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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Arthrotec 50 modified-release tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet consists of a gastro-resistant core containing 50mg diclofenac sodium surrounded by an outer mantle containing 200mcg misoprostol.

Excipient(s):

Each tablet contains 13 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Modified-release tablet.

White, round, biconvex tablets marked © on one side and 'Searle 1411' on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Arthrotec 50 is indicated for patients who require the non-steroidal antiinflammatory drug diclofenac together with misoprostol.

The diclofenac component of Arthrotec 50 is indicated for the symptomatic treatment of osteoarthritis and rheumatoid arthritis. The misoprostol component of Arthrotec 50 is indicated for patients with a special need for the prophylaxis of NSAID-induced gastric and duodenal ulceration.

4.2 Posology and method of administration

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

Adults

One tablet to be taken with food, two or three times daily. Tablets should be swallowed whole, not chewed.

Elderly/Renal Impairment/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. Nevertheless patients with renal or hepatic impairment should be closely monitored (see section 4.4 and section 4.8).

Children

The safety and efficacy of Arthrotec 50 in children has not been established.

4.3 Contraindications

Arthrotec 50 is contraindicated in:

-    Patients with active peptic ulcer/haemorrhage or perforation or who have active GI bleeding or other active bleedings e.g. cerebrovascular bleedings.

-    Pregnant women and in women planning a pregnancy.

-    Patients with a known hypersensitivity to diclofenac, aspirin, 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 aspirin or other non-steroidal anti-inflammatory agents.

-    Treatment of peri-operative pain in the setting of coronary bypass graft (CABG) surgery.

-    Patients with severe renal and hepatic failure.

-    Established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

4.4 Special warnings and precautions for use

Warnings

The use of diclofenac/misoprostol with concomitant NSAIDs including COX-2 inhibitors should be avoided.

Use in pre-menopausal women (see also section 4.3))

Arthrotec 50 should not be used in pre-menopausal women unless they use effective contraception and have been advised of the risks of taking the product if pregnant (see section 4.6). The label will state: ‘Not for use by pre-menopausal women unless using effective contraception’.

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).

• Renal/Cardiac/Hepatic

In patients with renal, cardiac or hepatic impairment caution is required since the use of NSAIDs may result in deterioration of renal function. In the following conditions Arthrotec 50 should be used only in exceptional circumstances and with close clinical monitoring: advanced liver disease, severe dehydration.

In a large trial where patients received diclofenac for a mean of 18 months, ALT/AST elevations were observed in 3.1% 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.

Diclofenac metabolites are eliminated primarily by the kidneys (see section 5.2). 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. In these patients, administration of an NSAID may precipitate overt renal decompensation, which is typically followed by recovery to pretreatment state upon discontinuation of NSAID therapy. Patients at greatest risk of such a reaction are those with congestive heart failure, liver cirrhosis, nephrotic syndrome and overt renal disease. Such patients should be carefully monitored while receiving NSAID therapy.

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.

As with all NSAIDS, diclofenac/misoprostol can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cardiovascular events. NSAIDs, including diclofenac/misoprostol, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with diclofenac/misoprostol and throughout the course of therapy.

Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with diclofenac after careful consideration. As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically.

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high dose (150mg daily) and in long term treatment may be associated with a small increased risk of serious arterial thrombotic events (for example myocardial infarction or stroke).

Physicians and patients should remain alert for the development of such events, even in the absence of previous cardiovascular symptoms. Patients should be informed about the signs and/or symptoms of serious cardiovascular toxicity and the steps to take if they occur (see section 4.3).

• Blood system/Gastrointestinal

NSAIDs, including diclofenac/misoprostol, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. When GI bleeding or ulceration occurs in patients receiving diclofenac/misoprostol, the treatment should be withdrawn. These events can occur at any time during treatment, with or without warning symptoms or in patients with a previous history of serious GI events.

Patients most at risk of developing these types of GI complications with NSAIDs are those treated at higher doses, the elderly, patients with cardiovascular disease, patients using concomitant aspirin, or patients with a prior history of, or active, gastrointestinal disease, such as ulceration, GI bleeding or inflammatory conditions.

Therefore, diclofenac/misoprostol should be used with caution in these patients and commence on treatment at the lowest dose available (see section 4.3).

