Napexa 500mg+20mg

Tablet
Naproxen Sodium + Esomeprazole
Unimed Unihealth MFG. Ltd

Other Strength:
- Napexa 375mg+20mg

Alternative:
- Napro-A Plus 500mg+20mg
- Xenole 500mg+20mg
- Solivo 500mg+20mg
- Naspro Plus 500mg+20mg
- Progut-N 500mg+20mg
- Anaflex Max 500mg+20mg
- Napxon 500mg+20mg
- Nescom 500mg+20mg
- Neso 500mg+20mg
- Naproben Plus 500mg+20mg
- Xenapro Plus 500mg+20mg



Napexa
Presentation
NapExa 375/20 tablet: Yellow, oval shaped tablet; each tablet contains delayed-release Naproxen USP 375mg and immediate-release Esomeprazole Magnesium Trihydrate USP equivalent to Esomeprazole 20mg.
NapExa 500/20 tablet: Red, oval shaped tablet; each tablet contains delayed-release Naproxen USP 500mg and immediate-release Esomeprazole Magnesium Trihydrate USP equivalent to Esomeprazole 20mg.

Indication
NapExa (Naproxen and Esomeprazole) tablets are 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 one NapExa 500/20 (Naproxen 500mg and Esomeprazole 20mg) tablet twice daily. Undesirable effects of Naproxen may be minimized by using the lowest effective dose for the shortest duration possible. In patients not treated with a NSAID previously, a lower daily dose of one NapExa 375/20 (Naproxen 375mg and Esomeprazole 20mg) tablet twice daily or of another NSAID should be considered. When total daily dose of 1000 mg of Naproxen (500mg twice daily) is not considered appropriate, alternative treatment with lower strength of one NapExa 375/20 (Naproxen 375mg and Esomeprazole 20mg) tablet twice daily or of other NSAIDs as non-fixed combination should be utilised. Treatment should be continued to achieve individual treatment goals, reviewed at regular intervals and discontinued if no benefit or if worsening is seen. Due to the delayed release of Naproxen from the enteric-coated formulation (3-5 hours), NapExa (Naproxen and Esomeprazole) tablets are not intended for rapid relief of acute pain conditions (such as dental pain). However, flares of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis may be treated with NapExa (Naproxen and Esomeprazole) tablets.

Method of administration: Oral use. NapExa (Naproxen and Esomeprazole) tablets must be swallowed whole with sufficient quantity of water. They must not be chewed or crushed. It is recommended that NapExa (Naproxen and Esomeprazole) tablets are taken at least 30 minutes prior to food intake.

Contra-indication, warnings, etc.
Contra-indication: Naproxen and Esomeprazole tablet is contra-indicated in patient with hypersensitivity to the Naproxen or Esomeprazole, 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. Childs-Pugh C), severe heart failure, severe renal impairment, active peptic ulceration, gastrointestinal bleeding, cerebrovascular bleeding or other bleeding disorders. Naproxen and Esomeprazole tablet must not be used concomitantly with atazanavir and nelfinavir.

