SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Indometacin Capsules BP 50 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Indometacin BP 50 mg

3 PHARMACEUTICAL FORM

Capsules for oral administration

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Non-steroidal anti-inflammatory agent indicated for the active stages of rheumatoid arthritis; osteoarthritis, ankylosing spondylitis, degenerative joint disease of the hip, acute musculoskeletal disorder; low back pain; and acute gout.

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

4.2 Posology and method of administration

The dosage of indometacin should be carefully adjusted to suit the needs of the individual patient.

In order to reduce the possibility of gastro-intestinal disturbances, indometacin capsules should always be taken with food, milk or an antacid.

In chronic conditions, starting therapy with a low dosage, increasing this gradually as necessary, and continuing a trial of therapy for an adequate period (in some cases, up to one month) will give the best results with a minimum of unwanted reactions.

Adults

The recommended dosage range is 50 - 200mg daily in divided doses.

Dosage in acute gouty arthritis: 150 - 200mg daily in divided doses until all symptoms and signs subside.

Dosage in dysmenorrhoea: up to 75mg a day, starting with onset of cramps or bleeding, and continuing for as long as the symptoms usually last.

Elderly

Indometacin should be used with particular care in older patients who are more prone to adverse reactions. If indometacin is considered necessary, the lowest dose should be used and the patient should be monitored regularly for gastrointestinal bleeding during treatment with indometacin.

Children

Safety for use in children has not been established. It is therefore not recommended for use in children.

Route of administration

Oral

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

4.3 Contraindications

• Hypersensitivity to Indometacin or to any of the excipients.

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

• 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.

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

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

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

• Not to be used in patients who have nasal polyps • Safety in children has not been established.

4.4 Special Warnings and Precautions for Use

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).

Headache, sometimes accompanied by dizziness and lightheadedness, may occur usually early in treatment. Starting therapy with a low dosage and increasing it gradually will usually minimise the incidence of headache. These symptoms frequently disappear on continuing therapy or reducing the dosage, but if headache persists despite dosage reduction, Indometacin should be withdrawn.

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)

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:

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.

In patients with reduced renal blood flow where renal prostaglandins play a major role in maintaining renal perfusion, administration of a NSAID may precipitate overt renal decompensation. The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, diabetes mellitus, congestive heart failure, those taking diuretics, extra-celluar volume depletion, sepsis, concomitant use of any nephrotoxic drug and the elderly. Indometacin should be given with caution and renal function should be monitored in these patients (see also section 4.3).

A non-steroidal anti-inflammatory drug should be given with caution and renal function should be monitored in any patient who may have reduced renal reserve. Discontinuation of non-steroidal anti-inflammatory 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 as fluid retention and oedema have been reported in association with NSAID therapy. The dose should be kept as low as possible and renal function monitored in these patients.

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 and 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 antiplatelet agents such as aspirin (see section 4.5).

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).

Gastro-intestinal disturbances may be minimised by giving Indometacin orally with food, milk or an antacid. They usually disappear on reducing the dosage; if not, the risks of continuing therapy should be weighed against the possible benefits. If gastrointestinal bleeding does occur, Indometacin should immediately be discontinued.

Caution is advised in patients with pre-existing sigmoid lesions (such as diverticulum or carcinoma) (or the development of these conditions) as indometacin can aggravate these conditions.

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).

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.

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

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.

Eye Disorder

During prolonged therapy, periodic ophthalmic examinations are recommended, as corneal deposits and retinal disturbances have been reported. In patients with rheumatoid arthritis, eye changes may occur which may be related to the underlying disease or to the therapy. Therefore, in chronic rheumatoid disease, ophthalmological examinations at periodic intervals are recommended. Discontinue therapy if eye changed are observed.

Indometacin should be used cautiously in patients with impaired renal function, bleeding disorders, psychiatric disorders, epilepsy, or Parkinsonism, as it may tend to aggravate these disorders.

Increase in plasma potassium concentration, including hyperkalaemia has 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 ‘drug interactions’).

Indometacin may mask the signs and symptoms of infection, so antibiotic therapy should be initiated promptly if an infection occurs during therapy with indometacin. Indometacin should be used with caution in patients with existing, but controlled infection. Caution is advised with concomitant use of live vaccines.

Patients should be periodically observed to allow early detection of any unwanted effects on peripheral blood (Anaemia), liver function or gastro-intestinal tract especially during prolonged therapy and drug hypersensitivity.

Indometacin can inhibit platelet aggregation. The effect usually disappears within 24 hours of discontinuing Indometacin. Bleeding time is prolonged (but within normal range) in normal adults. Because this effect may be exaggerated in patients with underlying haemostatic defects, Indometacin should be used cautiously in patients with coagulation defects.

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

Laboratory tests: borderline elevations of one or more liver tests may occur, and significant elevation of ALT (SGPT) or AST (SGOT) have been seen in less than 1% of patients receiving therapy with non-steroidal anti-inflammatory drugs 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.