Patients with a history of GI toxicity, particularly 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 medicines 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 aspirin (see section 4.5).

Arthrotec 50, in common with other NSAIDs, may decrease platelet aggregation and prolong bleeding time. Extra supervision is recommended in haematopoietic disorders or in conditions with defective coagulation or in patients with a history of cerebrovascular bleeding.

Caution is required in patients suffering from ulcerative colitis or Crohn's Disease as these conditions may be exacerbated (see section 4.8).

Care should be taken in elderly patients and in patients treated with corticosteroids, other NSAIDs, or anti-coagulants (see section 4.5).

• Skin Reactions

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 the use of NSAIDs, including diclofenac/misoprostol (see section 4.8). Patients appear to be at highest risk for these events early in the course of therapy, the onset of the event occurring in the majority of cases within the first month of treatment. Diclofenac/misoprostol should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity

•    Hypersensitivity

NSAIDs may precipitate bronchospasm in patients suffering from, or with a history of, bronchial asthma or allergic disease.

•    Long-term treatment

All patients who are receiving long-term treatment with NSAIDs should be monitored as a precautionary measure (e.g. renal, hepatic function and blood counts). During long-term, high dose treatment with analgesic/anti-inflammatory drugs, headaches can occur which must not be treated with higher doses of the medicinal product.

Arthrotec may mask fever and thus an underlying infection.

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

NSAIDs may attenuate the natriuretic efficacy of diuretics due to inhibition of intrarenal synthesis of prostaglandins. Concomitant treatment with potassiumsparing diuretics may be associated with increased serum potassium levels, hence serum potassium should be monitored.

Because of their effect on renal prostaglandins, cyclo-oxygenase inhibitors such as diclofenac can increase the nephrotoxicity of ciclosporin. There is a possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Steady state plasma lithium and digoxin levels may be increased and ketoconazole levels may be decreased.

Pharmacodynamic studies with diclofenac have shown no potentiation of oral hypoglycaemic and anticoagulant drugs. However as interactions have been reported with other NSAIDs, caution and adequate monitoring are, nevertheless advised (see statement on platelet aggregation in Precautions).

Because of decreased platelet aggregation caution is also advised when using Arthrotec 50 with anti-coagulants. NSAIDs may enhance the effects of anticoagulants, such as warfarin, antiplatelet agents, such as aspirin, and serotonin re-uptake inhibitors (SSRIs) thereby increasing the risk of gastrointestinal bleeding (see section 4.4).

Cases of hypo and hyperglycaemia have been reported when diclofenac was associated with antidiabetic agents.

Caution is advised when methotrexate is administered concurrently with NSAIDs because of possible enhancement of its toxicity by the NSAID as a result of increase in methotrexate plasma levels.

Concomitant use with other NSAIDs or with corticosteroids may increase the frequency of side effects generally.

Anti-hypertensives including diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists (ADA): NSAIDs can reduce the efficacy of diuretics and other antihypertensive drugs.

In patients with impaired renal function (e.g. dehydrated patients or elderly patients with compromised renal function), the co-administration of an ACE inhibitor or an AIIA with a cyclo-oxygenase inhibitor can increase the deterioration of the renal function, including the possibility of acute renal failure, which is usually reversible. The occurrence of these interactions should be considered in patients taking diclofenac/misoprostol with an ACE inhibitor or an ADA.

Antacids may delay the absorption of diclofenac. Magnesium-containing antacids have been shown to exacerbate misoprostol-associated diarrhoea.

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.

NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

4.6 Fertility, pregnancy and lactation

Pregnancy

Arthrotec 50 is contraindicated in pregnant women and in women planning a pregnancy because misoprostol induces uterine contractions and is associated with abortion, premature birth, and fetal death. Use of misoprostol has been associated with birth defects. Also diclofenac may cause premature closure of the ductus arteriosus.

Women of childbearing potential should not be started on diclofenac/misoprostol until pregnancy is excluded, and should be fully counseled on the importance of adequate contraception while undergoing treatment. If pregnancy is suspected, use of the product should be discontinued.

