Indometacin Capsules Bp 25mg
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Indometacin Capsules BP 25mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Indometacin BP 25mg
3 PHARMACEUTICAL FORM
Capsules
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Indometacin is a non-steroidal anti-inflammatory agent indicated for the active stages of :-Rheumatoid Arthritis, Osteoarthritis, Ankylosing Spondylitis, Acute Musculoskeletal Disorders, Degenerative Joint Disease of the Hip, Low Back Pain and Acute Gout. It is also indicated for Pain, Inflammation and Oedema following Orthopaedic procedures and pain 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).
ADULTS:
The recommended oral dosage range is 50- 200mg daily in divided doses. Dysmennorrhoea: Up to 75mg daily, staring with onset of symptoms and continuing for as long as they usually last.
Acute Gouty Arthritis: 150 - 200mg daily in divided doses until all signs and symptoms subside.
CHILDREN:
Safety and dosage has not been established, but Indometacin has been shown to be effective in Juvenile Rheumatoid Arthritis with a dosage range of 1.5-3mg/kg/day and a maximum daily dosage of 200mg.
ELDERLY:
Indometacin should be used with great care in elderly patients who are more prone to side effects.
RENAL IMPAIRMENT/HEPATIC DISEASE:
The use of Non-Steroidal anti-inflammatory Agents may result in deterioration of renal function. Renal function should be monitored (see warnings/precautions)
4.3 Contraindications
Hypersensitivity to Indometacin or to any of the exipients 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.
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).
Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episode of proven ulceration or bleeding).
History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Indometacin Capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.4 Special warnings and precautions for use
Headache, dizziness and light-headedness may occur with Indometacin and are usually minimised by starting therapy with a low dosage and increasing it gradually. Symptoms often disappear with continued therapy or by reducing the dosage, but if headache persists, Indometacin should be withdrawn.
Undesirable effects may be minimised by using the minimum effective dose for the shortest duration necessary to control symptoms (see section 4.2, and cardiovascular risks below).
The use of Indometacine with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).
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).
Particular care should be taken with older patients who are more susceptible to side-effects from Indometacin (see section 4.2)
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.
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). 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).
Indometacin may aggravate psychiatric disorders, epilepsy and parkinsonism and should therefore be used with caution in such cases.
Indometacin should be used with caution in patients with existing, but controlled infection as it may mask the signs and symptoms of 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 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.
Acute interstitial nephritis with haematuria, proteinuria and occasionally nephrotic syndrome have been reported in patients receiving long-term therapy with Indometacin.
The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. In patients with compromised renal blood flow where prostaglandins play a major role in maintaining renal perfusion, Indometacin may precipitate overt renal decompensation. Those at greatest risk are patients with renal or hepatic dysfunction, cardiac impairment, congestive heart failure, diabetes mellitus, sepsis, extracellular volume depletion, the elderly and patients already taking nephrotoxic drugs or diuretics. Renal function should be assessed prior to and during Indometacin therapy. Discontinuation of Indometacin will usually result in return of renal function to the pretreatment state. Elevations of plasma potassium concentration including hyperkalaemia, have been reported, even in some patients without renal impairment. Patients with significantly impaired renal function should be closely monitored and lower dosage used, in order to avoid excessive accumulation of drug and metabolites.
Eye changes may occur in patients with rheumatoid arthritis which may be related to the underlying disease or to therapy. Therefore, in patients receiving Indometacin for chronic rheumatoid arthritis, periodic ophthalmological examinations are recommended. If eye changes are noted Indometacin should be discontinued.
Patients should be observed for any untoward effects on liver function peripheral blood and gastrointestinal tract.
Indometacin should be used with caution in patients with coagulation defects as it can inhibit platelet aggregation. This effect usually disappears within 24 hours of discontinuing Indometacin.
Borderline elevations of certain liver function tests may occur with Indometacin administration. If these persist or worsen or symptoms of liver disease, a rash or eosinophilia develop, treatment with Indometacin should be stopped. Significant elevations of ALT (SGPT) or AST (SGOT) have been seen in less than 1% of patients receiving Indometacin in controlled clinical trials. Larger doses, particularly when used in children, have been associated with reports of hepatitis. False negative test results have been reported in the dexamethasone suppression test (DST) in patients receiving the drug.
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.
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.
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. misoprotol 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)
Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).
When GI bleeding or ulceration occurs in patients receiving Indometacin, the treatment should be withdrawn.
Caution is required in post-operative patients as bleeding time is prolonged (but within normal range) in normal adults.
NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease), pre-existing sigmoid lesions (such as diverticulum or carcinoma), or the development of these conditions as these conditions may be exacerbated (see section 4.8).
