Skelan Forte Drug Interactions

Naproxen sodium: Albumin-bound drugs (e.g., hydantoins, sulfonamides, sulfonylureas, coumarin-type anticoagulants, aspirin, other NSAIDs): Naproxen is highly bound to plasma albumin. Theoretically, it can be displaced from binding sites or it can displace other protein-bound drugs from binding sites. Thus, patients who are receiving naproxen concomitantly with any of these drugs should be carefully monitored for possible dosage adjustment and adverse effects.
Anticoagulants/Thrombolytic agents (e.g., warfarin, heparin, streptokinase): The concomitant use of warfarin and NSAIDs synergistically increases the risk of serious GI bleeding compared with either drug used alone. Administration of naproxen with warfarin results in a slight increase in free warfarin in serum, but does not affect the hypoprothrombinemic effect of warfarin. Caution should be exercised when giving naproxen to patients taking any anticoagulant or thrombolytic agent. Close monitoring of international normalized ratio (INR) should also be conducted.
ACE inhibitors (e.g., captopril, fosinopril, imidapril, enalapril), ARBs (e.g., losartan, telmisartan), and beta-blockers: NSAIDs, such as naproxen sodium, may reduce the anti-hypertensive effects of ACE inhibitors, ARBs, and beta-blockers. Moreover, naproxen may also increase the risk of renal dysfunction (i.e., acute renal failure) in patients taking ACE inhibitors and ARBs, particularly in elderly patients, volume-depleted patients (including those on diuretic therapy), or those with pre-existing poor renal function. The risk for acute renal failure and hyperkalemia may also be induced with the coadministration of naproxen with ACE inhibitors and ARBs.
Blood pressure, serum electrolyte levels, and renal function should be closely monitored, as the blood pressure may significantly increase during concurrent use. Patients should be adequately hydrated, and renal function should be assessed at the beginning and periodically during the concomitant treatment.
Anti-platelet Agents (e.g., aspirin, clopidogrel, cilostazol, dipyridamole): The coadministration of anti-platelet agents and naproxen in patients who have coagulation disorders may increase the risk of bleeding and may prolong bleeding time. The benefit of coadministration of naproxen with these drugs should be weighed against the risk.
Aspirin: The concomitant use of naproxen with aspirin is not recommended. Aside of the little to no increase in efficacy, the concomitant therapy may result to additive adverse reactions and may increase the risk for serious GI events. Moreover, naproxen may attenuate the anti-platelet property of aspirin.
There is no consistent evidence that low-dose aspirin lessens the increased risk of serious cardiovascular events associated with NSAIDs. Contrarily, some evidences demonstrated that the use of NSAIDs may significantly diminish the cardioprotective effects of aspirin.
Aspirin taken concomitantly with naproxen may decrease protein binding of naproxen, but clearance of free (unbound) naproxen does not seem to be altered.
The clinical importance of this pharmacokinetic interaction has not been established.
Bisphosphonates: Coadministration of NSAIDs and bisphosphonates may increase the risk of gastric mucosal damage.
Cholestyramine: Cholestyramine can delay the rate (but not the extent) of naproxen absorption. Naproxen sodium should be taken at least one hour prior, or four to six hours following cholestyramine administration.
Corticosteroids: Caution is advised when corticosteroids are given together with NSAIDs because of the increased risk of GI ulceration or bleeding, especially in patients older than 65 years of age.
If dosage of corticosteroid is to be reduced during naproxen therapy, it should be done gradually. Patients must be closely monitored for any adverse effects, including adrenal insufficiency or symptomatic exacerbation of the condition being treated.
Ciclosporin, tacrolimus: Caution is advised when ciclosporin or tacrolimus is given together with an NSAID because of the increased risk of nephrotoxicity.
Digoxin: NSAIDs may increase plasma digoxin concentrations and may prolong the half-life of digoxin, which may result in digitalis toxicity. NSAIDs may also exacerbate cardiac failure and reduce the glomerular filtration rate (GFR) in patients taking digoxin. Increased monitoring of serum levels and dosage adjustments of the cardiac glycosides may be required during and after concurrent NSAID therapy.
Diuretics: Naproxen can reduce the natriuretic effect of furosemide or thiazide diuretics. This interaction has been the result of the inhibition of renal prostaglandin synthesis. Moreover, the use of NSAIDs with diuretics may increase the risk for acute renal failure and hyperkalemia. Patients should be monitored closely for blood pressure and renal function (including serum electrolytes) to assure diuretic efficacy during concomitant therapy with NSAIDs.
Drugs affecting gastric pH [e.g., antacids (magnesium oxide, aluminum hydroxide, sodium bicarbonate), sucralfate]: Concomitant administration of naproxen with antacids or sucralfate may result to a delay in the absorption rate of naproxen.
Sodium bicarbonate increases the aqueous solubility of naproxen sodium, resulting to enhanced absorption rate of naproxen sodium.
H2 receptor antagonists: It has been demonstrated that the coadministration of cimetidine, ranitidine, or famotidine reduced the half-life of naproxen by approximately 50%. This interaction does not appear to be clinically important. However, since H2 antagonists may protect the gastric mucosa from the irritant effects of NSAIDs, the concurrent use of these drugs with naproxen sodium may be beneficial.
Lithium: NSAIDs may elevate plasma lithium concentrations by about 15% and reduce renal lithium clearance by approximately 20%, leading to an increased risk of lithium toxicity due to the inhibition of renal prostaglandin synthesis. Patients should be closely observed for signs of lithium toxicity, and monitoring of plasma lithium concentrations should be performed during the initial phases of the concomitant therapy and following dosage modifications. Appropriate lithium dosage adjustment may be required when therapy with naproxen sodium is discontinued.