Warnings and precautions: 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 shouldbegin 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 andoedema 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. Use in patients with impaired renal function: As Naproxen and its metabolites are eliminated to a large extent (95%) by urinary excretion via glomerular filtration, it should be used with great caution in patients with impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised in these patients. Naproxen and Esomeprazole tablet is contraindicated in patients having a baseline creatinine clearance of less than 30 ml/minute. Haemodialysis does not decrease the plasma concentration of Naproxen because of the high degree of protein binding. Certain patients, specifically those whose renal blood flow is compromised, because of extracellular volume depletion, cirrhosis of the liver, sodium restriction, congestive heart failure, and pre-existing renal disease, should have renal function assessed before and during Naproxen and Esomeprazole tablet therapy. A reduction in daily dosage should be considered to avoid the possibility of excessive accumulation of Naproxen metabolites in some patients (older patients in whom impaired renal function may be expected, as well as patients using diuretics, ACE-inhibitors or angiotensin II receptor antagonists). Hepatic effects: Borderline elevations of one or more liver tests may occur in patients taking NSAIDs. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. Hepatorenal syndrome: The use of NSAIDs may be associated with acute renal failure in patients with severe hepato-cirrhosis. These patients frequently also have concomitant coagulopathy related to inadequate synthesis of clotting factors. Antiplatelet effects associated with Naproxen could further increase risk of severe bleeding in these patients. Haematological effects: Naproxen: Patients who have coagulation disorders or are receiving drug therapy that interferes with haemostasis should be carefully observed if Naproxen-containing products are administered. Patients at high risk of bleeding and those on full anti-coagulation therapy (e.g. dicoumarol derivates) may be at increased risk of bleeding if given Naproxen-containing products concurrently. Naproxen decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined. When active and clinically significant bleeding from any source occurs in patients receiving Naproxen and Esomeprazole tablet, the treatment should be withdrawn. Dermatological effects: Naproxen and Esomeprazole tablet should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Anaphylactic (anaphylactoid) reactions: Naproxen: Hypersensitivity reactions may occur in susceptible individuals. Anaphylactic (anaphylactoid) reactions may occur both in patients with and without a history of hypersensitivity or exposure to acetylsalicylic acid, other NSAIDs or Naproxen-containing products. They may also occur in individuals with a history of angio-oedema, bronchospastic reactivity (e.g. asthma), rhinitis and nasal polyps. Pre-existing asthma: Naproxen: Naproxen and Esomeprazole tablet should not be administered to patients with acetylsalicylic acid sensitivity and should be used with caution in patients with pre-existing asthma. Female fertility: The use of Naproxen and Esomeprazole tablet, as with any drug known to inhibit cyclooxygenase / prostaglandin synthesis, may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Naproxen and Esomeprazole tablet should be considered. Hypomagnesaemia: Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like esomeprazole for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with digoxin or drugs that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment. Bone fracture: Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in older people or in presence of other recognised risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.

Drug interactions: Antiretroviral agents: Omeprazole, the racemate of D+S omeprazole (esomeprazole), has been reported to interact with some antiretroviral drugs. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, Cmax and Cmin). Co-administration of omeprazole (40 mg qd) reduced mean nelfinavir AUC, Cmax and Cmin by 36-39% and mean AUC, Cmax and Cmin for the pharmacologically active metabolite M8 was reduced by 75-92%. For other antiretroviral drugs, such as saquinavir, increased serum levels have been reported. However, due to the similar pharmacodynamic and pharmacokinetic properties of omeprazole and esomeprazole, the concomitant use of atazanavir and nelfinavir with esomeprazole is not recommended and concomitant administration with Naproxen and Esomeprazole tablet is contraindicated. 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. The concomitant use of Naproxen and Esomeprazole tablet with other NSAIDs, except for low-dose acetylsalicylic acid (< 325 mg/day), is not recommended. Acetylsalicylic acid: Naproxen and Esomeprazole tablet can be administered with low-dose acetylsalicylic acid (325 mg/day) therapy. The concurrent use of acetylsalicylic acid and Naproxen and Esomeprazole tablet may still increase the risk of serious adverse events. Tacrolimus: 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. During treatment with Naproxen and Esomeprazole tablet, a reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed. 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. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy. 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. Caution should be used when Naproxen and Esomeprazole tablet is administered concomitantly with methotrexate. In high-dose methotrexate administration a temporary withdrawal of Naproxen and Esomeprazole tablet is recommended. Clopidogrel: As a precaution, concomitant use of Naproxen and Esomeprazole tablet 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. Concomitant administration of 40 mg esomeprazole to warfarin-treated patients showed that, despite a slight elevation in the trough plasma concentration of the less potent R isomer of warfarin, the coagulation times were within the accepted range. 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. 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 inpeak plasma levels of cisapride. Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin and quinidine. CYP2C19 is 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. Concomitant administration of 40 mg esomeprazole resulted in a 13% increase in 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. Patients taking quinolones may have an increased risk of developing convulsions.

Use in pregnancy and lactation: Pregnancy: Naproxen: 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.

Side effects: 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.

Overdose: 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 usefuldue 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.

Pharmaceutical precautions
Store in a cool and dry place, protected from light.

Packaging quantities
NapExa 375/20 tablet: Cartons containing 28 tablets in Alu-Alu blister pack. NapExa 500/20 tablet: Cartons containing 28 tablets in Alu-Alu blister pack.

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