Summary of Product Characteristics (SmPC) - Indometacin capsules BP 25 mg
1. NAME OF THE MEDICINAL PRODUCT
Indometacin Capsules BP 25mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains indometacin 25mg.
Excipient of known effect: Lactose 200 mg per capsule.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
lndometacin capsules are presented as size 3, ivory opaque shells printed with ‘IND 25’ and company logo.
4.1 Therapeutic indications
Indometacin capsules are non-steroidal, 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
- Lumbago
- Acute gout
- Inflammation, pain and oedema following orthopaedic procedures
- Treatment of pain and associated symptoms of primary dysmenorrhoea. Since indometacin is not a simple analgesic, its use should be limited to the above conditions.
4.2 Posology and method of administration
Posology
The dosage should be carefully adjusted according to the needs of the individual patient, starting with a low dose.
To reduce the possibility of gastro-intestinal disturbances, indometacin capsules should always be taken with food, milk or immediately after meals, or with an antacid
and in chronic conditions start the therapy with a low dosage, increasing as required.
Adults:
The recommended oral dose range is 50 – 200 mg daily.
Acute rheumatoid arthritis
Initially 25 mg two or three times a day.
Chronic rheumatic disorders
25 mg two or three times daily, increase gradually by 25 mg if required. Adequate response is usually achieved with 150 mg daily, rarely more than 200 mg daily. (If this
causes any adverse effects, it should be reduced to a tolerable level for two or three
days, then carefully increased, as tolerated).
Acute gout
150 – 200 mg daily in divided doses until all signs and symptoms subside.
Acute musculoskeletal disorders
Initially 50mg two or three times daily, according to severity for 10-14 days. Normally 150mg daily, rarely 200mg daily.
Lumbago
50mg two or three times daily, according to severity. Duration of treatment is not normally more than five days, but may be continued for up to 10 days.
Dysmenorrhoea
Up to 75 mg daily until the symptoms subside.
Paediatric population:
Indometacin is contraindicated in children as its safety has not been 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.
Following orthopaedic procedures: Normally 100-150mg daily in divided doses until
symptoms subside.
In patients with persistent night pain and/or morning stiffness, a dose of up to 100mg at bed time may be helpful in affording relief.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
Method of Administration
For oral administration.
To be taken preferably with or after food, milk or an antacid.
4.3 Contraindications
- Hypersensitivity to indometacin or to any of the excipients listed in section 6.1.
- 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.
- 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).
- Safety in children has not been established.
4.4 Special warnings and special 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:
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.
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:
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.
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. When GI bleeding or ulceration occurs in patients receiving indometacin, the treatment should be withdrawn.
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).
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. They usually disappear on reducing the dosage; if not, the risks of continuing therapy should be weighed against the possible benefits.
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:
Indometacin may have a reversible inhibitory effect on women’s ovulation. 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.
Medication Overuse Headache (MOH):
After long term treatment with analgesics, headache may develop or aggravate. Headache caused by overuse of analgesics (MOH - medication-overuse headache) should be suspected in patients who have frequent or daily headaches despite (or because of) regular use of analgesics. Patients with medication overuse headache should not be treated by increasing the dose. In such cases the use of analgesics should be discontinued in consultation with a doctor.
Caution should be exercised in patients with renal function disorders, bleeding disorders, psychiatric disorders, epilepsy or parkinsonism as indometacin may aggravate these conditions.
Avoid concomitant use of two or more NSAIDs including cyclooxygenase-2 specific inhibitors (see section 4.5).
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”).
This medicine contains lactose
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Sodium
This medicine contains less than 1mmol sodium (23 mg) per capsule, that is to say essentially “sodium free”.
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. There is no enhancement of therapeutic effect
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).
Antacids: the bioavailability of indometacin may be reduced by concomitant antacid therapy.
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 (see section 4.4).
Antidepressants (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4).
Antipsychotics: increased drowsiness with indometacin and haloperidol.
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. The risk of acute renal insufficiency which is usually reversible, may be increased in some patients with compromised renal function (eg. dehydrated or elderly patients) when angiotensin II receptor antagonists are used with indometacin; patients should be adequately hydrated and consideration given to monitoring renal function. 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.
