INDOMETACIN CAPSULES BP 50 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Indometacin Capsules BP 50mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains indometacin 50mg

For excipients, see 6.1

3 PHARMACEUTICAL FORM

Indometacin capsules are presented as size 1, ivory opaque shells printed with ‘IND 50’ and company logo

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Indometacin capsules are indicated for the pain and inflammation associated with the following conditions:

Active stages of rheumatoid arthritis

Osteoarthritis

Ankylosing spondylitis

Degenerative joint disease of the hip

Acute musculoskeletal disorders

Low back pain

Acute gout

Inflammation, pain and oedema following orthopaedic procedures

Pain and associated symptoms of primary dysmenorrhoea

4.2 Posology and method of administration

For oral administration. To be taken preferably with or after food, milk or an antacid.

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

Chronic conditions

Adults: 50mg once or twice daily increased if required, up to 200mg daily.

The recommended oral dose range is 50 – 200mg daily in divided doses.

Acute gouty arthritis

Adults: 150 – 200mg daily in divided doses until all signs and symptoms subside.

Dysmenorrhoea

Up to 75mg daily until the symptoms subside.

Paediatric dosage: Not established

Elderly: The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

4.3 Contraindications

Hypersensitivity to indometacin or to any of the excipients.

NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs (see section 4.4).

Use with concomitant NSAIDs including cyclooxygenase 2 specific inhibitors (see section 4.5).

Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

Nasal polyps associated with angioneurotic oedema.

Severe hepatic, renal and cardiac failure (see section 4.4).

During the last trimester of pregnancy (see section 4.6).

4.4 Special warnings and precautions for use

In all patients:

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 indometacin with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

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 – posology and administration).

Respiratory disorders:

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

Cardiovascular, Renal and Hepatic Impairment:

The administration of an NSAID may cause a dose dependant reduction in prostaglandin formation and precipitate renal failure in patients with reduced renal blood flow where prostaglandins play a major role in maintaining renal perfusion. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, diabetes mellitus, extracellular volume depletion, sepsis, those taking diuretics, the elderly or concomitant use of any nephrotoxic drug. NSAIDs should be given with caution and renal function should be monitored in these patients (see also section 4.3 – contraindications). Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state.

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 or other conditions predisposing to fluid retention, 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). There are insufficient data to exclude such a risk for indometacin.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with indometacin 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).

Gastrointestinal bleeding, ulceration and perforation:

GI 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.

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 (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

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 medications 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 interactions).

When GI bleeding or ulceration occurs in patients receiving indometacin, the treatment should be withdrawn.

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 – undesirable effects).

Gastro-intestinal disorders which occur can be reduced by giving indometacin with food, milk or antacids.

Patients should be carefully observed to detect any unusual manifestations of drug sensitivity.

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 – undesirable effects).

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

Impaired female fertility:

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.

Patients should be periodically observed to allow early detection of any unwanted effects on peripheral blood (anaemia), liver function (also see section 4.8 Undesirable effects), or gastrointestinal tract especially during prolonged therapy.

Headache, dizziness and light-headedness can occur, usually early in treatment. These disappear on continuing therapy or reducing the dosage. If headache persists despite dosage reduction, treatment should then be discontinued.

Caution should be exercised in patients with bleeding disorders, psychiatric disorders, epilepsy or parkinsonism as indometacin may aggravate these conditions.

Indometacin may mask the signs and symptoms of infection therefore care should be taken in patients with existing, but controlled infection. Caution is advised with concomitant use of live vaccines.

Eye changes can occur in patients suffering from rheumatoid arthritis, which may be related to the underlying disease or to the therapy. During prolonged therapy, periodic ophthalmic examinations are recommended, as corneal deposits and retinal disturbances have been reported. Therapy should be discontinued in the event of changes in the eye.

Caution should be exercised in patients with coagulation defects as indometacin inhibits platelet aggregation and prolongs bleeding time. This effect may be exaggerated in patients with underlying haemostatic defects. Inhibition of platelet aggregation usually disappears within 24 hours of discontinuing indometacin.

Caution is required in post-operative patients as bleeding time is prolonged (but within normal range) in normal adults.

Increase in plasma potassium concentration including hyperkalemia have been reported even in some patients without renal impairment. In patients with normal renal function these effects have been attributed to a hyporeninaemic-hypoaldosteronism state. (See 4.5 “Interactions with other medicinal products and other forms of interaction”).

