INDOMETHACIN 25 MG CAPSULES BP - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Indometacin Capsules BP 25mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Capsule contains 25mg of Indometacin Ph.Eur.

Capsule, hard.

Description: Ivory coloured, hard gelatin capsule.

4.1 Therapeutic indications

Indometacin is a non-steroidal anti-inflammatory agent indicated for the active stages of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, degenerative joint disease of hip, acute musculoskeletal disorders, low-back pain, and acute gout. It is also indicated in inflammation, pain and oedema following orthopaedic procedures, and in the treatment of pain and associated symptoms of primary dysmenorrhoea.

4.2 Posology and method of administration

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

The dosage of indometacin should be carefully adjusted to suit the needs of the individual patient. In order to reduce the possibility of gastrointestinal disturbances indometacin should always be taken with food, milk or an antacid.

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

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

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

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

Use in children: Not recommended.

Use in the elderly: The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest dose should be used and the patient should be monitored for GI bleeding for 4 weeks following initiation of therapy.

4.3 Contraindications

Known hypersensitivity to Indometacin, other NSAIDs or to any of the excipients.

Patients with angioneurotic oedema, including patients with nasal polyps associated with angioneurotic oedema.

Patients who have experienced acute asthmatic attacks, urticaria or rhinitis in response to aspirin or other NSAIDs.

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

Active peptic ulcer or haemorrhage

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

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

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

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).

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

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

■ Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

* 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 4.8). Patients appear to be at highest risk of 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.

* The use on Indometacin with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

■ 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.

■ Indometacin may mask the signs and symptoms of infectious disease and this should be borne in mind in order to avoid delay in starting treatment for infections. Indometacin should be used with caution in patients with an existing, albeit controlled infection. Caution is advised with concomitant use of live vaccines.

■ 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. Patients at greatest risk of this reaction are those with renal or hepatic dysfunction, diabetes mellitus, advanced age, extracellular volume depletion, congestive heart failure, sepsis or concomitant use of any nephrotoxic drug. Indometacin should be given with caution and renal function should be monitored in any patient who may have reduced renal reserve. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Increases in plasma potassium concentration, including hyperkalaemia 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.

* Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

■ 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.

NSAIDs should be given with care to patients

with ulcerative colitis and Crohn’s disease, as their condition may be exacerbated. Perforation of pre-existing sigmoid lesions (diverticulum, carcinoma etc.) has also occurred.

The risk of GI bleeding, ulceration or

perforation is higher with increasing NSAID doses, in patients with the history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose possible. 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.

■ In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis

■ 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.

■ Indometacin should be used with caution in patients with coagulation defects as indometacin can inhibit platelet aggregation. 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.

■ During prolonged therapy,  periodic ophthalmic examinations are

recommended, as corneal deposits and retinal disturbances havebeen 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 are periodic intervals are recommended. Therapy should be discontinued if eye changes are observed.

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

■ Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding, such as corticoseroids, anticoagulants such as warfarin or anti-platelet agents such as aspirin and selective serotonin-reuptake inhibitors.

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 non-steroidal antiinflammatory 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.

Indometacin Capsules BP 25mg contains tartrazine (E102). Can cause allergic- type reactions including asthma. Allergy is more common in those people who are allergic to aspirin.

4.5 Interaction with other medicinal products and other forms of interaction

■ Analgesics – avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects.

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

■ Anticoagulants- NSAIDs may enhance the effects of anti-coagulants, such as warfarin

■ Antidepressants (SSRI) – increased risk of bleeding.

■ Antidiabetics – the effect of sulphonylureas may be increased by NSAIDs. Isolated case of metabolic acidosis with metformin.

■ Antiepileptics – effect of phenytoin possibly increased by NSAIDs.

■ Antihypertensives – indometacin may acutely reduce the antihypertensive effect of beta-blockers due partly to indometacin's in­hibition of prostaglandin synthesis. 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. Hyperkalaemia has also been reported with ACE inhibitors.

■ Antiplatelet drugs – increased risk of 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.

■ Antipsychotics – increased drowsiness with indometacin and haloperidol.

■ Antivirals – pharmacokinetic changes have been recorded with zalcitabine/in­dometacin. Also increased risk of haematological toxicity with zidovudine. Risk of indometacin toxicity with ritonavir, avoid concomitant use.

■ Benzodiazepines – increased risk of dizziness with diazepam and Indometacin.

■ Cardiac Glycosides – NSAIDs may exacerbate heart failure, reduce GFR, and increase plasma-cardiac glycoside concentration.

■ Ciclosporin – administration of NSAIDs concomitantly with ciclosporin has been associated with an increase in ciclosporin-induced toxicity, 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.

■ Corticosteroids- increased risk of gastrointestinal bleeding and ulceration (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.

■ 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.

■ 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 occurs. Fatal gastro-intestinal haemorrhage has occurred.

■ Diuretics- NSAIDS may reduce the effectiveness of all types of diuretics. Indometacin may reduce the diuretic and antihypertensive effect of thiazides and furosemide in some patients. Indometacin may cause blocking of the furosemide -induced increase in plasma renin activity. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

■ Lithium – indometacin is an inhibitor of prostaglandin synthesis and therefore the following drug interactions may occur; indometacin may raise plasma lithium levels and reduce lithium clearance in subjects with steady state plasma lithium concentrations. At the onset of such combined therapy, plasma lithium concentration should be monitored more frequently.

