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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Napratec OP

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Napratec is a combination pack containing 56 Naproxen 500mg tablets and 56 Cytotec (misoprostol) 200mcg tablets.

For excipients, see 6.1

3 PHARMACEUTICAL FORM

Tablet

Naproxen 500mg tablets are yellow, oblong and engraved ‘NXN500’ with a breakline on one side and CP on the reverse.

Cytotec is a white/off-white hexagonal tablet, scored on both sides, engraved SEARLE 1461 on one side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Napratec combination pack is indicated for patients who require Naproxen 500mg twice daily and Cytotec 200mcg twice daily.

Naproxen is indicated for the treatment of rheumatoid arthritis, osteoarthritis (degenerative arthritis) and ankylosing spondylitis.

Cytotec is indicated for the prophylaxis of nonsteroidal anti-inflammatory drug (NSAID)-induced gastroduodenal ulceration.

4.2 Posology and method of administration

For oral administration

Adults 1 tablet of Naproxen and 1 tablet of Cytotec to be taken together twice daily with or after food.

Elderly

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly.

With Cytotec the usual dosage may be used in the elderly.

Napratec should only be used in those patients for whom 500mg naproxen twice daily is appropriate and in whom no reduction of naproxen dosage is necessary (see also sections on renal and hepatic impairment).

The elderly are at an increased risk of the serious consequences of adverse reactions. The patient should be monitored regularly for GI bleeding during NSAID therapy.

Renal Impairment

As the final pathway for the elimination of naproxen metabolites is largely (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 is not recommended in patients having a baseline creatinine clearance of less than 20ml/minute.

Certain patients, specifically those whose renal blood flow is compromised, such as in 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 therapy. Some elderly patients in whom impaired renal function may be expected could also fall within this category. Where there is a possibility of accumulation of naproxen metabolites, such patients may not be suitable to receive naproxen 500mg twice daily.

With Cytotec no dosage alteration is necessary in patients with impaired renal function.

Hepatic Impairment

Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased.

With Cytotec no dosage alteration is necessary in patients with impaired hepatic function.

Children

Napratec is not recommended.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

4.3 Contraindications

Use in Pregnancy and Lactation

Napratec is contraindicated in pregnancy and lactation (see section 4.6)

This medicine is also contraindicated in patients planning to become pregnant.

Napratec is contraindicated in patients with a known hypersensitivity to naproxen, or to misoprostol or to any of the excipients.

As the potential exists with naproxen for cross-sensitivity to aspirin and other nonsteroidal anti-inflammatory drugs, Napratec should not be administered to patients in whom aspirin, ibuprofen and other NSAIDs induce asthma, rhinitis, urticaria or angioedema.

As Napratec is a "prevention pack" it should not be used for treating arthritis in patients with active gastric or duodenal ulceration / haemorrhage. Such patients may be treated with a healing dose of Cytotec, 800 micrograms daily in divided doses with meals, and the NSAID continued or discontinued at the physician's discretion.

Use in pre-menopausal women

Napratec should not be used in pre-menopausal women unless the patient is at high risk of complications from NSAID-induced ulceration. In such patients it is advised that Napratec should only be used if the patient:

-    takes effective contraceptive measures

-    has been advised of the risks of taking the product if pregnant

Napratec is contraindicated in patients with severe heart failure, hepatic failure and renal failure (see section 4.4).

4.4 Special warnings and precautions for use

Precautions

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

The use of Naproxen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

Naproxen, in common with other NSAIDs, decreases platelet aggregation and prolongs bleeding time. This effect should be considered when bleeding times are determined.

Elderly:

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2)

Respiratory disorders:

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma or allergic disease since NSAIDs have been reported to precipitate bronchospasm in such patients.

Cardiovascular, Renal and Hepatic Impairment:

The administration of an NS AID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients (see also section 4.3).

Mild peripheral oedema has been observed in a few patients receiving naproxen. Although sodium retention has not been reported in metabolic studies, it is possible that patients with questionable or compromised cardiac function may be at a greater risk when taking naproxen.

Cardiovascular and cerebrovascular effects:

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.

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.

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).

Gastrointestinal bleeding, ulceration and perforation:

Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. When GI bleeding or ulceration occurs in patients receiving Napratec OP, the treatment should be withdrawn. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation and in the elderly.

Patients with a history of GI toxicity, particularly if complicated when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or antiplatelet agents such as aspirin. (see section 4.5)

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 (see section 4.8).

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8)

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with use of NSAID (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: onset of the reaction occurring in the majority of cases within the first month of treatment. Napratec should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Sporadic abnormalities in laboratory tests (e.g. liver function tests) have occurred in patients on naproxen, but no definite trend was seen in any test indicating toxicity.