Gastro-intestinal disorders which occur can be reduced by giving indometacin with food, milk or antacids.
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.
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).
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.
4.5 Interaction with other medicinal products and other forms of interaction
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. 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.
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4)
Antipsychotics: increased drowsiness with indometacin and haloperidol.
Antivirals: pharmacokinetic changes have been recorded with
zalcitabine/indometacin. Risk of indometacin toxicity with ritonavir, avoid concomitant use.
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.
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.
Desmopressin: effect potentiated by indometacin.
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.
Selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see Section 4.4).
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.
If the patient is receiving corticosteroids concomitantly, a reduction in dosage of these may be possible but should only be effected slowly under supervision. With corticosteroids, there is an increased risk with GI bleeding (see section 4.4- Special Warnings and Precautions for Use).
Indometacin antagonises diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. There is increased risk of hyperkalaemia when Indometacin and potassium-sparing diuretics are co-administered. Indometacin and Triamterine should not be given together due to reports of reversible acute renal failure.
Indometacin may reduce the diuretic and antihypertensive effect of thiazides and frusemide in some patients. Indometacin may cause blocking of the frusemide-induced increase in plasma rennin activity.
Indometacin decreases the excretion of lithium and methotrexate which may increase risk of toxicity of these drugs.
Probenecid delays excretion of Indometacin, with resultant increase in plasma levels of Indometacin.
Indometacin is highly protein-bound and should be used with caution in combination with other highly protein-bound drugs such as oral anticoagulants, hydantoins, sulphonylureas and some sulphonamides. Interactions have been reported with these agents and other non-steroidal antiinflammatory drugs. NSAIDs may enhance the effects of anticoagulants, such as warfarin (see section 4.4 Special Warnings and Precautions for use). Antidiabetics: the effect of sulphonylureas may be increased by NSAIDs. Isolated case of metabolic acidosis with metformin.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).
Co-administration of diflunisal with Indometacin increases the plasma level of Indometacin by approximately one third with a concomitant decrease in renal clearance. Fatal gastrointestinal haemorrhage has occurred. The combination should not be used.
Cardiac Glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
There is an increased risk of nephrotoxicity when used with ciclosporin.
NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
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.
Skin reactions and neurotoxicity have been reported with ciprofloxacin.
Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
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. 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.
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, Indometacin is contraindicated during the third trimester of pregnancy.
Lactation:
In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.
See section 4.4 Special Warnings and Precautions for Use, regarding female fertility.
4.7 Effects on ability to drive and use machines
Indometacin may cause dizziness or light-headedness, drowsiness, fatigue and visual disturbances. If these effects occur, the patient should not drive or operate machinery.
4.8 Undesirable effects
Side effects include headache, dizziness and dyspepsia; patients should be warned that they may experience dizziness and should therefore avoid driving or undertaking other activities which require full alertness. If headache persists even after dosage reduction Indometacin should be withdrawn.
Non-steroidal anti-inflammatory drugs may precipitate renal decompensation in those with renal or hepatic dysfunction, diabetes mellitus, advanced age, extracellular volume depletion, congestive cardiac failure, sepsis or concomitant use of other nephrotoxic drugs.
Central nervous system - visual disturbances, optic neuritis, headaches, dizziness, light-headedness, depression, vertigo and fatigue. Infrequently, mental confusion, dysarthria, syncope, drowsiness, anxiety, coma, cerebral oedema, nervousness, convulsions, muscle weakness, acceleration of cartilage degeneration, peripheral neuropathy, insomnia, involuntary muscle movements and psychiatric disturbances such as depersonalisation have been reported. Rarely, parasthesiae and aggravation of epilepsy and parkinsonism occur which are often transient and frequently disappear spontaneously or with reduced dosage. Occasionally, severe reactions require stopping therapy. Reports of aseptic meningitis (especially in patients with existing autoimmune 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 and drowsiness.
Gastrointestinal system - the most commonly observed adverse events are gastrointestinal in nature. Anorexia, epigastric discomfort, ulceration at any point in the gastro-intestinal tract (even with stenosis and obstruction), bleeding (even without obvious ulceration or from a diverticulum) and perforation of pre-existing sigmoid lesions (such as diverticulum or carcinoma). peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, 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. Intestinal strictures and regional ileitis have been rarely reported. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.
Haematological - blood dyscrasias may occur infrequently including leucopenia, neutropenia, aplastic or haemolytic anaemia, agranulocytosis, petechiae or ecchymosis purpura, bone marrow depression, disseminated intravascular coagulation and particularly thrombocytopenia. Appropriate blood determinations are recommended since some patient may develop anaemia secondary to obvious or occult gastrointestinal bleeding.