4.5 Interaction with other Medicament and other forms of Interaction

Care should be taken in patient treated with any of the following drugs as interactions have been reported in some patients:

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).

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

Anti-coagulants: Although clinical studies indicate that Indometacin does not influence the hypoprothombinaemia induced by anticoagulants, patients also receiving anticoagulants should be closely observed for alterations of the prothrombin time. NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).

Probenecid: Co-administration of 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.

Antidepressants (SSRls): increased risk of gastrointestinal bleeding.

Antidiabetics: the effect of sulphonylureas may be increased by NSAIDs.

Methotrexate: Indometacin has been reported to decrease the tubular secretion of methotrexate (decreased elimination of methotrexate) and to potentiate toxicity. Simultaneous use should be undertaken with caution

Ciclosporin: There is an increased risk of (ciclosporin-induced toxicity) nephrotoxicity when administering Indometacin and cyclosporine together, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking ciclosporin, and renal function should be monitored carefully.

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

Corticosteroids: Indometacin Increased risk of gastrointestinal ulceration or bleeding (see section 4.4). If the patient is receiving corticosteroids concomitantly, a reduction in dosage of these may be possible but should only be effected slowly under supervision.

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.

Lithium: Decreased elimination of lithium. Indometacin is an inhibitor of prostaglandin. Indometacin 50 mg three times a day has produced a clinically relevant elevation of plasma lithium and reduction in renal lithium clearance patients and normal subjects with steady state plasma lithium concentrations. This effect has been attributed to inhibition of prostaglandin synthesis. As a consequence, when Indometacin and lithium are given concomitantly, the patient should be observed more frequently and carefully 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.

Anti-hypertensives: Reduced anti-hypertensive effect. Because Indometacin may acutely reduce the antihypertensive effect of beta-blockers (due to indometacin's inhibition of prostaglandin synthesis) and other drugs used to lower blood pressure, patients receiving dual therapy should have the antihypertensive effect of their therapy reassessed.

Therefore, caution should be exercised when considering the addition of Indometacin to the regimen of a patient taking any of the following antihypertensive agents: alpha-adrenergic blocking agents, ACE inhibitors, beta-adrenergic blocking agents, angiotensin-2-receptor antagonists, hydralazine or nifedipine. An increased risk of hyperkalaemia has also been reported when NSAIDs are taken with ACE inhibitors.

Antiplatelet drugs and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

Antipsychotics: increased drowsiness with indometacin and haloperidol.

Antivirals: 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. Risk of indometacin toxicity with ritonavir, avoid concomitant use.

Diuretics: Reduced diuretic effect. Indometacin can reduce the diuretic and antihypertensive effects of thiazides and furosemide diuretics in some patients. Indometacin may cause blocking of the furosemide -induced increase in plasma renin activity. Diuretics can also increase the risk of nephrotoxicity of Indometacin.

Indometacin reduces basal plasma rennin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma rennin activity in hypertensive patients.

It has been reported that the addition of triamterene to a maintenance schedule of Indometacin resulted in reversible acute renal failure in two of four healthy volunteers. Indometacin and triamterene should not be administered together.

Indometacin and potassium-sparing diuretics each may be associated with increased plasma potassium levels.

Cardiac glycosides: NSAIDs may exacerbate heart failure, reduce GFR, and increase plasma glycoside levels.

Desmopressin: effect potentiated by indometacin.

Diflunisal: avoid concomitant use. Increased plasma levels of indometacin by about a third with a concomitant decrease in renal clearance. Fatal gastro-intestinal haemorrhage has occurred.

Muscle Relaxants: increased risk of baclofen toxicity due to reduced rate of excretion.

Pentoxifylline: possible increased risk of bleeding when taken with NSAIDs.

Tacrolimus: possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Tiludronic acid: the bioavailability of tiludronic acid is increased by Indometacin.

Laboratory tests: 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 Pregnancy and Lactation

Pregnancy:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre-and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, <INN> should not be given unless clearly necessary. If <INN> is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

-    cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

-    renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

the mother and the neonate, at the end of pregnancy, to:

-    possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

-    inhibition of uterine contractions resulting in delayed or prolonged labour. Consequently, indomethacin is contraindicated during the third trimester of pregnancy

Lactation:

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

There has been as isolated report of convulsions in an infant. Therefore use of indomethacin should be avoided during breast-feeding.