As with other NSAIDs, there have been reports of acute interstitial nephritis with haematuria, proteinuria, and occasionally nephrotic syndrome in patients receiving long-term administration of indometacin.

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

In patients with renal, cardiac, hepatic impairment, hypertension, heart failure or conditions predisposing to fluid retention caution is required since the use of NSAIDs may result in deterioration of renal function (see section 4.8). The dose should be kept as low as possible and renal function should be monitored. NSAIDs may also cause fluid retention which may further aggravate these conditions.

4.5 Interaction with other medicinal products and other forms of interaction

Aspirin or other salicylates: Not recommended, as blood levels of indometacin will be lowered and the incidence of gastro-intestinal side-effects is increased.

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 effects (see section 4.4).

Baclofen: NSAIDs possibly reduce excretion of baclofen (may increase risk of toxicity).

Corticosteroids: The risk of gastro-intestinal bleeding and ulceration associated with NSAIDs is increased when used with corticosteroids (see section 4.4 – special warnings and precautions for use). A reduction in dosage of corticosteroids may be possible when given with indometacin, but should only be effected slowly under supervision.

Probenecid: May increase plasma levels of indometacin. When increases in the dose of indometacin are made under these circumstances, they should be made cautiously and in small increments.

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

Diflunisal: Increases the plasma level of indometacin by about a third with concomitant decrease in renal clearance. Fatal gastrointestinal haemorrhage can occur.

Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4 – special warnings and precautions for use).

Administration with coumarin or indanedione derivative anticoagulants may displace these anticoagulants from their protein binding sites leading to an increased anticoagulant effect. Administration with heparins may increase risk of bleeding.

Antiplatelet agents: There is an increased risk of gastrointestinal bleeding with clopidogrel. 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.

Sibutramine (appetite suppressant): Increased risk of bleeding when given with indometacin.

Antidepressants SSRIs, venlafaxine: Administration with antidepressants can increase the risk of gastrointestinal bleeding.

Haloperidol: Co-administration can result in severe drowsiness.

Lithium: Produces elevation of plasma lithium and decreased elimination of lithium due to inhibition of prostaglandin synthesis. Therefore, during concomitant therapy, patients should be carefully observed for signs of lithium toxicity. In addition the frequency of monitoring serum lithium concentrations should be increased at the outset of such combination drug treatment.

Diuretics: Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. Therefore when indometacin and diuretics are used concomitantly, patients should be observed to ascertain the diuretic effect. Indometacin reduces basal plasma renin activity as well as those elevations of plasma renin activity induced by furosemide, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. Indometacin and triamterene should not be administered together as it may result in reversible acute renal failure. Indometacin may reduce the antihypertensive effect of thiazides and furosemide in some patients.

Indometacin and potassium sparing diuretics are both associated with increased plasma potassium levels. The potential effects of indometacin and potassium sparing diuretics on potassium kinetics and renal function should be considered when these agents are administered concurrently.

Most of the above effects concerning diuretics have been attributed, at least in part, to a mechanism involving inhibition of prostaglandin synthesis by indometacin.

Anti-hypertensives: Reduced anti-hypertensive effect. Indometacin may acutely reduce the antihypertensive effect of beta-blockers due partly to indometacin’s in­hibition of prostaglandin synthesis. Therefore, caution should be exercised when considering the addition of indometacin to the regimen of a patient taking any antihypertensive agents including: alpha-adrenergic blocking agents, ACE inhibitors, beta-adrenergic blocking agents, diuretics, angiotensin II receptor antagonists (also risk of hyperkalaemia), calcium channel blockers, vasodilators, hydralazine or nifedipine and centrally acting hypotensives. Patients receiving dual therapy should have the antihypertensive effect of their therapy reassessed. Hyperkalaemia has also been reported with ACE inhibitors.

ACE Inhibitors, Angiotensin-II Antagonists, Alpha blockers, diazoxide: There is also an increased risk of renal impairment.

Pentoxifylline: There is a possible increased risk of bleeding with concomitant use of pentoxifylline and NSAIDs.

Drospirenone (combined contraceptive): Risk of hyperkalaemia, need to monitor serum potassium during first cycle.

Phenylpropano­lamine: Hypertensive crises have been reported due to oral phenylpropanolamine alone and, rarely, to phenylpropanolamine given with indometacin.

Methotrexate: Indometacin decreases the elimination of methotrexate and potentiates toxicity.