Lactation

Misoprostol is rapidly metabolised in the mother to misoprostol acid, which is biologically active and is excreted in breast milk. Diclofenac is excreted in breast milk in very small quantities. In general, the potential effects on the infant from any exposure to misoprostol and its metabolites via breast feeding are unknown. However, diarrhoea is a recognised side effect of misoprostol and could occur in infants of nursing mothers. Arthrotec 50 should therefore not be administered to nursing mothers.

4.7 Effects on ability to drive and use machines

Patients who experience dizziness or other central nervous system disturbances while taking NSAIDs should refrain from driving or operating machinery.

4.8 Undesirable effects

In the table below the incidence of adverse drug reactions reported in controlled clinical studies where Arthrotec was administered to more than 2000 patients are listed. Additionally, adverse drug reactions reported during post-marketing surveillance are whose frequency cannot be estimated from the available data, such as spontaneous reports, have been listed at frequency ‘unknown’. The most commonly observed adverse events are gastrointestinal in nature.

Organ System	Very Common (> 1/10)	Common (>1/100 and <1/10)	Uncommo n (>1/1,000 and <1/100)	Rare (>1/10,000, and <1/1,000)	Very Rare (<1/10,000)	Frequency: Unknown (Post marketing experience)
Infections and infestations						Aseptic meningitis1
Blood and lymphatic system disorders			Thrombo cytopenia			Aplastic anaemia, agranulocytosis , haemolytic anaemia, leucopenia
Immune system disorders				Anaphylact ic reaction		Hypersensitivit y
Metabolism and nutrition disorders						Anorexia
Psychiatric disorders		Insomnia				Psychotic reaction, disorientation, depression, anxiety, nightmares, mood change, irritability
Nervous system disorders		Headache, dizziness				Convulsions, memory disturbance, drowsiness, tremor, taste disturbance, paraesthesia
Eyes disorders						Visual disturbances, blurred vision
Ear and labyrinth disorders						Tinnitus
Cardiac disorders						Cardiac failure, palpitations
Vascular disorders						Shock, hypertension, hypotension, vasculitis
Respiratory,						Asthma,

thoracic and mediastinal disorders						pneumonitis, dyspnoea
Gastrointesti nal disorders	Abdomin al pain, diarrhoea1 , nausea, dyspepsia	Gastritis, vomiting, flatulence, eructation, constipatio n, peptic ulcer	Stomatitis			GI perforation 3 gastrointestinal bleeding 2, melaena, haematemesis, colitis, Crohn's disease, oesophageal disorder, mouth ulceration, glossitis, tongue odema, dry mouth
Hepato biliary disorders		Alanine amino transferase increased, aspartate aminotransf erase increased		Hepatitis, jaundice	Hepatic failure	Hepatitis fulminant, blood bilirubin increased
Skin and subcutaneous tissue disorders		Erythema multiforme, rash, pruritus	Purpura, urticaria	Angio- edema		Toxic epidermal necrolysis3, Stevens- Johnson syndrome3, dermatitis exfoliative3, dermatitis bullous, Henoch Schonlein purpura, mucocutaneou s rash, rash vesicular, photosensitivit y reaction, alopecia, urticaria
Renal and urinary disorders						Renal failure, acute renal failure, renal papillary necrosis, nephritis interstitial, nephrotic syndrome, proteinuria, haematuria
Pregnancy, puerperium and						Intra-uterine death, uterine rupture,

perinatal conditions						incomplete abortion, premature baby, anaphylactoid syndrome of pregnancy, retained placenta or membranes, uterine contractions abnormal
Reproductive system and breast disorders			Menorr hagia, metrorr hagia, vaginal haemo rrhage, postmeno -pausal haemorr hage			Uterine haemorrhage
Congenital, familial and genetic disorders						Birth defects
General disorders and administrati on site conditions						Oedema4 1 2 3 5, chest pain, face oedema, fatigue, pyrexia, chills, inflammation
Investigation s		Blood alkaline phosphatas e increased				Decreased haemoglobin
Injury, poisoning and procedural complication s						Uterine perforation

3

GI perforation or bleeding can sometimes be fatal, particularly in the elderly (see section 4.4).

⁴    Serious skin reactions, some of them fatal, have been reported very rarely (see section 4.4).

⁵    Especially in patients with hypertension or impaired renal function (see section 4.4).

Given the lack of precise and/or reliable denominator and numerator figures, the spontaneous adverse event reporting system through which post marketing safety data are collected does not allow for a medically meaningful frequency of occurrence of any undesirable effects.

