Indolar* (Indometacin) SR Capsules 75mg.

Each capsule contains indometacin 75mg

Slow release capsule.

Non-steroidal analgesic and anti-inflammatory agent indicated in active rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, degenerative joint disease of the hip, acute musculo-skeletal disorders and low back pain. Also indicated in periarticular disorders such as bursitis, tendinitis, synovitis, tenosynovitis and capsulitis.

Also indicated in inflammation, pain and oedema following orthopaedic procedures and the treatment of pain and associated symptoms of primary dysmenorrhoea.

Indolar* SR Capsules should always be given with food or milk to reduce the chance of gastro-intestinal disturbance.

Adults:

One capsule once or twice daily, depending on patients needs and response.

Dosage in dysmenorrhoea: one capsule a day, starting with onset of cramps or bleeding, and continuing for as long as symptoms usually last.

Children:

Safety for use in children has not been established.

Elderly:

Particular care should be taken with the elderly.

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

Patients with angioneurotic oedema or who have, with aspirin or other non-steroidal anti-inflammatory drugs, experienced acute asthmatic attacks, urticaria or rhinitis.

Active peptic ulcer, a history of recurrent gastro-intestinal lesions, sensitivity to indometacin, to aspirin, to other non-steroidal anti-inflammatory drugs or to any of the other ingredients in the capsule.

Patients who show sensitivity to indometacin or any other ingredient in this product.

Severe heart failure.

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).

NSAIDs should only be given with care to patients with a history of gastrointestinal disease.

Caution is required in patients with renal, hepatic or cardiac impairment since the use of NSAIDs may result in deterioration of renal function. The dose should be kept as low as possible and renal function should be monitored in these patients. NSAIDs should be given with care to patients with a history of heart failure or hypertension since oedema has been reported in association with NSAIDs administration.

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

It is reported that a few patients receiving non-steroidal anti-inflammatory drugs manifest borderline elevations in liver function test results. If these persist or worsen, or symptoms of liver disease, a rash or eosinophilia develop, treatment with indometacin should be stopped. Periodic assessment to detect, at an early stage, unwanted effects on peripheral blood (anaemia) and liver function are advisable.

Particular care should be taken with elderly patients who are more susceptible to side-effects from indometacin.

In common with other anti-inflammatory analgesic anti-pyretic agents, indometacin may mask the signs and symptoms of infectious disease and this should be borne in mind in order to avoid delay in starting treatment for infection. Indometacin should be used with caution in patients with an existing, albeit controlled infection.

The use of indometacin 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 indometacin should be considered.

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 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).

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with indomethacin after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Concomitant use of two or more NSAIDs should be avoided.

Use of indometacin with aspirin or other salicylates is not recommended because there is no enhancement of therapeutic effect while the incidence of gastro-intestinal side-effects is increased. Moreover, co-administration of aspirin may decrease the blood concentration of indometacin.

Co-administration of diflunisal increases the plasma level of indometacin by about a third with concomitant decrease in renal clearance. Fatal gastro-intestinal haemorrhage has occurred. The combination should not be used.

Indometacin may decrease the tubular secretion of methotrexate thus potentiating toxicity. Simultaneous use should be undertaken with caution.

Patients receiving anticoagulants should be observed carefully for alteration of prothrombin time even though clinical studies suggest no influence from indometacin on hypoprothrombinaemia induced by anticoagulants.

Indometacin can inhibit platelet aggregation - an effect which disappears within 24 hours of discontinuation; the bleeding time may be prolonged and this effect may be exaggerated in patients with an underlying haemostatic defect.

Diuretics may increase the risk of nephrotoxicity of NSAIDs. Indometacin and triamterene should not be administered together since reversible renal failure may be induced.

Indometacin may reduce the diuretic and antihypertensive effects of thiazides and furosemide in some patients and may cause blocking of the furosemide-induced increase in plasma renin activity.

Co-administration of probenecid may increase plasma levels of indometacin.

Because indometacin may reduce the effect of antihypertensive drugs, patients receiving dual therapy should have the antihypertensive effect of their therapy reassessed.

The risk of gastrointestinal bleeding may be increased by concomitant administration of corticosteroids. A reduction in dosage of these may be possible but should only be effected slowly under supervision.

Indometacin may raise plasma lithium levels and reduce renal lithium clearance in subjects with steady state plasma lithium concentrations. At the onset of such combined therapy, plasma lithium concentration should be monitored more frequently.

When indometacin is taken with antidepressants such as SSRI's or venlafaxine there is an increased risk of bleeding. Indometacin may cause severe drowsiness if taken with haloperidol.

There is a risk of an increase in plasma concentration of indometacin if it is taken with the antiviral ritonavir, if indometacin is taken with the antiviral zidovudine there is a risk of haematological toxicity.

When given with cardiac glycosides, NSAIDs may exacerbate cardiac failure, reduce glomerular filtration rate and increase plasma glycoside levels.

Concomitant administration of ciclosporin may lead to increased risk of nephrotoxicity.

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

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.

Indometainc may enhance the effects of the antidiabetic sulphonylureas and the antiepileptic phenytoin.

There is an increased risk of bleeding if pentoxifylline (oxypentifylline) is taken with indometacin.

There is an increased risk on nephrotoxicity when indometacin is taken concomitantly with tacrolimus.

