in the renal clearance of lithium and that NSAIDs interfere with lithium excretion. Typically, increased lithium concentrations develop over 5 - 10 days after adding a NSAID and return to pretreatment levels within 7 days of stopping the NSAID. Lithium concentrations should be monitored when patients initiate or discontinue NSAIDs such as naproxen. Observe patients carefully for signs of lithium toxicity.
In general, nonsteroidal anti-inflammatory drug (NSAID) therapy can decrease the clearance of methotrexate, resulting in elevated and prolonged serum methotrexate concentrations. Nonsteroidal anti-inflammatory drugs 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. It should be noted that the doses of methotrexate used for rheumatoid arthritis are lower than those used for psoriasis or malignant disease; these higher doses may lead to unexpected toxicity in combination with NSAIDs. Also, 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 concentrations should be closely monitored when systemic cyclosporine is given with salicylates or other nonsteroidal antiinflammatory drugs (NSAIDs). Renal dysfunction associated with cyclosporine may be potentiated by concurrent usage of diclofenac, naproxen, or sulindac. The effects of NSAIDs on the production of renal prostaglandins may cause changes in the elimination of cyclosporine. Potentiation of renal dysfunction may especially occur in a dehydrated patient. Serum creatinine, potassium, and cyclosporine concentrations should be closely monitored if cyclosporine is given with salicylates or other NSAIDs. Patients should be monitored for signs and symptoms of cyclosporine toxicity and infection, as NSAIDs may mask fever, pain, or swelling. Increased tear production was not seen in patients receiving ophthalmic NSAIDs or using punctual plugs concurrently with cyclosporine ophthalmic emulsion.
Substantial increases in the plasma concentration of naproxen anion have been observed following concomitant administration with probenecid. Plasma concentrations of naproxen can be increased by 50% and its half-life increased to 37 hours. The mechanism of this interaction may be through the inhibition of the formation of naproxen’s glucuronide metabolite as well as inhibition of renal clearance.
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen decrease platelet aggregation. Garlic, Allium sativum, ginger, Zingiber officinale, and ginkgo, Ginkgo biloba, also have clinically significant effects on platelet aggregation; concurrent use with a NSAID may lead to a potential increased risk of bleeding. A case of fatal intracerebral bleeding has been reported with the combination of ginkgo and ibuprofen.
An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia. Notable interactions may occur with myelosuppressive antineoplastic agents, antithymocyte globulin and strontium-89 chloride. Patients receiving naproxen concurrently with antineoplastic agents, antithymocyte globulin, or strontium-89 chloride should be monitored closely for bleeding.
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, most 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%). Patients using risedronate and naproxen concurrently should be monitored closely for gastrointestinal adverse effects including signs and symptoms of bleeding.
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in combination with alendronate has been noted as an independent risk factor for the development of GI adverse reactions with alendronate therapy. In clinical trials, the incidence of upper gastrointestinal adverse events was increased in patients who received aspirin-containing medicines with alendronate 10 mg daily or higher. One patient with a history of peptic ulcer disease and gastrectomy that received alendronate 10 mg daily and aspirin got an anastomotic ulcer with mild hemorrhage. The patient recovered upon alendronate and aspirin discontinuation. In a prospective study, women taking concomitant naproxen and alendronate were significantly more likely to develop gastric ulcers than women receiving either agent alone. In addition, alendronate plus naproxen was poorly tolerated with 69% of patients receiving the combination reporting side effects compared to 23% of those receiving naproxen alone and 54% of those receiving alendronate. Patients using alendronate and naproxen concurrently should be monitored closely for gastrointestinal adverse effects including signs and symptoms of bleeding.
Nonsteroidal anti-inflammatory drugs (NSAIDs), to varying degrees, have been associated with an elevation in blood pressure (approximately 5 mmHg) when given over a period of weeks. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs 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. Concomitant volume depletion caused by diuretics and prostaglandin inhibition caused by naproxen may increase the risk of renal failure due to inadequate kidney perfusion. 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.
Due to the inhibition of renal prostaglandins by naproxen, concurrent use with other nephrotoxic agents may lead to additive nephrotoxicity. Naproxen should be given with caution to patients taking aminoglycosides, amphotericin B, systemic bacitracin, cisplatin, gold compounds, ganciclovir, pamidronate, pentamidine, tacrolimus, tenofovir, PMPA, foscarnet, parenteral vancomycin, or zoledronic acid. Monitor renal function carefully during concurrent therapy.
