Rectal suppositories 1. Name of the Medicinal Product: Indacin 2. Qualitative & Quantitative Composition: Each one suppository contains: Indomethacin 100 mg For the full list of excipients, see section 6.1. 3. Pharmaceutical Form: Rectal suppositories Pale yellow torpedo shaped smooth suppository. 4. Clinical Data: 4.1. Therapeutic Indications: 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 gouty arthritis. Also indicated in inflammation, pain and oedema following orthopaedic procedures; and the treatment of pain and associated symptoms of primary dysmenorrhoea. Indacin may be used where night pain and morning stiffness are prominent. One suppository at bedtime will frequently give relief from pain and stiffness for 13 to 16 hours after administration. 4.2. Posology and Method of administration: The dosage of indomethacin should be carefully adjusted to suit the needs of the individual patient. Posology Adult One suppository to be inserted once or twice a day. One should be used at bedtime. If another is necessary, it should be used in the morning. Elderly Indacin should be used with particular care in older patients who are more prone to adverse reactions. Pediatric population The safety and efficacy of indomethacin in children has not yet been established. 4.3 Contraindications: - Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1 - History of peptic ulcer or active peptic ulcer - Recurrent history of gastro-intestinal lesions - Patients who have nasal polyps associated with angioneurotic oedema, who show sensitivity to indomethacin or any of the ingredients in this product, or who have experienced acute asthmatic attacks, urticaria or rhinitis as a result of therapy with aspirin or other non-steroidal anti-inflammatory drugs. - Patients with a history of proctitis or recent rectal bleeding. - During the third trimester of pregnancy or lactation (see Section 4.6) - NSAIDs is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. 4.4 Special Warnings for use: Indomethacin may have a reversible inhibitory effect on women's ovulation. The use of indomethacin 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 indomethacin should be considered. Headache, sometimes accompanied by dizziness and light-headedness, may occur, usually early in treatment. Starting therapy with a low dosage and increasing it gradually will usually minimize the incidence of headache. These symptoms frequently disappear on continuing therapy or reducing the dosage, but if headache persists despite dosage reduction, indomethacin should be withdrawn. Patients should be warned that they may experience dizziness and, if they do, should not drive a car or undertake potentially dangerous activities needing alertness. Indacin should be used cautiously in patients with a history of bronchial asthma and in patients with psychiatric disorders, epilepsy, or parkinsonism, as indomethacin may tend to aggravate these disorders. Single or multiple ulcerations, including perforation and haemorrhage of the oesophagus, stomach, duodenum or small or large intestine, have been reported to occur with indomethacin. Fatalities have been reported in some instances. Rarely, intestinal ulceration has been associated with stenosis and obstruction. NSAIDs should only be given with care to patients with a history of gastro-intestinal disease. NSAIDs cause an increased risk of serious gastrointestinal adverse events including inflammation, bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. Gastro-intestinal bleeding without obvious ulcer formation and perforation of pre-existing sigmoid lesions (diverticulum, carcinoma, etc.) have occurred. Increased abdominal pain in ulcerative colitis patients or the development of ulcerative colitis and regional ileitis have been reported to occur rarely. Fluid retention and peripheral oedema have been observed in some patients taking indomethacin. Indomethacin should therefore be used with caution in patients with cardiac dysfunction, hypertension or other conditions predisposing to fluid retention. Tenesmus and irritation of the rectal mucosa have been reported occasionally with indomethacin. Indacin may mask the signs and symptoms of infection. Indomethacin should be used with caution in patients with existing but controlled infection. In patients with rheumatoid arthritis, eye changes may occur which may be related to the underlying disease or to the therapy. Therefore, in chronic rheumatoid disease, ophthalmological examinations at periodic intervals are recommended. Discontinue therapy if eye changes are observed. Patients should be periodically observed to allow early detection of any unwanted effects on peripheral blood (anaemia), liver function, or gastro-intestinal tract. Indacin can inhibit platelet aggregation. This effect usually disappears within 24 hours of discontinuing indomethacin. Bleeding time is prolonged (but within normal range) in normal adults. Because this effect may be exaggerated in patients with underlying haemostatic defects, indomethacin should be used cautiously in patients with coagulation defects. As with other non-steroidal anti-inflammatory drugs, there have been reports of acute interstitial nephritis with haematuria, proteinuria, and occasionally nephrotic syndrome in patients receiving long-term administration of indomethacin. In patients with reduced renal blood flow where renal prostaglandins play a major role in maintaining renal perfusion, administration of a non-steroidal anti-inflammatory agent 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. A non- steroidal anti-inflammatory drug should be given with caution and renal function should be monitored in any patient who may have reduced renal reserve. Discontinuation of non-steroidal anti-inflammatory therapy is usually followed by recovery to the pretreatment state. Increases 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 'Interaction with other medicinal products and other forms of interactions'). Since indomethacin is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored; a lower daily dosage should be used to avoid excessive drug accumulation. • Cardiovascular Risk: NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. 4.5. Interaction with other medicines and other forms of interaction: Aspirin: the use of indomethacin with aspirin or other salicylates is not recommended. Controlled clinical studies have shown no enhanced therapeutic effect, and one study showed a significant increase in the incidence of gastro-intestinal side effects. A study in normal volunteers showed that chronic administration of 3.6 g aspirin with indomethacin lowered the indomethacin blood levels by approximately 20%. Diflunisal: co-administration of diflunisal with indomethacin increases the plasma level of indomethacin by about a third, with a concomitant decrease in renal clearance. Fatal gastro-intestinal haemorrhage has occurred. The combination should not be used. Other NSAIDS: the concomitant use of indomethacin with other NSAIDs is not recommended due to the increased possibility of gastro-intestinal toxicity, with little or no increase in efficacy. Anticoagulants: although clinical studies suggest that indomethacin does not influence the hypoprothrombinaemia induced by anticoagulants, patients also receiving anticoagulants should be closely observed for alterations of the prothrombin time. Probenecid: co-administration of probenecid may increase plasma levels of indomethacin. Methotrexate: caution should be exercised with simultaneous use of indomethacin with methotrexate. Indomethacin has been reported to decrease the tubular secretion of methotrexate and to potentiate toxicity. Cyclosporine: administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be monitored carefully. Lithium: indomethacin 50 mg three times a day produced a clinically relevant elevation of plasma lithium and reduction in renal lithium clearance in psychiatric patients and normal subjects with steady-state plasma lithium concentrations. This effect has been attributed to inhibition of prostaglandin synthesis. As a consequence, when indomethacin and lithium are given concomitantly, the patient should be observed carefully for signs of lithium toxicity. In addition, the frequency of monitoring serum lithium concentrations should be increased at the outset of such combination drug treatment. Diuretics: in some patients, the administration of indomethacin can reduce the diuretic and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when indomethacin and diuretics are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by frusemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. It has been reported that the addition of triamterene to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Indomethacin and potassium-sparing diuretics each may be associated with increased plasma potassium levels. The potential effects of indomethacin 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 mechanisms involving inhibition of prostaglandin synthesis by indomethacin.