The dexamethasone suppression test may give false negative results.

Indometacin can adversely affect the foetus. It is not clear whether the risk is increased the earlier indometacin is used in gestation. However the use of Indolar* SR during pregnancy should if possible be avoided.

Reported adverse effects of indometacin during pregnancy include: transient constriction of the ductus arteriosus, pulmonary hypertension, bronchopulmonary dysplasia, oligohydramnios and possible renal damage. In view of these known effects on the fetal cardiovascular system, use in late pregnancy should be avoided.

Administration of Indolar* SR is not recommended in breast-feeding mothers.

Patients should be warned not to drive or operate machinery if they become dizzy.

The most common side-effects are gastrointestinal in nature. Nausea, vomiting, constipation or diarrhoea, dyspepsia, epigastric discomfort or abdominal pain have been reported following administration. More rarely anorexia, stomatitis, flatulence, melaena and haematemesis have also been reported.

Ulceration at any point in the gastro-intestinal tract (even with resultant stenosis and obstruction) may also occur accompanied by haemorrhage and perforation (a few fatalities have been reported). Bleeding without obvious ulceration and perforation of pre-existing sigmoid lesions (such as a diverticulum or carcinoma) have also occurred. Increased abdominal pain in patients with ulcerative colitis (or the development of this condition) and regional ileitis have rarely been reported. If gastro-intestinal bleeding does occur, treatment with indometacin should be discontinued.

Occurrence of gastro-intestinal disorders can be reduced by giving indometacin with food, milk or antacids.

Blood dyscrasias, including thrombocytopenia, neutropenia, leucopenia, petechiae, ecchymosis, purpura, aplastic or haemolytic anaemia, agranulocytosis, bone marrow depression and disseminated intravascular coagulation have been reported.

Oedema, increased blood pressure, hypertension, tachycardia, chest pain, arrhythmia, palpitations, congestive cardiac failure, elevation of blood urea and haematuria may also occur.

Hypersensitivity reactions including pruritus, urticaria, angioneurotic oedema, angiitis, erythema nodosum, rash and exfoliative dermatitis have been reported infrequently - as have Stevens Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, hair loss, acute anaphylaxis (including acute loss of blood pressure). Photosensitivity reactions have also been reported.

Acute respiratory distress, including sudden dyspnoea, asthma and pulmonary oedema have been reported on rare occasions. Bronchospasm may be precipitated in patients suffering from, or with a previous history of bronchial asthma or allergic disease.

Non-steroidal anti-inflammatory drugs have been reported to cause nephrotoxicity in various forms and their use may precipitate renal decompensation in those with renal or hepatic dysfunction, diabetes mellitus, advanced age, extracellular volume depletion. Also, there have been reports of acute interstitial nephritis with haematuria, proteinuria and occasionally nephrotic syndrome, renal insufficiency or failure in long-term therapy with indometacin.

Abnormal liver function, hepatitis and jaundice (including some fatalities) have been reported rarely.

Headache, dizziness, light-headedness, fainting, malaise, depression, vertigo and fatigue are not uncommon. Infrequently confusion, anxiety or other psychiatric disorders, drowsiness, convulsions, neuropathy, paraesthesia, hallucinations, involuntary movements, insomnia, aggravation of epilepsy and Parkinsonism may also occur. All are often transient and likely to abate or disappear with reduced or ceased dosage. If headache persists, even after dosage reduction, indometacin should be withdrawn. There have also been reports of peripheral neuropathy.

Optic neuritis, blurred vision and orbital and peri-orbital pain are seen infrequently. Corneal deposits and retinal disturbances have been reported in some patients with rheumatoid arthritis on prolonged therapy with indometacin, and ophthalmic examinations are desirable in patients given prolonged treatment.

Tinnitus or hearing disturbance (rarely deafness) have been reported.

Hyperglycaemia, glycosuria, hyperkalaemia, vaginal bleeding, epistaxis, breast changes (enlargement, tenderness, gynaecomastia), flushing, sweating and ulcerative stomatitis all have been reported rarely.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

Many of the unwanted symptoms associated with indometacin therapy may be seen. Treatment is symptomatic and supportive. Emptying the stomach by induction of vomiting and/or lavage and use of activated charcoal may be appropriate. Antacid therapy may be useful. Close monitoring thereafter is required because intestinal ulceration may develop.

Indometacin is a non-steroidal analgesic and anti-inflammatory agent.

Indometacin has a biphasic plasma elimination with the terminal phase showing a half-life ranging between 2 and 12 hours. The following pharmacokinetic particulars were obtained with Indolar* SR 75mg capsules (n = 8).

No additional data provided. The pre-clinical safety of indometacin is already well documented.

Sucrose, corn starch, lactose, povidone, talc, magnesium stearate and polymethacrylates. The capsule shells contain gelatin and the colours titanium dioxide (E171), erythrosine (E127), indigotine (E132) and yellow iron oxide (E172).

Not applicable.

36 months.

Capsules should be stored in a cool dry place and protected from light.

Polypropylene securitainers with polyethylene closures, containing 28, 30, 56, 60, 84, 90 or 100 capsules.

Not applicable.

Sandoz Ltd

Woolmer Way

Bordon

Hampshire

GU35 9QE

PL 4416/0066

30 January 1994

03/2007

* trade mark