In vitro studies indicate that the M1 metabolite of leflunomide inhibits cytochrome P450 2C9, the enzyme responsible for the metabolism of naproxen. The clinical significance of the 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 anti-inflammatory drugs (NSAIDs) may cause additive pharmacodynamic GI effects with cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, or tacrine), leading to gastrointestinal 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 Alzheimer’s disease, there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with cholinesterase inhibitors result in synergistic effects in Alzheimer’s disease.
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 concentrations. 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.
The enteric-coated, delayed-release naproxen tablets (EC Naprosyn®) are designed to dissolve at a pH of 6 or greater. Concomitant use of this particular naproxen product with antacids, sucralfate, H2-blockers, or proton pump inhibitors (PPIs) is not recommended due to the gastric pH alteration. Increased gastric pH will affect the dissolution site and thus, absorption characteristics of the enteric-coated, delayed-release naproxen tablets. Periodic antacid use should not be problematic as long as the antacid and enteric-coated naproxen administration are separated by at least 2 hours.
An interaction may occur between naproxen and hydantoins, sulfonylureas, or sulfonamides. Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with hydantoins, sulfonylureas, or sulfonamides, monitor patients for toxicity from any of the drugs.
Voriconazole is a substrate and inhibitor of cytochrome P450 isoenzyme 2C9, which is the isoenzyme responsible for the metabolism of naproxen. Thus, increased plasma concentrations of naproxen are possible. The clinical significance of this potential interaction is unknown. If voriconazole is administered concurrently with naproxen, monitor for NSAID-related side-effects, such as fluid retention or GI irritation, or renal dysfunction and adjust the naproxen dose, if needed.
Sulfinpyrazone is an inhibitor of CYP2C9, and naproxen is a substrate of CYP2C9. Thus, concurrent use may lead to increased plasma naproxen concentrations. During concurrent therapy, monitor for potential NSAID-induced toxicity, such as GI irritation or bleeding. Sulfinpyrazone has been independently associated with GI bleeding in some cases; concurrent therapy with NSAIDs such as naproxen could potentially increase the risk of adverse GI effects.
Use of pemetrexed with naproxen, 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.
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.
The combined use of selective serotonin reuptake inhibitors (SSRIs) with aspirin, ASA or nonsteroidal anti-inflammatory drugs (NSAIDs) may elevate the risk for bleeding including upper gastrointestinal (GI) bleeds. Selective serotonin reuptake inhibitors may inhibit serotonin uptake by platelets, which may augment the antiplatelet effects of aspirin. As determined by analysis of data from >26,000 patients included in a cohort study, SSRI use alone increased the risk for serious GI bleed by 3.6-fold as compared with nonusers of an SSRI. Combined use of an SSRI and NSAIDs increased the risk 12.2-fold whereas use of low-dose aspirin with an SSRI increased the risk 5.2-fold. The absolute risk of GI bleed from concomitant therapy with an NSAID and a SSRI was 17/4107 patients. If the drugs are used concurrently, monitor patients for signs of increased bleeding.
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.
[ Last revised: 1/13/2006 9:04:00 PM ]
References
. Runkel R, Mroszczak E, Chaplin M et al. Naproxen-probenecid interaction. Clin Pharm Ther 1978;24:706 - 13.
. The sixth report of the Joint National Committee on detection, evaluation, and treatment of high blood pressure. National Institute of Health publication No. 99 - 4080. 1997:1 - 64.
. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. Ann Intern Med 1991;115:787 - 96.
. Lamant V, Mauco G, Braquet P et al. Inhibition of the metabolism of platelet activating factor (PAF-acether) by three specific antagonists from Ginkgo biloba. Bio Pharmacol 1987;36:2749 - 52.
. Ariga T. Platelet aggregation inhibitor in garlic (letter). Lancet 1980;i:150.
. Collier HOJ, Butt NM, McDonald-Gibson WJ, et al. Extract of feverfew inhibits prostaglandin biosynthesis (letter). Lancet 1980;2:922 - 3.
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