Methotrexate: Severe and sometimes fatal toxicity has occurred following the concomitant use of NSAIDs with high-dose methotrexate in patients with various malignant neoplasms or rheumatoid arthritis. The mechanism of this interaction is not yet established, but it is suggested that NSAIDs decrease the renal perfusion of methotrexate either by inhibition of renal prostaglandin synthesis or by competing for renal elimination. Thus, caution is advised in the coadministration of naproxen with methotrexate. Patients should be monitored for renal function, full blood counts, and signs of methotrexate toxicity.
Other NSAIDs (e.g., ibuprofen, mefenamic acid, ketorolac, diclofenac): Concomitant use of naproxen with other NSAIDs (including selective COX-2 inhibitors) is not recommended, since it may result to additive adverse reactions and may increase the risk for serious GI events.
Pemetrexed: The use of naproxen sodium with pemetrexed may increase the risk of pemetrexed-associated myelosuppression, nephrotoxicity, and GI toxicity. Patients should be monitored for the signs of increased pemetrexed toxicity.
Probenecid: Probenecid has been suggested to interfere with the metabolism and excretion of naproxen. The mechanism of this interaction involves the marked decrease in urinary excretion of native naproxen and an increase in urinary 6-O-desmethylnaproxen, resulting to increased naproxen anion plasma levels and significantly prolonged plasma half-life (i.e., from 14 hours to 37 hours following a single dose of naproxen 500 mg). Thus, probenecid should be carefully coadministered with naproxen, and patients should be monitored for possible dosage adjustments.
Quinolone antibiotics: Patients taking quinolones together with NSAIDs may have an increased risk of convulsions.
Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, citalopram, sertraline) and serotonin-norepinephrine reuptake inhibitors (SNRIs): An increased risk of GI ulceration and bleeding may occur when naproxen sodium and SSRIs are taken concomitantly. Caution should be exercised in the administration of naproxen during SSRI therapy.
Zidovudine: Since NSAIDs may interfere with the metabolism of zidovudine, the coadministration of these drugs may result to higher zidovudine plasma levels and increased risk of zidovudine toxicity, especially hematological effects. Dose reduction may be considered.
Paracetamol: Alcohol: The effects of alcohol in the pharmacokinetics of paracetamol are complex. Excessive alcohol consumption may induce hepatic cytochrome enzymes. However, alcohol may also act as a competitive inhibitor in the metabolism of paracetamol. Coadministration of paracetamol with alcohol can increase the risk of paracetamol-induced hepatotoxicity (see Precautions).
Anticonvulsants (e.g., barbiturates, carbamazepine, phenytoin): Some anticonvulsants induce the hepatic microsomal enzymes, resulting to the increased conversion of paracetamol to hepatotoxic metabolites and increasing the risk of paracetamol-induced hepatotoxicity.
Chloramphenicol: The coadministration of paracetamol may increase chloramphenicol concentrations.
Cholestyramine: Cholestyramine, especially if taken within one hour of paracetamol administration, may reduce the absorption of paracetamol.
Domperidone or metoclopramide: The absorption of paracetamol may be accelerated by drugs that increase gastric emptying, such as metoclopramide or domperidone.
Enzyme-inducing agents (e.g., amoxicillin + clavulanic acid, anticoagulants, ethanol, isoniazid, zidovudine): Administering paracetamol with drugs that induce hepatic cytochrome enzymes (especially CYP2E1) may result in an increased level of paracetamol's hepatotoxic metabolites, thus increasing the risk of hepatotoxicity. Caution should be performed in the coadministration of paracetamol with these drugs. Patients receiving these drugs should be instructed to limit their paracetamol intake.
Drugs that decrease gastric emptying: The absorption of paracetamol may be reduced if it is concomitantly administered with drugs that decrease gastric emptying (e.g., propantheline, antidepressants with anticholinergic properties, narcotic analgesics).
Hepatotoxic drugs (e.g., isoniazid): The risk of paracetamol toxicity may be increased in patients taking paracetamol together with other potentially hepatotoxic drugs.
Lamotrigine: Multiple oral doses of paracetamol may reduce the AUC and half-life of lamotrigine. Moreover, paracetamol may also increase the percentage of lamotrigine recovered in the urine.
Oral anticoagulants (e.g., warfarin and other coumarins): Chronic ingestion of large doses of paracetamol may potentiate the anticoagulant effect of warfarin and other coumarin- and indanedione-derivative anticoagulants, which may result in increased risk of bleeding. Prothrombin time (PT) and International Normalized Ratio (INR) must be monitored.
Phenothiazines: Concomitant use of paracetamol with phenothiazines may increase the risk of severe hypothermia.
Probenecid: Probenecid may alter the plasma concentration and excretion of paracetamol.
Interactions with Laboratory Tests: Naproxen sodium: In the determination of bleeding time, it should be kept in mind that naproxen may decrease platelet aggregation and prolong bleeding time.
Naproxen may increase urinary values of 17-ketogenic steroids due to its interaction with the m-dinitrobenzene used in the assay. Discontinue naproxen sodium therapy temporarily for 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Naproxen may interfere with urinary assays of 5-hydroxy indoleacetic acid.
Paracetamol: Paracetamol may yield false-positive test results for urinary 5-hydroxyindoleacetic acid.