MISOFEN

4). Adults One tablet to be taken with food, two times daily. Tablets should be swallowed whole, not chewed. Elderly/Renal, Cardiac and Hepatic Impairment No adjustment of dosage is necessary in the elderly or in patients with hepatic impairment or mild to moderate renal impairment as pharmacokinetics are not altered to any clinically relevant extent.

8). Paediatric population (under 18 years) The safety and efficacy of Misofen Tablets in children has not been established.

Summary of the safety profile In the table below the incidence of adverse drug reactions reported in controlled clinical studies where diclofenac/misoprostol was administered to more than 2000 patients are listed. Additionally, adverse drug reactions have been identified during post-marketing surveillance and the frequency of some ADRs cannot be estimated from the available data, The most commonly observed adverse events are gastrointestinal in nature.

In general, the adverse event profile of diclofenac/misoprostol in patients 65 years of age and older (556 subjects) was similar to that of younger patients (1564 subjects). The only clinically relevant differences were that patients 65 years of age and older appeared to be less tolerant to the gastrointestinal effects of diclofenac/misoprostol given three times a day.

Organ System Very Commo n ( 1/10) Common ( 1/100 and <1/10) Uncommon ( 1/1,000 and <1/100) Rare ( 1/10,0 00, and <1/1,000) Very Rare (<1/10,0 00) Frequency: Unknown (Post- marketing experience) Infections and infestations Vaginal infection Blood and lymphatic system disorders Thrombo- cytopaenia leucopenia Aplastic anaemia, agranulocytos is, haemolytic anaemia, platelet aggregation inhibition Immune system disorders Hypersensi tivity Anaphyla ctic reaction Metabolis m and nutrition disorders Decreased appetite Fluid retention Psychiatric disorders Insomnia Depression, anxiety Nightmar es Psychotic disorder, disorientation , mood change, irritability Nervous system disorders Headache, dizziness Cerebrovas cular accident, somnolenc e , tremor, Paraesthesi a Meningitis aseptic1, convulsion, memory impairment, dysgeusia Eyes disorders Vision blurred Visual impairment Ear and labyrinth disorders Tinnitus Cardiac disorders Cardiac failure, myocardial Infarction palpitations , Kounis syndrome Vascular disorders hypertensi on hypotens ion Shock, vasculitis Respirator y, thoracic and mediastinal disorders dyspnoea pneumoni tis Asthma, Gastrointes tinal disorders Abdom inal pain, diarrho ea2 , nausea, dyspeps ia Gastritis, vomiting, flatulence, eructation, constipation , peptic ulcer gastrointest inal inflammati on, gastrointest inal ulcer, duodenitis, oesophagiti s Stomatitis melaena, mouth ulceration, dry mouth, gastrointest inal bleeding3 Pancreati tis, haemate me sis, colitis, oesophag ea l disorder, glossitis Gastrointestin al perforation3, Crohn's disease, tongue oedema Hepato- biliary disorders Hepatitis, jaundice Hepatic failure Hepatitis fulminant Skin and subcutaneo us tissue disorders rash, pruritus Purpura, urticaria Angioede ma dermatitis bullous, photosens it ivity reaction, alopecia Erythema multiforme, Toxic epidermal necrolysis4 , Stevens- Johnson syndrome4 , dermatitis exfoliative4 , , Henoch Schönlein purpura, mucocutaneo us rash, rash vesicular, DRESS syndrome Fixed drug eruption Generalised bullous fixed drug eruption Renal and urinary disorders Renal failure, acute renal failure, renal papillary necrosis, tubulointerstit ial Nephritis nephrotic syndrome, proteinuria, haematuria, glomerulonep hritis, glomerulonep hritis minimal lesion, glomerulonep hritis membranous, renal impairment Pregnancy, puerperium and perinatal conditions Foetal death, incomplete abortion, premature baby, anaphylactoid syndrome of pregnancy, retained placenta or membranes, uterine contractions abnormal Reproducti ve system and breast disorders Menorrhagi a, metrorrhagi a, vaginal haemorrha ge, postmenop ausal haemorrha ge, menstrual disorder Breast pain, dysmenor rhea Uterine haemorrhage uterine spasm, infertility (female fertility decreased) Congenital , familial and genetic disorders Foetal malformati on General disorders and administrat ion site conditions Oedema5 , chest pain, face oedema, fatigue, pyrexia, chills inflammation Investigati ons Alanine aminotransf erase increased, blood alkaline phosphatas e increased, haematocrit decreased Blood bilirubim increased, aspartate aminotrans f erase increased Injury, poisoning and procedural complicati ons Uterine perforation Uterine rupture, 1 Symptoms of aseptic meningitis (stiff neck, headache, nausea, vomiting, fever or impaired consciousness) have been reported during treatment with NSAIDs.

Warnings The use of diclofenac/misoprostol with concomitant systemic NSAIDs including COX-2 inhibitors should be avoided except for patients requiring low dose acetylsalicylic acid –caution is advised in such patients with close monitoring.

Concomitant use of a systemic NSAID and another systemic NSAID may increase frequency of gastrointestinal ulcers and bleeding. 6). The label will state: 'Not for use in women of childbearing potential unless using effective contraception'.

2, and GI and cardiovascular risks below). Renal/Cardiac/Hepatic impairment In patients with renal, cardiac or hepatic impairment and in the elderly, caution is required since the use of NSAIDs may result in deterioration of renal function.

In the following conditions, Misofen Tablets should be used only in exceptional circumstances and with close clinical monitoring, advanced liver disease, severe dehydration. 1% of patients. ALT/AST elevations usually occur within 1-6 months.

In clinical trials, hepatitis has been observed in patients who received diclofenac, and in postmarketing experience, other hepatic reactions have been reported, including jaundice and hepatic failure. During diclofenac/misoprostol therapy, liver function should be monitored periodically.

If diclofenac/misoprostol is used in the presence of impaired liver function, close monitoring is necessary. If abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur, treatment with diclofenac should be discontinued.

2). The extent to which the metabolites may accumulate in patients with renal failure has not been studied. As with other NSAIDs, metabolites of which are excreted by the kidney, patients with significantly impaired renal function should be more closely monitored.

In rare cases, NSAIDs, including diclofenac/misoprostol, may cause interstitial nephritis, glomerulitis, papillary necrosis and the nephrotic syndrome. NSAIDs inhibit the synthesis of renal prostaglandin which plays a supportive role in the maintenance of renal perfusion in patients whose renal blood flow and blood volume are decreased.

1. g. 8). - Patients with a known hypersensitivity to diclofenac, acetylsalicylic acid, other NSAIDs, misoprostol, other prostaglandins, or any other ingredient of the product, - Patients in whom, attacks of asthma, urticaria or acute rhinitis are precipitated by acetylsalicylic acid or other non-steroidal anti-inflammatory agents, - Treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery, - Patients with severe renal and hepatic failure, - Patients with established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease.