Non-steroidal anti-inflammatory drugs (NSAIDs, phenylacetic acid) / prostaglandin analogues.

Diclofenac sodium, misoprostol

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.

Modified-release tablet. White, round, biconvex tablets marked on one side 'Searle 1411'.

Arthrotec 50 is indicated for patients who require the non-steroidal anti-inflammatory 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

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

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

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms

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

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.

- Patients with severe heart failure

Warnings

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

Use in pre-menopausal women

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. 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.

•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 cardiac failure, advanced kidney failure, advanced liver disease, severe dehydration.

Diclofenac metabolites are eliminated primarily by the kidneys. 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 uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with diclofenac 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).

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.

•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.

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.

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.

Care should be taken in elderly patients and in patients treated with corticosteroids, other NSAIDs, or anti-coagulants.

•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. 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.

NSAIDs may attenuate the natriuretic efficacy of diuretics due to inhibition of intrarenal synthesis of prostaglandins. Concomitant treatment with potassium-sparing 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 anti-coagulants, such as warfarin, antiplatelet agents, such as aspirin, and serotonin re-uptake inhibitors (SSRIs) thereby increasing the risk of gastrointestinal bleeding.

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 (AIIA): 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 AIIA.

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.

The incidence of adverse drug reactions reported in controlled clinical studies where Arthrotec was administered to more than 2000 patients are listed in the table below.

Organ System	Very Common ( 10%)	Common (1% , <10%	Uncommon (0.1%, <1%	Rare(0.01%, <0.1%)
Gastrointestinal	Abdominal Pain, Diarrhoea*, Nausea, Dyspepsia	Flatulence, Vomiting, Gastritis, Eructation, Constipation	Stomatitis	;">
Skin/Hypersensitivity		Rashes (erthyema multiforme), Pruritus	Purpura, Urticaria	Anaphylactic reaction, Angioedema
Liver		Elevations of SGPT and Alkaline phosphotase		Hepatitis (with or without jaundice)
Female reproductive system			Menorrhagia, Intermenstrual bleeding, Vaginal bleeding (including pre and post menopausal)
Blood system			Thrombocytopenia
CNS		Insomnia, Headache, Dizziness

*= Diarrhoea is usually mild to moderate and transient and can be minimised by taking Arthrotec 50 with food and by avoiding the use of predominantly magnesium-containing antacids.

The following undesirable effects have been reported during post marketing surveillance and have been arranged in order to reflect the relative frequency of reporting by body system:

Gastrointestinal:

The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, decrease in haemoglobin associated with GI blood loss, oesophageal lesions, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, anorexia, dry mouth, glossitis, exacerbation of colitis and Crohn's disease have been reported following administration. Less frequently, gastritis has been observed.

Liver: Elevations of SSGOT, or bilirubin. In very rare cases, severe fulminant hepatitis may occur, possibly without prodromal symptoms.

Skin/Hypersensitivity: Photosensitivity reactions, Stevens-Johnson syndrome, Lyell's syndrome (acute toxic epidermal necrolysis), hypersensitivity including, asthma allergic purpura and hair loss, vasculitis and pneumonitis.Cutaneous reactions (including rash and bullous eruptions with vesiculation and erythroderma, dermatitis exfoliative, erythema multiforme, urticaria, mucocutaneous reactions.

Anaphylactoid systemic reactions; oedema of the face and tongue, hypotension and shock.

CNS: Drowsiness, paraesthesia, changes in mood, memory disorders, disorientation, visual disturbances, tinnitus, insomnia, irritability, convulsions, depression, anxiety, nightmares, tremors, psychotic reactions, taste disturbance and tiredness. Symptoms of aseptic meningitis (stiff neck, headache, nausea, vomiting, fever or impaired consciousness) have been reported during treatment with NSAIDs. Patients suffering form autoimmune disease (e.g. lupus erythematosus, mixed connective tissue disorders) seem to be more susceptible.

Blood system: Leucopenia, thrombocytopenia, agranulocytosis, haemolytic anaemia, aplastic anaemia.

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

Cardiovascular System: Hypotension, hypertension, palpitations, chest pain and cardiac failure.

Respiratory, thoracic and mediastinal disorders: dyspnea.

Eye disorders: blurred vision.

Pregnancy, puerperium and perinatal conditions: abnormal uterine contractions, uterine rupture/perforation, retained placenta, amniotic fluid embolism, incomplete abortion, premature birth, fetal death.

Reproductive system and breast disorders: uterine hemorrhage.

Congenital, familial and genetic disorders: birth defects.

General disorders and administration site conditions: chills, fever.

Other: Oedema, especially in patients with hypertension or impaired renal function.

In very rare cases worsening of inflammation associated with infections have been reported in association with NSAID treatment.

A number of side effects have been reported in clinical studies or in the literature following use of misoprostol for non-approved indications. These include abnormal uterine contractions, uterine haemorrhage, retained placenta, amniotic fluid embolism, incomplete abortion and premature birth.

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

Pharmacia Limited

(POM)

08 June 2009