Ciclosporin: Increased risk of nephrotoxicity or ciclosporin induced toxicity, possibly due to decreased synthesis or renal prostacyclin. Patients taking both indometacin and ciclosporin should have renal function monitored carefully.

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.

Cardiac glycosides/Digoxin: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels. Indometacin increases the serum concentration and prolongs the half-life of digoxin. If co-administered serum digoxin levels should be closely monitored.

Desmopressin: Indometacin enhances the effects of desmopressin.

Tiludronic acid: Indometacin increases bioavailability of tiludronic acid (bisphosphonates).

Antidiabetic agents: Clinical studies have shown that indometacin can be given together with oral antidiabetic agents without influencing their clinical effect. However there have been isolated reports of hypoglycaemic and hyperglycaemic effects which have required adjustment to the dosage of hypoglycaemic agents. The effect of sulphonylureas may be increased by NSAIDs. Isolated case of metabolic acidosis with metformin.

Phenytoin: NSAIDs may enhance the effect of phenytoin.

Antivirals: There is an 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. Concomitant use of NSAIDs with ritonavir may increase NSAID plasma concentration (indometacin toxicity). Pharmacokinetic changes have been recorded with zalcitabine/in­dometacin. Also increased risk of haematological toxicity with zidovudine.

Tacrolimus: Concomitant use of tacrolimus with NSAIDs may increase the risk of nephrotoxicity.

Antibacterials – NSAIDs possibly increase the risk of convulsions with 4-quinolones. Also skin reactions and neurotoxicity have been reported with ciprofloxacin.

Benzodiazepines – increased risk of dizziness with diazepam and indometacin.

Cytotoxics – caution should be employed in use with cyclophosphamide as acute water intoxication has been reported. Indometacin may decrease the tubular secretion of methotrexate thus potentiating toxicity; simultaneous use should be undertaken with caution.

Muromonab-CD3 – significant rise in incidence of psychosis and encephalopathy in patients receiving both these drugs.

Vasodilators – possible increased risk of bleeding with NSAIDs.

Laboratory tests: borderline elevations of one or more liver tests may occur, and significant elevations of ALT (SGPT) or AST (SGOT) have been seen in less than 1% of patients receiving therapy with NSAIDs in controlled clinical trials. If abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations such as rash or eosinophilia occur, indometacin should be stopped. False-negative results in the dexamethasone suppression test (DST) in patients being treated with indometacin have been reported. Thus, results of this test should be used with caution in these patients.

4.6 Fertility, pregnancy and lactation

Pregnancy :

Indometacin crosses the placental barrier. Studies in humans have not been conducted. Studies carried out on rats and mice have shown that (at a dose of 4mg/kg body weight/day) indometacin causes decreased average foetal weight and retarded ossification and when administered during the last three days of gestation there is increased evidence of neuronal necrosis in the diencephalon and some maternal and foetal deaths. Other studies in mice with higher doses (5 to 15mg/kg body weight/day) have resulted in maternal toxicity and death, increased foetal resorption and congenital malformations.

Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see section 4.3 contraindi­cations). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

Lactation:

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

See section 4.4 – special warnings and precautions for use, regarding female fertility.

4.7 Effects on ability to drive and use machines

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

4.8 Undesirable effects

Gastro-intestinal: The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, anorexia, vomiting, epigastric distress, abdominal pain, constipation, diarrhoea, flatulence, dyspepsia, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (see section 4.4 – special warnings and precautions for use) have been reported following administration. Less frequently, intestinal strictures (diaphragms) and intestinal ulceration followed by stenosis and obstruction, perforation of pre-existing sigmoid lesions such as diverticula and carcinomata, and regional ileitis and gastritis has been observed. Pancreatitis has been reported very rarely. Ulceration at any point in the gastro-intestinal tract (even with resultant stenosis and obstruction), bleeding (even without obvious ulceration or from a diverticulum). If gastrointestinal bleeding does occur treatment with indometacin should be discontinued. Gastro-intestinal disorders which occur can be reduced by giving indometacin with food, milk or antacids.

Metabolism and nutrition disorders: hyperglycaemia, hyperkalaemia and glycosuria have been reported rarely.

Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis, rapid fall in blood pressure resembling a shock-like state, (b) respiratory tract reactivity comprising of asthma, aggravated asthma, pulmonary oedema, bronchospasm or dyspnoea, or © assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme), angitis, erythema nodosum, Stevens-Johnson syndrome.

