INDOREM Hard capsule Ref.[51164] Active ingredients: Indometacin

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 minimise the incidence of headache. These symptoms frequently disappear on continuing therapy or reducing the dosage, but if headache persists despite dosage reduction, Indorem should be withdrawn.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.

Indorem should be used cautiously in patients with a history of bronchial asthma and in patients with psychiatric disorders, epilepsy, or parkinsonism, as indometacin may tend to aggravate these disorders.

NSAIDs should only be given with care to patients with a history of gastro-intestinal disease.

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

Single or multiple ulcerations, including perforation and haemorrhage of the oesophagus, stomach, duodenum or small or large intestine, have been reported to occur with Indorem. Fatalities have been reported in some instances. Rarely, intestinal ulceration has been associated with stenosis and obstruction.

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 Indorem. Indorem should therefore be used with caution in patients with cardiac dysfunction, hypertension or other conditions predisposing to fluid retention.

Indorem may mask the signs and symptoms of infection. Indorem 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, ophtalmological 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.

Indorem can inhibit platelet aggregation. This effect usually disappears within 24 hours of discontinuing Indorem. Bleeding time is prolonged (but within normal range) in normal adults. Because this effect may be exaggerated in patients with underlying haemostatic defects, Indorem 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 indometacin.

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 nonsteroidal anti-inflammatory 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 (see 4.5 “Interaction with other medicinal products and other forms of interaction”).

Since Indorem 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.

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

Aspirin

The use of Indorem 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 Indometacin 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 Indometacin 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 Indometacin 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 Indometacin with methotrexate. Indometacin has been reported to decrease the tubular secretion of methotrexate and to potentiate toxicity.

Cyclosporin

Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporin has been associated with an increase in cyclosporin-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporin, 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 indometacin can reduce the diuretic and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when indometacin and diuretics are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Indometacin 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 indometacin resulted in reversible acute renal failure in two of four healthy volunteers. Indometacin and triamterene should not be administered together.

Indometacin and potassium-sparing diuretics each may be associated with increased plasma potassium levels. 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 mechanisms involving inhibition of prostaglandin synthesis by indometacin.

Cardiac glycosides / Digoxin

Indometacin given concomitantly with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Therefore, when indometacin and digoxin are used concomitantly, serum digoxin levels should be closely monitored.

Antihypertensive medications

Co-administration of indometacin and some antihypertensive agents may attenuate acutely the hypotensive effect of the latter, due partly to indomethacin’s inhibition of prostaglandin synthesis. 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, diuretics, or hydralazine, or losartan (an angiotensin II receptor antagonist).

Phenylpropanolamin

Hypertensive crises have been reported due to oral phenylpropanolamine alone and, rarely, to phenylpropanolamine given with indometacin. This additive effect is probably due partly to indomethacin’s inhibition of prostaglandin synthesis. Caution should be exercised when indometacin and phenylpropanolamine are administered concomitantly.

Corticosteroids

The risk of gastro-intestinal bleeding and ulceration associated with NSAIDs is increased when used with corticosteroids.

Mifepristone

NSAIDs and aspirin should be avoided until at least 8 to 12 days after administration of mifepristone.

Quinolones antibiotics

There have been reports that 4-quinolones may induce convulsions in patients with or without a history of convulsions; taking NSAIDs at the same time may also induce them.

Pregnancy

Indorem should be used during the first two trimesters of pregnancy only if the potential benefit justifies the potential risk to the foetus.

From the 20th week of pregnancy onward, Indorem 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, Indorem should not be given unless clearly necessary. If Indorem 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 monitroting for oligohydramnios and ductus arteriosus constriction should be considered after exposure to Indorem for several days from gestational week 20 onward. Indorem 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 (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 prolonger labour.

Consequently, Indorem is contraindicated during the third trimester of pregnancy (see sections 4.2 and 5.3).

Breast-feeding

Administration of Indorem is not recommended in breast-feeding mothers. Indometacin is excreted in breast milk.

Patients should be warned that they may experience dizziness, drowsiness, visual disturbances or headaches and if they do, should not drive or undertake activities requiring alertness.

CNS reactions: headaches, dizziness, light-headedness, depression, vertigo, and fatigue (including malaise and listlessness). Reactions reported infrequently include mental confusion, anxiety, syncope, drowsiness, convulsions, coma, peripheral neuropathy, muscle weakness, involuntary muscle movements, insomnia, psychiatric disturbances such as hallucinations, depersonalisation; and, rarely, paraesthesia, dysarthria, aggravation of epilepsy and Parkinsonism. These are often transient and disappear frequently with continued treatment or with reduced dosage. However, occasionally, severe reactions require stopping therapy.

Gastro-intestinal: the more frequent reactions are nausea, anorexia, vomiting, epigastric distress, abdominal pain, constipation, and diarrhoea. Others which may develop are ulceration – single or multiple – of oesophagus, stomach, duodenum or small or large intestine, including perforation and haemorrhage with a few fatalities having been reported; gastro-intestinal tract bleeding without obvious ulcer formation; and increased abdominal pain when used in patients with pre-existing ulcerative colitis. Reactions occurring infrequently are stomatitis; gastritis; flatulence; bleeding from the sigmoid colon – occult or from a diverticulum – and perforation of pre-existing sigmoid lesions (diverticula, carcinoma). Rarely, intestinal strictures (diaphragms) and intestinal ulceration followed by stenosis and obstruction has been reported. With suppositories, tenesmus and irritation of the rectal mucosa have occasionally been reported. Other gastro-intestinal side effects which may or may not be caused by indomethacin include: ulcerative colitis and regional ileitis.

Hepatic: rarely, hepatitis and jaundice. (Some fatalities reported.)

Cardiovascular / Renal: oedema, increased blood pressure, tachycardia, chest pain, arrhythmia, palpitation, hypotension, congestive heart failure, blood urea elevation, and haematuria (all infrequent).

Dermatological / Hypersensitivity: pruritus, urticaria, angioneurotic oedema, angiitis, erythema nodosum, skin rash and photosensitivity, exfoliative dermatitis, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, loss of hair, rapid fall in blood pressure resembling a shocklike state, acute anaphylaxis, acute respiratory distress including sudden dyspnoea, asthma and pulmonary oedema (all infrequent).Bronchospasm may be precipitated in patients suffering from, or with a history of, bronchial asthma or allergic disease.

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

Ocular: infrequently, blurred vision, diplopia, and orbital and peri-orbital pain. Corneal deposits and retinal disturbances, including those of the macula, have been reported in patients with rheumatoid arthritis on prolonged therapy, but similar changes may also be expected in patients with rheumatoid arthritis who have not received indomethacin.

Aural: tinnitus, hearing disturbances (rarely deafness).

Genito-urinary: proteinuria, nephrotic syndrome, interstitial nephritis, and renal insufficiency including renal failure (all rare).

Miscellaneous: vaginal bleeding, hyperglycaemia, glycosuria, hyperkalaemia, flushing and sweating, epistaxis, breast changes including enlargement and tenderness, gynaecomastia, and ulcerative stomatitis (all rare).

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 anti-inflammatory drugs in controlled clinical trials. If abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations such as rash or eosinophilia occur, Indorem should be stopped.

False-negative results in the dexamethasone suppression test (DST) in patients being treated with Indorem have been reported. Thus, results of this test should be used with caution in these patients.

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 national reporting system: Cyprus, Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Tel: +357 22608607, Fax: +357 22608669, Website: www.moh.gov.cy/phs.

Not applicable.