Napexa Tablet 375mg+20mg

Product Information

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 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. 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 in peak 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 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.

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.