Cardiovascular and cerebrovascular: Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Reactions occurring infrequently, tachycardia, chest pain, arrhythmia, palpitation and hypotension.

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).

Other adverse events reported less commonly include:

Renal and urinary disorders: haematuria, nephrotic syndrome, proteinuria, interstitial nephritis, renal insufficiency or failure have all been reported. In patients with renal, cardiac or hepatic impairment, caution is required since the use of non-steroidal anti-inflammatory drugs may result in deterioration of renal function. The dose should be kept as low as possible and renal function should be monitored.

Hepatic: cholestasis, abnormal liver function. Rarely hepatitis, jaundice (associated with some fatalities).

Neurological and special senses: Visual disturbances, optic neuritis, blurred or double vision, orbital and periorbital pain, corneal deposits, retinal disturbances including those of the macula have been reported in patients with rheumatoid arthritis on long-term therapy. Headaches, dizziness, paraesthesia, 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, nausea, vomiting, fever or disorientation (see section 4.4), depression, confusion, hallucinations, vertigo, malaise, fatigue, drowsiness, cerebral oedema, nervousness, light-headedness and listlessness, tinnitus, hearing disturbances (rarely deafness). Starting therapy with a low dose and increasing gradually minimises the incidence of headache. These symptoms frequently disappear on continued therapy or reducing the dosage, but if headache persists despite dosage reduction, indometacin should be withdrawn.

Rarely mental confusion, anxiety, syncope, convulsions, coma, peripheral neuropathy, muscle weakness, involuntary muscular movements, insomnia, psychiatric disturbances such as depersonalisation, dysarthria, aggravation of epilepsy, Parkinsonism. These effects are often transient and abate or disappear on reduced or stopping treatment. However, the severity of these may, on occasion, require cessation of therapy.

Haematological: blood dyscrasias (thrombocytopenia, neutropenia, leukopenia, agranulocytosis, petechiae, ecchymosis, purpura, aplastic or haemolytic anaemia), bone marrow depression, elevation of blood urea, epistaxis, and disseminated intravascular coagulation may occur infrequently. Some patients manifest anaemia secondary to obvious or occult gastrointestinal bleeding.

Dermatological: itching, urticaria, angioneurotic oedema, angiitis, photosensitivity, erythema nodosum, rash and exfoliative dermatitis all have been reported infrequently – as have Stevens Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, hair loss, sweating and exacerbation of psoriasis..

Reproductive system and breast disorders: vaginal bleeding, interstitial nephritis, breast changes (enlargement, tenderness, gynaecomastia).

Vascular disorders: sweating and flushing has been reported.

Respiratory, thoracic and mediastinal disorders: pulmonary eosinophilia. There may be bronchospasm in patients with a history of bronchial asthma or other allergic disease.

Miscellaneous:

Musculo-skeletal, connective tissue and bone disorders: Muscle weakness and acceleration of cartilage degeneration.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

a) Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions, mental confusion or lethargy. Numbness and paraesthesiae have been reported. In cases of significant poisoning acute renal failure and liver damage are possible.

b) Therapeutic measure

Patients should be treated symptomatically as required. Within 1 hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose. Good urine output should be ensured.

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.

The patient should be followed for several days because gastrointestinal ulceration and haemorrhage have been reported as adverse reactions of indometacin. Use of antacids may be helpful.

The plasma elimination of indometacin is biphasic with the half-life of the terminal plasma half-life phase between 2.6 and 11.2 hours.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Anti-inflammatory and Anti-rheumatic products, Non-steroids; Acid Derivatives and Related Substances

ATC Code: M01A B01

Indometacin inhibits the action of cyclo-oxygenase, hence decreases the formation of precursors of prostaglandins and thromboxanes from arachidonic acid.

The analgesic action of indometacin involves blocking pain impulse generation via a peripheral action that may result from inhibition of the synthesis of prostaglandins and possibly inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation. Inhibition of prostaglandin synthesis in the central nervous system may also contribute to the analgesic effect. Indometacin acts as anti rheumatic via analgesic and anti-inflammatory mechanisms; the therapeutic effects are not due to pituitary-adrenal stimulation. The production of rheumatoid factor (IgM) may be decreased during indometacin therapy; however the medication does not affect the progressive course of rheumatoid arthritis.

Indometacin acts as an anti-gout agent via analgesic and anti-inflammatory mechanisms; it does not affect hyperuricaemia.