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

Gastrointestinal disorders: The most commonly-observed adverse events are gastrointestinal in nature. Anorexia, epigastric discomfort,ulceration at any point in the gastro-intestinal tract (even with resultant stenosis and obstruction), bleeding (even without obvious ulceration or from a diverticulum) and perforation of pre existing sigmoid lesions (such as diverticulum or carcinoma), increased abdominal pain or exacerbation of the condition in patients with ulcerative colitis or Crohns disease (or the development of this condition), intestinal strictures and regional ileitis have been rarely reported. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). If gastro-intestinal 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. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis , ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (See section 4.4) have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Immune System disorders: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, rhinitis, or (c) 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). Other skin reactions include: angioneurotic oedema, angiitis, erythema nodosum, photosensitivity, exfoliative dermatitis, bullous reactions including Stevens Johnson syndrome and Toxic Epidermal Necrolysis (very rare), hair loss, sweating and exacerbation of psoriasis.

Cardiovascular and cerebrovascular: oedema, increase blood pressure, tachycardia, chest pain, arrhythmia, palpitation, hypotension, congestive heart failure.

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).

Vascular disorders: flushing has been reported rarely

Other adverse reactions reported less commonly include:

Renal and urinary disorders: Nephrotoxicity in various forms, including interstitial nephritis, nephritic syndrome, renal insufficiency and renal failure. Blood urea elevation and haematuria, proteinuria have all been reported (infrequent). In patients with renal, cardiac or hepatic impairment, caution is required since the use of nonsteroidal 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.

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

Nervous system disorders: headaches, lightheadedness, 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, headache, nausea, vomiting, fever or disorientation (See section 4.4) , depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue, dysarthria, cerebral oedema, nervousness, and drowsiness. 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.

Reactions reported infrequently include, anxiety, syncope, hearing disturbances, convulsions, coma, peripheral neuropathy, involuntary muscle movements, insomnia, psychiatric disturbances such as depersonalisation and rarely, paraesthesiae, aggravation of epilepsy and Parkinsonism. These are often transient and disappear frequently with continued or reduced dosage or stopping treatment. However, occasionally, severe reactions require stopping therapy.

Respiratory, thoracic and mediastinal disorders:

Asthma and pulmonary oedema, pulmonary eosinophilia (all infrequent).

Epistaxis (rare)

Bronchospasm may be precipitated in patients suffering from or with a history of bronchial asthma or allergic disease.

Blood and lymphatic disorders: infrequently, blood dyscrasias may occur including neutropenia, leucopenia, petechiae or ecchymosis, purpura, disseminated intravascular coagulation, aplastic or haemolytic anaemia, agranulocytosis, bone marrow depression, and particularly thrombocytopenia. Because some patients may develop anaemia secondary to obvious or occult gastro-intestinal bleeding, appropriate blood determinations are recommended.

Eye disorders: Visual disturbances, infrequently, blurred vision, diplopia, optic neuritis and orbital and periorbital pain. Corneal deposits and retinal disturbances including those of the macula have been reported in patients with rheumatoid arthritis on prolonged therapy, but similar changes may also be expected in patients with rheumatoid arthritis who have not received Indometacin. Ophthalmic examinations are desirable in patients given prolonged treatment.

Ear and labyrinth disorders: tinnitus or hearing disturbances (rarely deafness) have been reported.

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

Reproductive system and breast disorders: vaginal bleeding, breast changes including enlargement and tenderness and gynaecomastia

Metabolic and nutrition disorders: hyperglycaemia, glycosuria, hyperkalaemia

4.9 Overdose

a) Symptoms

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

b) Therapeutic measure

Patients should be treated symptomatically as required. Within one 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.

Depending on the condition of the patient, close medical observation and nursing care may be required. The patient should be followed for several days because gastro-intestinal ulceration and haemorrhage have been reported as adverse reactions of indomethacin. Use of antacids may be helpful.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Indometacin has prominent ant-inflammatory and analgesic-antipyretic properties in experimental animals similar to those of the salicylates, and comparable effects have been demonstrated in man.

Indometacin is one of the most potent inhibitors of the prostaglandin-forming cyclooxygenase. Like colchicine, it inhibits motility of polymorphonuclear leukocytes. Like many other of the aspirin-like drugs, indometacin uncouples oxidative phosphorylation in supra-therapeutic concentrations and depresses the biosynthesis of mucopolysaccharides.

5.2 Pharmacokinetic properties

Indometacin is readily absorbed from the gastro-intestinal tract; peak plasma concentrations are reached 14 to 2 hours after a dose. More than 90% is bound to plasma proteins. It is metabolised in the liver and kidneys and is excreted in the urine, mainly as the glucuronide, and to a much less extent in the faeces. Indometacin is also excreted in milk.

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

5.3 Preclinical safety data

None

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Magnesium Stearate BP

Sodium Lauryl Sulphate BP Primojel BP Lactose BP

Capsule Shell (size 3)

Erythrosin E127 Quinoline Yellow E104 Titanium Dioxide E171 Gelatin NF XVI

6.2 Incompatibilities

None known.

6.3    Shelf life

3 years

6.4    Special Precautions for Storage

Store in the original package in order to protect from light.

Store below 30°C.

6.5    Nature and contents of container

PVC/Aluminium blister pack containing 28, 100, 250, 500 or 1000 capsules