Naproxen /Esomeprazole

Brands of Naproxen /Esomeprazole in Kenya

Prezola, Medisel Kenya Ltd

MODE OF ACTION

Naproxen is a NSAID with analgesic and antipyretic properties. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Esomeprazole is the S-enantiomer of omeprazole and reduces gastric acid secretion through a specific targeted mechanism of action. Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+K+-ATPase – the acid pump and inhibits both basal and stimulated acid secretion.

INDICATIONS

Indicated in adults for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, in patients who are at risk for developing non-steroidal anti-inflammatory drug (NSAID)-associated gastric and/or duodenal ulcers and where treatment with lower doses of naproxen or of other NSAIDs is not considered sufficient.

DOSAGE AND ADMINISTRATION

The recommended dose is (500 mg/20 mg) twice daily.

Undesirable effects of naproxen may be minimised by using the lowest effective dose for the shortest duration possible

CONTRAINDICATIONS

  • Hypersensitivity to the active substances or to any of the excipients  or substituted benzimidazoles.
  • History of asthma, urticaria or allergic-type reactions induced by administration of acetylsalicylic acid or other NSAIDs
  • Third trimester of pregnancy
  • Severe hepatic impairment (e.g. Child-Pugh C).
  • Severe heart failure.
  • Severe renal impairment.
  • Active peptic ulceration .
  • Gastrointestinal bleeding, cerebrovascular bleeding or other bleeding disorders .
  • This combination must not be used concomitantly with atazanavir and nelfinavir .

DRUG INTERACTIONS

Contraindications of concomitant use

Antiretroviral agents

Omeprazole, the racemate of D+S omeprazole (esomeprazole), has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19.

Concomitant use with precaution

Other analgesics including cyclooxygenase-2 selective inhibitors

Concomitant use of two or more NSAIDs should be avoided as this may increase the risk of adverse effects, especially gastrointestinal ulcers and bleeding.

Acetylsalicylic acid

It can be administered with low-dose acetylsalicylic acid (≤325 mg/day) therapy. However, the concurrent use of acetylsalicylic acid and this drug may still increase the risk of serious adverse events .

Tacrolimus

As with all NSAIDs, there is a possible risk of nephrotoxicity when naproxen is co-administered with tacrolimus. Concomitant administration of esomeprazole has been reported to increase the serum levels of tacrolimus.

Ciclosporin

As with all NSAIDs, caution is advised when ciclosporin is co-administered because of the increased risk of nephrotoxicity.

Diuretics

Clinical studies, as well as postmarketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Concomitant use of NSAIDs, including COX-2 selective inhibitors, and SSRIs increases the risk of gastrointestinal bleeding .

Corticosteroids

There is an increased risk of gastrointestinal bleeding when corticosteroids are combined with NSAIDs including COX–2 selective inhibitors. Caution should be used when NSAIDs are administered concomitantly with corticosteroids .

ACE-inhibitors/Angiotensin II receptor antagonists

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II receptor antagonists. NSAIDs may also increase the risk of renal impairment associated with the use of ACE-inhibitors or angiotensin II receptor antagonists. The combination of NSAIDs and ACE-inhibitors or angiotensin II receptor antagonists should be given with caution in patients who are older, volume-depleted, or with impaired renal function .

Digoxin

NSAIDs may increase plasma cardiac glycoside levels when co-administered with cardiac glycosides such as digoxin.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate

When given together with proton pump inhibitors, methotrexate levels have been reported to increase in some patients. NSAIDs have been reported to reduce the tubular secretion of methotrexate in an animal model. This may indicate that both esomeprazole and naproxen could enhance the toxicity of methotrexate. The clinical relevance is likely to be greater in patients receiving high doses of methotrexate and in patients with renal dysfunction.

Sulphonylureas, Hydantoins

Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as sulphonylureas, and hydantoins. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

Clopidogrel

No clinical studies on the interaction between clopidogrel and the fixed dose combination of naproxen+esomeprazole  have been performed.

Inconsistent data on the clinical implications of a PK/PD interaction of esomeprazole in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of this drug and clopidogrel should be discouraged .

Anti-coagulants and thrombocyte aggregation inhibitors

NSAIDs may enhance the effects of oral anti-coagulants (e.g. warfarin, dicoumarol) heparins and thrombocyte aggregation inhibitors .Close monitoring is recommended when initiating and ending treatment with warfarin or other coumarine derivatives.

Beta receptor-blockers

Naproxen and other NSAIDs can reduce the antihypertensive effect of propranolol and other beta-blockers.

Probenecid

Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.

Drugs with gastric pH-dependent absorption

The gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of drugs with a gastric pH dependent absorption. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, itraconazole, posaconazole and erlotinib can decrease while the absorption of drugs such as digoxin can increase during treatment with esomeprazole. Concomitant use with posaconazole and erlotinib should be avoided. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects).

Other Information Concerning Drug Interactions

Studies evaluating concomitant administration of esomeprazole and either naproxen (non-selective NSAID) or rofecoxib (COX-2-selective NSAID) did not identify any clinically relevant interaction.

As with other NSAIDs, concomitant administration of cholestyramine can delay the absorption of naproxen.

In healthy volunteers, concomitant administration of 40 mg esomeprazole resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t1/2) but no significant increase in peak plasma levels of cisapride.

Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin and quinidine.

Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Esomeprazole is also metabolised by CYP3A4. The following have been observed in relation to these enzymes:

  • Concomitant administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. This interaction is unlikely to be of clinical relevance.
  • Concomitant administration of 40 mg esomeprazole resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients.
  • Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure.
  • Concomitant administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg twice daily), resulted in a doubling of the exposure (AUC) to esomeprazole.

Dose adjustment of esomeprazole is not required in any of these cases.

Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John’s Wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.

Omeprazole as well as esomeprazole act as inhibitors of CYP 2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.

Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking quinolones may have an increased risk of developing convulsions.

Drug/Laboratory Test Interaction

Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined.

ADVERSE EFFECTS

Headache.
Feeling tired.
Feeling thirsty.
Feeling depressed.
Feeling breathless.
Increased sweating.
Itchy skin and skin rashes.
Spinning feeling (vertigo).
Red or purple marks, bruising or spots on your skin.
Feeling sick (nausea) or being sick (vomiting).
A fluttering feeling in your heart (palpitations).
Disturbed sleep or trouble sleeping (insomnia).
Hearing problems or Tinnitus.
Dizziness, feeling drowsy or feeling light-headed.
Swelling of your hands, feet and ankles (oedema).
An inflammation inside the mouth.
Eyesight problems.
Diarrhoea, stomach pain, heartburn, indigestion, constipation, burping or wind (flatulence).
Stomach ulcer or ulcer in the first part (duodenum) of the small intestine.
Inflammation of the lining of the stomach (gastritis).
Benign polyps in the stomach.

Reporting of suspected adverse reactions:

The PPB Department of Pharmacovigilance was set up with a vision to develop, implement and continuously upgrade an appropriate system for detecting, reporting, and monitoring adverse drug reactions (ADRs) and other relevant problems with medicines in Kenya. The department strives to ensure the safety and efficacy of pharmaceutical products in Kenya.
Reporting suspected adverse reactions after authorization of the medicinal product are important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals/ Patients are encouraged to report any suspected adverse reactions via Pharmacovigilance Yellow Form, pv@pharmacyboardkenya.org or clicking below button:

Naproxen /Esomeprazole in Kenya
Naproxen /Esomeprazole in Kenya
Naproxen /Esomeprazole in Kenya
Naproxen /Esomeprazole in Kenya
Naproxen /Esomeprazole in Kenya

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