Cytotec should be used with caution in disease states where hypotension might precipitate severe complications, e.g. cerebrovascular disease, coronary artery disease or severe peripheral vascular disease including hypertension.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Drug Interactions

Due to the high plasma protein binding of naproxen, patients simultaneously receiving hydantoins, anti-coagulants or a highly protein-bound sulphonamide should be observed for signs of over dosage of these drugs. No interactions have been observed in clinical studies with naproxen and anti-coagulants or sulphonylureas, but caution is nevertheless advised since interaction has been seen with other non-steroidal agents of this class.

Diuretics: NSAIDs may attenuate the natriuretic efficacy of diuretics due to inhibition of intrarenal synthesis of prostaglandins. NSAIDs may also cause a reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Ciclosporin: Because of their effect on renal prostaglandins, cyclo-oxygenase inhibitors such as naproxen can increase the nephrotoxicity of ciclosporin

Other analgesics including cyclooxygenase-2-selective inhibitors: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse events (see section 4.4).

Lithium: NSAIDs including naproxen have been reported to increase steady state plasma lithium levels. It is recommended that these are monitored whenever initiating, adjusting or discontinuing naproxen products.

Cardiac glycosides: Concomitant administration of Naproxen with cardiac glycosides may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Anti-hypertensives: Concomitant administration of naproxen with beta-blockers may reduce their antihypertensive effect.

In patients who are elderly, volume-depleted (including those on diurectic therapy), or with compromised renal function, co-administration of NSAIDs with ACE inhibitors may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.

Corticosteroids: Concomitant administration of naproxen with corticosteroids increases the risk of gastrointestinal ulceration or bleeding (see section 4.4) and may increase the frequency of side effects generally.

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

Probenecid: Increases naproxen plasma levels and extends its plasma half-life considerably.

Methotrexate: Caution is advised when methotrexate is administered Concurrently because of possible enhancement of its toxicity since naproxen, among other NSAIDs, has been reported to induce the tubular secretion of methotrexate in an animal model.

Mifepristone: NSAIDs should not be used for 8 - 12 days after mifepristone

administration as NSAIDs can reduce the effect of mifepristone.

Anti-coagulants'. NSAIDs may enhance the effects of anti-coagulatnts, such as warfarin (see section 4.4).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4).

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Naproxen therapy should be temporarily withdrawn before adrenal function tests are performed as it may artificially interfere with some tests for 17 ketogenic steroids. Similarly, naproxen may interfere with some assays of urinary 5-hydroxyindoleacetic acid.

Cytotec is predominantly metabolised via fatty acid oxidising systems and has shown no adverse effect on the hepatic microsomal mixed function oxidase (P450) enzyme system. No drug interactions have been attributed to Cytotec, and in specific studies, no clinically significant pharmacokinetic or pharmacodynamic interaction has been demonstrated with antipyrine, diazepam, propranolol or NSAIDs.

4.6 Fertility, pregnancy and lactation

Napratec is contraindicated in pregnancy and lactation. The product is contraindicated in pregnancy on the basis that Cytotec is contraindicated in pregnancy or women planning a pregnancy as it increases uterine tone and contractions in pregnancy which may cause partial or complete expulsion of the products of conception.

Teratology studies with naproxen in rats and rabbits at dose levels equivalent on a human multiple basis to those which have produced foetal abnormality with certain other NSAIDs, e.g. aspirin, have not produced evidence of foetal damage with naproxen. As with other drugs of this type, naproxen delays parturition in animals (the relevance of this finding to human patients is unknown) and also affects the human foetal cardiovascular system (closure of the ductus arteriosus).

Based on the mechanism of action, the use of NSAIDs, INCLUDING NAPRATEC^,ii may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. In women who

have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs, including NAPRATEC OP, should be considered.

Inhibition of prostaglandin synthesis might adversely affect pregnancy.

Data from epidemiological studies suggest an increased risk of spontaneous abortion after use of prostaglandin synthesis inhibitors in early pregnancy. In animals, administration of prostaglandin synthesis inhibitors has been shown to result in increased pre- and postimplantation loss.

4.7 Effects on ability to drive and use machines

Dizziness, drowsiness, fatigue, visual disturbances or headaches are possible undesirable effects after taking NSAIDs. If affected, patients should not drive or operate machinery.

4.8. Undesirable effects

Naproxen:

Gastrointestinal: The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain or discomfort and epigastric distress, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (see section 4.4) have been reported following administration. The more serious reaction, colitis, may occasionally occur. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Naproxen also causes gastrointestinal bleeding and gastric and duodenal ulceration, the consequences of which may be haemorrhage and perforation. The inclusion of Cytotec in the combination pack is to prevent naproxeninduced gastric and duodenal ulceration.

Hypersensitivity and Dermatological: Non-specific allergic reactions and anaphylaxis, respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, assorted skin disorders including rashes of various types,, pruritus, purpura, urticaria, angio-oedema.. Anaphylactic reactions to naproxen and naproxen sodium formulations; eosinophilic pneumonitis, alopecia, photosensitivity reactions and more rarely epidermolysis bullosa, epidermal necrolysis, erythema multiforme, pseudoporphyria, Stevens Johnson syndrome and toxic epidermal necrolysis (very rare).