Genitourinary tract rarely, nephrotic syndrome, proteinuria, interstitial nephritis, renal failure and renal insufficiency occur.
Hepato-biliary disorders - cholestasis, 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. Abnormal liver function, hepatitis and jaundice.
Dermatological/hypersensitivity - non-specific allergic reaction an anaphylaxis urticaria, pruritus, angiitis, angioneurotic oedema, erythema nodosum, skin rash and exfoliative dermatitis occur. Infrequently erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, alopecia, acute anaphylaxis, rapid fall in blood pressure resembling a shock-like state and acute respiratory distress including sudden dyspnoea, asthma, aggravated asthma, rhinitis, pulmonary eosinophilia and pulmonary oedema. Bronchospasm may be precipitated in patients suffering from or with a history of bronchial asthma or allergic disease. Photosensitivity.
Cardiovascular system infrequently increased blood pressure, tachycardia, chest pain, arrhythmia, palpitation, congestive heart failure and hypotension occur. 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 or stroke) (see section 4.4).
Other infrequently, blurred vision, diplopia, orbital and peri-orbital pain, elevation of blood urea nitrogen and haematuria. Corneal deposits and retinal disturbances have been reported in some patients with rheumatoid arthritis on prolonged therapy with Indometacin, and ophthalmic examinations are desirable in patients given prolonged treatment. Hearing disturbances, tinnitus and rarely, deafness have occurred. Other rare effects including hyperglycaemia, hyperkalaemia, glycosuria, epistaxis, ulcerative stomatitis, flushing and sweating, exascerbation of psoriasis, gynaecomastia, breast changes including enlargement and tenderness and vaginal bleeding.
4.9 Overdose
The symptoms observed following overdose are nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, excitation, coma, drowsiness, dizziness, tinnitus, fainting, mental confusion, intense headache, lethargy and disorientation, paraesthesiae, convulsions and numbness have also been reported. In cases of significant poisoning acute renal failure and liver damage are possible.
Treatment is symptomatic and supportive. The stomach should be emptied as quickly as possible if ingestion is recent, and if vomiting has not occurred spontaneously, it should be induced with syrup of IPECAC. Gastric lavage should be considered within one hour if the patient is unable to vomit. Activated charcoal - 25g or 50g may be given once the stomach has been emptied. The patient should be monitored for several days since gastrointestinal haemorrhage and ulceration have been reported as adverse effects of Indometacin. The use of antacids may be helpful.
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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Indometacin is an Indoleacetic Acid derivative with Anti-Inflammatory, Antipyretic and Analgesic effects. It inhibits the activity of the Enzyme Cyclo-oxygenase which results in decreased formation of the precursors of Prostaglandins and Thromboxanes from Arachidonic Acid. While resultant decrease in synthesis and activity of Prostaglandins may be responsible for many of the effect of Indometacin, other actions may also contribute to its therapeutic effects.
5.2 Pharmacokinetic properties
Indometacin is rapidly and well absorbed from the Gastro-Intestinal Tract, with peak Plasma levels being reached within 2 hours. It is highly bound (97%) to Plasma Proteins. Indometacin undergoes extensive O-
Demethylation and N-Deacylation in the Liver to inactivate Metabolites. Both the Parent Drug and Metabolites undergo Enterohepatic Re-Cycling. Twenty to forty-two percent of an Indometacin dose is excreted in the Urine, of which about 10-20% is unchanged drug. The half-life of Indometacin (2.6 - 11.2 hours) is subject to large inter-individual variation, possibly due to differences in Enterohepatic Circulation and subsequent reabsorption. Indometacin is not dialysable.
5.3 Preclinical safety data
There is no pre-clinical data of relevance to a prescriber which is additional to that already included in other sections of the SmPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose, colloidal silicon dioxide, magnesium stearate, sodium lauryl sulphate and hard gelatin shells with permitted colours (erythrosine E127, quinoline yellow E104, titanium dioxide E171).
6.2 Incompatibilities
None stated
6.3 Shelf life
4 years.
6.4 Special precautions for storage
Store in a dry place below 25°C.
6.5 Nature and contents of container
The product is available in packs of 500 in securitainers/tampertainers.
Securitainers / tampertainers:
These are made up of High Density Polypropylene and Low Density Polyethylene.
6.6 Special precautions for disposal
None Stated
7 MARKETING AUTHORISATION HOLDER
Strides Pharma Limited Themistokli Dervi 3 Julia House CY-1066 Nicosia Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 41061/0010
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
21 September 2005
10 DATE OF REVISION OF THE TEXT
02/10/2012