■ Mifepristone – manufacturer recommends avoid NSAIDs until 8–12 days after mifepristone administration.

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

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

■ 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.

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

■ Tacrolimus – increased risk of nephrotoxicity

■ Tiludronic acid – bisphosphonates bioavailability increased by indometacin.

■ Triamterene- indometacin and triamterene should not be administered together since reversible renal failure may be induced.

■ Vasodilators- possible increased risk of bleeding with NSAIDs.

■ 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: 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). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patients 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 for information on female fertility.

4.7 Effects on ability to drive and use machines

Indometacin may cause dizziness, drowsiness, visual disturbances or headache and patients should not drive or operate machinery unless it has been shown not to affect his/her mental or physical state.

4.8 Undesirable effects

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

Hypersensitivity: 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, or © assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

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

Nervous system disorders: headache, dizziness and lightheadedness are common side effects. 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. Other CNS effects include reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus or mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4), depression, vertigo, fatigue, malaise, dysarthria, syncope, coma, cerebral oedema, nervousness, confusion, anxiety and other psychiatric disturbances, depersonalisation, hallucinations, drowsiness, convulsions and aggravation of epilepsy, peripheral neuropathy, paraesthesia, involuntary movements, insomnia and 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 vision, optic neuritis, diplopia and orbital and peri-orbital pain are seen infrequently. Corneal deposits and retinal or macular disturbances disturbances have been reported in some patients with rheumatoid arthritis on prolonged therapy with indometacin, and ophthalmic examinations are desirable in patients given prolonged treatment.

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

Cardiovascular/re­nal: Increased blood pressure, tachycardia, chest pain, arrhythmia, palpitation, hypotension, congestive heart failure, blood urea elevation and haematuria. Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.

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 of stroke) (see section 4.4).

Gastrointestinal disorders: nausea, anorexia, vomiting, gastritis, epigastric discomfort or abdominal pain, constipation or diarrhoea all have been reported; more rarely, stomatitis, flatulence, 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) have occurred; and increased abdominal pain or exacerbation of the condition in patients with ulcerative colitis or Crohns disease (or the development of this condition) 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.

Hepato-biliary disorders: cholestasis, elevation of LFTs (see section 4.4). Rarely hepatitis and jaundice (associated with some fatalities).

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, interstitial nephritis, breast changes (enlargement, tenderness, gynaecomastia).

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

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.

Vascular disorders: flushing has been reported.

4.9 Overdose

The following symptoms may be observed following overdosage: nausea, vomiting, intense headache, drowsiness, dizziness, mental confusion, disorientation, lethargy and fainting. There have been reports of paraesthesiae, numbness, and convulsions.

Treatment is symptomatic and supportive. The stomach should be emptied as quickly as possible if the ingestion is recent.

If vomiting has not occurred spontaneously, the patient should be induced to vomit with syrup of ipecac. If the patient is unable to vomit, gastric lavage should be performed. Once the stomach has been emptied, 25 or 50 g of activated charcoal may be given. Correction of severe electrolyte abnormalities may need to be considered. 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 gastrointestinal ulceration and haemorrhage have been reported as adverse reactions of indometacin. Use of antacids may be helpful.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Indometacin has prominent anti-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 prostaglandin forming cyclooxygenase. Like colchicine it inhibits motility of polymorphonuclear leucocytes. In supratherapeutic concentrations it uncouples oxidative phosphorylation and depresses the biosynthesis of mucopolysaccha­rides.

5.2 Pharmacokinetic properties

Indometacin is rapidly and almost completely absorbed from the gastrointestinal tract following oral ingestion. The peak concentration in plasma is attained within 2 hours in the fasting subject but may be somewhat delayed when the drug is taken after meals. The concentrations in plasma required for an anti-inflammatory effect have not been accurately determined but are probably less than 1 mg/ml. Steady-state concentrations in plasma after chronic administration are approximately 0.5 mg/ml. Indometacin is 90% bound to plasma proteins and also extensively bound to tissues. The concentration of the drug in the CSF is low, but its concentration in synovial fluid is equal to that in plasma within 5 hours of administration.

It is metabolised in the liver and kidneys and is excreted in the urine mainly as the glucuronide and to a much lesser extent in the faeces.

5.3 Preclinical safety data

Not available.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Polysorbate 80, colloidal anhydrous silica, lactose monohydrate, purified talc.

Capsule shell: Erythrosin (E127), tartrazine (E102), titanium dioxide (E171), gelatin.

6.2 Incompatibilities

Not Applicable.

6.3 Shelf life

Container : 3 Years

Blister : 24 months

6.4 Special precautions for storage

Containers: Do not store above 25°C. Store in the original container.

Keep the container tightly closed.

Blister pack: Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

Tablet container (polypropylene tubes with low density polyethylene caps).

Pack sizes: 84, 100, 250, 500 and 1000 capsules.

Blister packing ( Aluminium/ PVC-PVdC 0.020 mm/ 0.25 mm )

Pack sizes: 28, 56 and 84 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Not applicable.

Ashby Regulatory Services Ltd Ta Mila, Spoil Lane, Tongham, Farnham, Surrey

GU10 1BP

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 36275/0004