The exact mechanism for anti-inflammatory action has not been determined. It is thought to act peripherally in inflamed tissue, probably by inhibiting the synthesis of prostaglandins and possibly by inhibiting the synthesis and/or actions of other local mediators of the inflammatory response. Inhibition of leucocyte migration, inhibition of the release and/or actions of lysosomal enzymes, inhibition of phosphodiesterase with resultant increase in intracellular cyclic adenosine monophosphate concentration and actions on other cellular and immunological process in mesenchymal and connective tissue may be involved.

Indometacin has an antipyretic action. It produces antipyresis by acting centrally on the hypothalamic heat-regulating centre to produce peripheral vasodilation resulting in increased cutaneous blood flow, sweating and heat loss. The central action may involve inhibition of prostaglandin synthesis in the hypothalamus.

Indometacin also acts as an anti-dysmenorrheal by inhibiting the synthesis of uterine prostaglandin hence decreases uterine contractions, increases uterine perfusion and relieves ischaemic, as well as spasmodic pain.

Indometacin may also relieve extrauterine symptoms caused by excessive prostaglandin production, such as headache, nausea and vomiting.

Other actions of indometacin include reversible inhibition of platelet aggregation, but to lesser extent than does aspirin. Recovery of platelet function results within 1 day after discontinuation of the medication.

5.2 Pharmacokinetic properties

Following oral administration indometacin is absorbed rapidly and completely from the gastrointestinal tract. Approximately 90% of the dose is absorbed within 4 hours.

Absorption is slightly delayed when indometacin is administered concomitantly with food or an aluminium or magnesium containing antacid. Approximately 99% is bound to albumin.

Half-life is biphasic, distribution occurs in 1 hour and elimination in approximately 4.5 hours (usual range being 2.6 to 11.2 hours); and is subject to large inter-individual variation, possibly due to inter-individual differences in enterohepatic circulation and subsequent reabsorption. Onset of action as an anti-rheumatic usually occurs within 7 days, but may require up to 14 days, depending on the severity of condition. Anti-gout action occurs within 2 – 4 hours. Peak plasma concentration is reached in 0.5 – 2.0 hours following an oral dose; peak serum concentration for 50mg capsule being 2.5 – 4.0pg/ml. Indometacin is metabolised in the liver, approximately 60% of a dose being excreted in urine (10 – 20% as unchanged indometacin) and 33% via the biliary route (1.5% as unchanged indometacin). It is also excreted in the breast milk.

5.3 Preclinical safety data

Not applicable

6 Pharmaceutical particulars

6.1 List of Excipients

Talc

Magnesium stearate

Sodium starch glycolate

Sodium lauryl sulphate Lactose

Capsule shell components:

Body

Quinoline yellow (E104)

Titanium dioxide (E171)

Gelatin

Cap

Quinoline yellow (E104)

Titanium dioxide E171)

Gelatin

Printing ink:

Black ink containing shellac, ethanol, isopropyl alcohol, iron oxide black (E172), N-butyl alcohol, propylene glycol, ammonium hydroxide.

6.2 Incompatibilities

None reported

6.3 Shelf life

5 years for opaque plastic containers

4 years for blister packaging

6.4 Special precautions for storage

Opaque plastic containers:

Keep the capsules in the pack provided in order to protect from heat, light and moisture.

Blister packs:

Store below 25°C.

Keep the blisters in the outer carton in order to protect from light and moisture.

6.5 Nature and contents of container

Indometacin capsules are packed in the following containers and closures.

Opaque plastic containers composed of polypropylene tubes and polyethylene tamper-evident closures for all pack sizes (28, 42, 50, 56, 84, 100, 112, 250, 500 and 1000).

Opaque plastic containers composed of either high density polypropylene or high density polyethylene with a tamper evident or child resistant tamper evident closure composed of high density polyethylene for all pack sizes (28, 42, 50, 56, 84, 100, 112, 250, 500 and 1000) with a packing inclusion of standard polyether foam or polyethylene or polypropylene filler.

Blister packs of aluminium/opaque 250^m PVC or aluminium/clear 250^m PVC coated with a 40g/m2 PVdC layer. It is subsequently packed in printed boxboard cartons in pack sizes of 28, 42, 56, 84 and 112.

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

Crescent Pharma Limited

Units 3 & 4, Quidhampton Business Unit

Polhampton Lane

Overton

Hampshire

RG25 3ED

8 MARKETING AUTHORISATION NUMBER(S)

PL 20416/0095

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

17/02/2006