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-cardiac 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.
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:
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.
From the 20th week of pregnancy onward, Indometacin use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy, Indometacin should not be given unless clearly necessary. If indometacin 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. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to Indometacin for several days from gestational week 20 onward. Indometacin should be discontinued if oligohydramnios or ductus arteriosus constriction are found.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:
- cardiopulmonary toxicity (with premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
- renal dysfunction (see above);
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, indometacin is contraindicated during the third trimester of pregnancy (see sections 4.3).
Breast-feeding:
In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.
Fertility:
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
Undesirable effects can occur with the following frequencies:
very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1,000) and very rare (< 1/10,000, including isolated reports), not known (cannot be estimated from the available data).
Blood and lymphatic system disorders: 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 gastro-intestinal bleeding, appropriate blood determinations are recommended.
Immune system disorders: 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 (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), angiitis, erythema nodosum, Stevens-Johnson syndrome.
Metabolic and nutrition disorders: hyperglycaemia, hyperkalaemia and glycosuria have been reported rarely.
Nervous system disorders: Visual disturbances, optic neuritis. 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. 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.
Eye disorders: 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.
Ear and labyrinth disorders: tinnitus, hearing disturbances (rarely deafness).
Cardiac disorders: 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).
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.
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 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.
Hepato-biliary disorders: cholestasis, abnormal liver function. Rarely hepatitis, jaundice (associated with some fatalities).
Skin and subcutaneous tissue disorders: 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.
Musculo-skeletal, connective tissue and bone disorders: Muscle weakness and acceleration of cartilage degeneration.
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.
Reproductive system and breast disorders: vaginal bleeding, breast changes (enlargement, tenderness, gynaecomastia).
Reporting of suspected adverse reactions:
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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Anti-inflammatory and Antirheumatic 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 antidysmenorrheal 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
Absorption:
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. Onset of action as an antirheumatic 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 in fasting subjects, longer if taken with or after food; peak serum concentration for 50 mg capsule being 2.5
- 4.0 μg/ml.
Distribution:
Approximately 99% is bound to albumin. Distribution occurs in 1 hour. It is distributed into synovial fluid, CNS and placenta. Low concentrations have been found in breast milk. The concentration in synovial fluid is equal to that in plasma within 5 hours.
Metabolism:
Indometacin is metabolised in the liver primarily by demethylation and deacetylation, it also undergoes glucuronidation and enterohepatic circulation. Enterohepatic cycling of metabolites, and probably indometacin itself, occurs. Indometacin is largely converted to inactive metabolites.
Half-life is biphasic and its half-life in plasma is variable from 2 – 11 hours.
Elimination:
Elimination is in approximately 4.5 hours (usual range being 2.6 to 11.2 hours) and is subject to large interindividual variation, possibly due to interindividual differences in enterohepatic circulation and subsequent reabsorption.
Approximately 60% of a dose being excreted in urine (10 – 20% as unchanged indometacin), the pH of the urine can affect this amount, and 33% via the biliary route (1.5% as unchanged indometacin). Lesser amounts in the faeces. It is also excreted in the breast milk in small amounts.
5.3 Preclinical safety data
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 4 mg/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 15 mg/kg body weight/day) have resulted in maternal toxicity and death, increased foetal resorption and congenital malformations.
In pregnant mice and rats, indometacin treatment (during organogenesis) induced developmental defects including retarded foetal ossification and skeletal malformations at doses of 0.02-0.95 times the MRHD.
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 PVC. It is subsequently packed in printed boxboard cartons in pack sizes of 28, 42, 56, 84 and 112.
6.6 Instructions for use and handling
None
7 MARKETING AUTHORISATION HOLDER
Crescent Pharma Ltd.,
Key House, Sarum Hill,
Basingstoke, RG21 8SR, UK.
8. MARKETING AUTHORISATION NUMBER
PL 20416/0094
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
17/02/2006
10 DATE OF REVISION OF THE TEXT
09/02/2025