With regard to the relative frequency of reporting of adverse reactions during post marketing surveillance, the undesirable effects at the gastrointestinal level were those received most frequently by the MAH (approximately 45% of all case reports in the company safety database) followed by cutaneous/hypersensitivity-type reactions, which is in agreement with the known side effects profile of the NSAIDs drug class.

Clinical trial and epidemiological data consistently point towards an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high dose (150mg daily) and in long term treatment (see section 4.3 and 4.4 for Contraindications and Special warnings and special precautions for use).

4.9 Overdose

The toxic dose of Arthrotec 50 has not been determined and there is no experience of overdosage. Intensification of the pharmacological effects may occur with overdosage. Management of acute poisoning with NSAIDs essentially consists of supportive and symptomatic measures. It is reasonable to take measures to reduce absorption of any recently consumed drug by forced emesis, gastric lavage or activated charcoal.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group (ATC code): M01BX

Arthrotec 50 is a non-steroidal, anti-inflammatory drug which is effective in treating the signs and symptoms of arthritic conditions.

This activity is due to the presence of diclofenac which has been shown to have anti-inflammatory and analgesic properties.

Arthrotec 50 also contains the gastroduodenal mucosal protective component misoprostol which is a synthetic prostaglandin E₁ analogue that enhances several of the factors that maintain gastroduodenal mucosal integrity.

5.2 Pharmacokinetic properties

The pharmacokinetic profiles of diclofenac and misoprostol administered as Arthrotec 50 are similar to the profiles when the two drugs are administered as separate tablets and there are no pharmacokinetic interactions between the two components.

Diclofenac sodium is completely absorbed from the gastrointestinal (GI) tract after fasting oral administration. Only 50 % of the absorbed dose is systemically available due to first pass metabolism. Peak plasma levels are achieved in 2 hours (range 1-4 hours), and the area-under-the plasma-concentration curve (AUC) is dose proportional within the range of 25 mg to 150 mg. The extent of diclofenac sodium absorption is not significantly affected by food intake.

The terminal half-life is approximately 2 hours. Clearance and volume of distribution are about 350 ml/min and 550 ml/kg, respectively. More than 99 % of diclofenac sodium is reversibly bound to human plasma albumin, and this has been shown not to be age dependent.

Diclofenac sodium is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Approximately 65 % of the dose is excreted in the urine and 35 % in the bile. Less than 1 % of the parent drug is excreted unchanged.

Misoprostol is rapidly and extensively absorbed, and it undergoes rapid metabolism to its active metabolite, misoprostol acid, which is eliminated with an elimination t/₂ of about 30 minutes. No accumulation of misoprostol acid was found in multiple-dose studies, and plasma steady state was achieved within 2 days. The serum protein binding of misoprostol acid is less than 90 %. Approximately 70 % of the administered dose is excreted in the urine, mainly as biologically inactive metabolites.

5.3 Preclinical safety data

In co-administration studies in animals, the addition of misoprostol did not enhance the toxic effects of diclofenac. The combination was also shown not to be teratogenic or mutagenic. The individual components show no evidence of carcinogenic potential.

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

Arthrotec 50 tablets contain:

Core:

Lactose monohydrate microcrystalline cellulose corn starch povidone

magnesium stearate Mantle/Coat:

methylacrylic acid copolymer type C

sodium hydroxide

talc

tri ethyl citrate hypromellose crospovidone hydrogenated castor oil colloidal silicon dioxide microcrystalline cellulose

6.2    Incompatibilities

Not applicable.

6.3 Shelf life

Arthrotec 50 has a shelf-life of 3 years when stored in cold-formed blisters.

6.4 Special precautions for storage

Store in a dry place. Do not store above 25^oC.

6.5 Nature and contents of container

1

2

Diarrhoea is usually mild to moderate and transient and can be minimised by

3

taking Arthrotec 50 with food and by avoiding the use of predominantly

4

   Symptoms of aseptic meningitis (stiff neck, headache, nausea, vomiting, fever or impaired consciousness) have been reported during treatment with NSAIDs. Patients suffering from autoimmune disease (e.g. lupus erythematosus, mixed connective tissue disorders) seem to be more susceptible.

5

magnesium-containing antacids.