Cardiovascular and cerebrovascular:

Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of 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) (see section 4.4).

Neurological and special senses: Headache, visual disturbances, insomnia, optic neuritis, paraesthesia, inability to concentrate, cognitive dysfunction, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4), depression, confusion, hallucinations, tinnitus, hearing impairment, vertigo, dizziness, malaise, fatigue and drowsiness.

Renal: As a class NSAIDs have been associated with renal pathology including nephropathy, papillary necrosis, interstitial nephritis, nephrotic syndrome and renal failure.

Hepatic: Abnormal liver function, fatal hepatitis and jaundice.

Haematological: Thrombocytopenia, neutropenia, granulocytopenia, agranulocytosis, aplastic anaemia and haemolytic anaemia may occur rarely.

Other: Mild peripheral oedema, vasculitis, and haematuria.

Reproductive system and breast disorders: Decreased fertility in females.

Cytotec:

Gastrointestinal: Diarrhoea has been reported and is occasionally severe and prolonged, and may require withdrawal of the drug. It can be minimised by taking Cytotec with food and by avoiding the use of predominantly magnesium containing antacids when an antacid is required. Abdominal pain with or without associated dyspepsia can follow Cytotec therapy. Other gastrointestinal adverse effects reported include dyspepsia, flatulence, nausea and vomiting.

Female Reproductive System: Menorrhagia, vaginal bleeding and intermenstrual bleeding have been reported in both pre- and post-menopausal women.

Other Adverse Effects: Skin rashes have been reported. Dizziness has been infrequently reported.

4.9 Overdose Naproxen:

Symptoms - Symptoms include drowsiness, heartburn, indigestion, nausea, vomiting, headache, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientataion, excitation, coma, dizziness, tinnitus, fainting, occasionally convulsions. A few patients have experienced seizures, but it is not clear whether these were naproxen-related or not. In cases of significant poisoning acute renal failure and liver damage are possible. It is not known what dose of the drug would be life-threatening.

Therapeutic measures - In the event of overdosage with naproxen, the stomach may be emptied and usual supportive measures employed.

•    Patients should be treated symptomatically as required.

•    Within one hour of ingestion of a potential toxic amount, activated charcoal should be considered. Animal studies indicate that the prompt administration

of activated charcoal in adequate amounts would tend to reduce markedly the absorption of the drug. Alternatively, in adult, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.

•    Good urine output should be insured.

•    Renal and liver function should be closely monitored

•    Patients should be observed for at least four hours after ingestion of potentially toxic amounts

•    Frequent or prolonged convulsions should be treated with intravenous diazepam

•    Other measures may be indicated by the patient's clinical condition.

Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding. However, haemodialysis may still be appropriate in a patient with renal failure who has taken naproxen.

Cytotec:

Intensification of pharmacological and adverse effects may occur with overdose. In the event of overdosage with Cytotec, symptomatic and supportive therapy should be given as appropriate.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Naproxen is a non-steroidal anti-inflammatory drug with well-documented properties, i.e. analgesic, antipyretic and anti-inflammatory.

Misoprostol is a synthetic prostaglandin E₁ analogue which enhances several of the factors that maintain gastroduodenal mucosal integrity.

5.2 Pharmacokinetic properties

Naproxen is readily absorbed from the GI tract. Peak plasma concentrations are obtained 2-4 hours after ingestion. At therapeutic concentrations, naproxen is more than 98% bound to plasma proteins and has an elimination half-life of between 12-15 hours.

Misoprostol is rapidly absorbed following oral administration with peak plasma levels of the active metabolite (misoprostol acid) occurring after about 30 minutes. The plasma elimination half-life of misoprostol acid is 20-40 minutes.

Increases in Cmax and AUC for misoprostol acid have been observed when coadministered with naproxen in a single dose study. These changes are not thought to be clinically significant since the higher values are still well within the variation seen after 200 micrograms misoprostol in other studies. No accumulation of misoprostol acid in plasma occurs after repeated dosing of 400 micrograms twice daily.

5.3 Preclinical safety data

Naproxen causes gastric erosions when given orally or subcutaneously to fasting rats. There is no evidence of mutagenicity or carcinogenicity when administered to rats in studies of two years duration. There is no evidence of teratogenicity in mice, rats or rabbits.

Misoprostol in multiples of the recommended therapeutic dose in animals has produced gastric mucosal hyperplasia. This characteristic response to E-series prostaglandins reverts to normal on discontinuation of the compound.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Naproxen 500mg tablets contain: Lactose, maize starch, povidone, sodium starch glycolate, magnesium stearate, yellow lake CLF 3076 (E104 and E172).

Cytotec 200mcg tablets contain: microcrystalline cellulose, sodium starch glycolate, hydrogenated castor oil and hypromellose.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30°C. Store in the original package.