Naprosyn Plus tablet is indicated for the relief of signs & symptoms of-

• Osteoarthritis
• Rheumatoid arthritis
• Ankylosing spondylitis &
• To decrease the risk of developing gastric ulcers in patients at risk of developing NSAID-associated gastric ulcers.

This consists of an immediate release Esomeprazole Magnesium layer & an enteric-coated Naproxen core. As a result, Esomeprazole is released first into the stomach, prior to the dissolution of Naproxen in the small intestine.

Naproxen is a NSAID with analgesic & antipyretic properties. The mechanism of action of Naproxen is to inhibit the prostaglandin synthesis. Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H⁺/k⁺ -ATPase in the gastric parietal cell by acting specifically on the proton pump, Esomeprazole blocks the final step in acid production, thus reducing gastric acidity.

Carefully consider the potential benefits & risks of this tablet & other treatment options before deciding to use this tablet. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. If a dose of Esomeprazole lower than a total daily dose of 40 mg is more appropriate, a different treatment should be considered.

Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis-

• Adults: One tablet twice daily of either: 375 mg naproxen/20 mg of esomeprazole; or 500 mg naproxen/20 mg of esomeprazole

Juvenile Idiopathic Arthritis in Adolescent Patients 12 Years of Age & Older-

• Weight greater than 50 kg: 375 mg naproxen/20 mg of esomeprazole; or 500 mg naproxen/20 mg of esomeprazole
• Weight 38 kg to less than 50 kg: One tablet twice daily of 375 mg naproxen/20 mg of esomeprazole.

Do not split, chew, crush or dissolve the tablet. This tablet is to be taken at least 30 minutes before meals.

With medicine:

• Concomitant use of NSAIDs may reduce the antihypertensive effect of ACE inhibitors, diuretics & beta-blockers
• Concomitant use of this tablet and warfarin may result in an increased risk of a bleeding complication.
• Esomeprazole inhibits gastric acid secretion & may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (eg. Ketoconazole, iron salts and digoxin).

With food & others: Administration of Naproxen & Esomeprazole together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs t_max by 10 hours and decreases peak plasma concentration (C_max) by about 12%

• Known hypersensitivity to any component of this tablet or substituted benzimidazoles.
• History of asthmay urticaria or other allergic-type reactions after taking aspirin or other NSAIDs.
• Use during the peri-operative period in the setting of coronary artery bypass graft (CABG) surgery.

Immediate release esomeprazole has been included in the tablet formulation to decrease the incidence of gastrointestinal side effects from Naproxen. Naproxen and Esomeprazole tablet has been shown to significantly decrease the occurrence of gastric ulcers and NSAID associated upper gastrointestinal adverse events compared to Naproxen alone. Naproxen: Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Although data suggest that the use of Naproxen (1000 mg daily) may be associated with a lower risk, some risk cannot be excluded. Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in older people, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported following administration. Less frequently, gastritis has been observed.

Pregnancy: In women attempting to conceive or during the first and second trimester of pregnancy, Naproxen and Esomeprazole tablet should not be given unless the potential benefit to the patient outweighs the potential risk to the foetus. Naproxen and Esomeprazole tablet is contraindicated during the third trimester of pregnancy.

Breast-feeding: Naproxen is excreted in low quantities in human milk. It is unknown whether esomeprazole is excreted in human milk. Naproxen and Esomeprazole tablet should not be used during breastfeeding.

Fertility: The use of NSAIDs like Naproxen may impair female fertility. The use of Naproxen and Esomeprazole tablet is not recommended in women attempting to conceive.

General: The combination of Naproxen and Esomeprazole tablet and NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided because of the cumulative risks of inducing serious NSAID-related adverse events. Naproxen and Esomeprazole tablet can be used with low dose acetylsalicylic acid. Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. Risk-factors to develop NSAID related gastro-intestinal complications include high age, concomitant use of anticoagulants, corticosteroids, other NSAIDs including low-dose acetylsalicylic acid, debilitating cardiovascular disease, Helicobacter pylori infection, and a history of gastric and/or duodenal ulcers and upper gastrointestinal bleeding. In patients with the conditions such as Inducible porphyries, Systemic lupus erythematosis and mixed connective tissue disease, Naproxen should only be used after a rigorous benefit-risk ratio. Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.

Older people: Naproxen: Older people have an increased frequency of adverse reactions especially gastro-intestinal bleeding, and perforation, which may be fatal. The esomeprazole component of Naproxen and Esomeprazole tablet decreased the incidence of ulcers in older people.

Gastrointestinal effects: Naproxen: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events. The risk of GI bleeding, ulceration or perforation with NSAIDs is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in older people. These patients should begin treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose acetylsalicylic acid, or other drugs likely to increase gastrointestinal risk. Patients with a history of GI toxicity, particularly older people, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving NSAIDs with concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid. When GI bleeding or ulceration occurs in patients receiving Naproxen and Esomeprazole Tablet, the treatment should be withdrawn. NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated. Esomeprazole: Dyspesia could still occur despite the addition of Esomperazole to the combination tablet. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter. Esomeprazole, as all acid-blocking medicines, might reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors of reduced vitamin B12 absorption on long-term therapy.

Cardiovascular and cerebrovascular effects: Naproxen: Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with Naproxen after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Renal effects: Naproxen: Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Elderly patients: Studies indicate that although the total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Use caution when high doses are required & some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly use the lowest effective dose.

Patients with Moderate to Severe Renal impairment: Naproxen-containing products are not recommended for use in patients with moderate to severe or severe renal impairment (creatinine clearance <30 ml/min).

Hepatic insufficiency: Monitor patients with mild to moderate hepatic impairment closely & consider a possible dose reduction based on the Naproxen component of this tablet. This is not recommended in patients with severe hepatic impairment because Esomeprazole dosage should not exceed 20 mg daily in these patients.

Symptoms: Related to Naproxen overdose- Significant Naproxen overdosage may be characterized by lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation or vomiting. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. It is not known what dose of the drug would be life-threatening.

Related to esomeprazole overdose- The symptoms described in connection with deliberate esomeprazole overdose (limited experience of doses in excess of 240 mg/day) are transient. Single doses of 80 mg esomeprazole were uneventful.

Management: Related to Naproxen- Patients should be managed by symptomatic and supportive care following a NSAID overdose, particularly with respect to GI effects and renal damage. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of Naproxen because of the high degree of its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may not be useful due to high protein binding.

Related to Esomeprazole- No specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.

Drugs for Osteoarthritis, Drugs used for Rheumatoid Arthritis, Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Store at temperature of below 30°C, protect from light & moisture. Keep out of reach of children.