Source: Υπουργείο Υγείας (CY) Revision Year: 2016 Publisher: Medochemie Ltd, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
Indylon is contraindicated in patients with:
Indylon is also contraindicated in patients that experienced asthmatic attacks, urticaria or rhinitis with aspirin or other non-steroidal anti-inflammatory drugs.
Safety in children has not been established.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. ( see section 4.2 and effects on the gastrointestinal tract and cardiovascular below)
The use of Indylon with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.
Elderly: The elderly have an increased risk of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.
Caution should be exercised when treating elderly patients who are more susceptible to side-effects. Consequences such as gastrointestinal bleeding and/or perforation are often more serious and can occur at any time during treatment without warning symptoms and without having occurred in the past. It is also more likely to older patients suffering from impaired renal, cardiac and liver function.
Gastrointestinal bleeding, ulceration and perforation: Gastrointestinal bleeding, ulceration or perforation, which can be fatal, have been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events.
The risk of gastrointestinal 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 gastrointestinal toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment. Patients should report any symptom they notice.
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).
NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated (See section 4.8 – undesirable effects).
Treatment with Indylon should be discontinued if the patient shows signs of gastrointestinal bleeding or ulceration.
Patients with gastrointestinal disease or previous duodenal or ventriculus ulcers as well as patients with ulcerative colitis and Crohn’s disease or haematological disorders and coagulation defects when bleeding time may be extended should be carefully monitored during treatment with NSAIDs.
Caution and appropriate monitoring is required in patients with a history of hypertension and/or mild to moderate 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 indomethacin.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and /or cerebrovascular disease should only be treated with indomethacin 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).
In the treatment of patients with mild to moderate heart failure, kidney disease or liver disease, especially when the patients follow treatment with diuretics, the risk of fluid retention and impaired renal function are taken into account.
Patients with rare hereditary problems of the lapp lactase deficiency should know that this medicine contains lactose.
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 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. Indylon should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Caution is required if NSAIDs are administered to patients suffering from or with a previous history of bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.
In common with other anti-inflammatory analgesic antipyretic agents, indomethacin 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. indomethacin should be used with caution in patients with an existing, albeit controlled infection.
Caution should be exercised in patients with epilepsy, parkinsonism or psychiatric disorders as indomethacin may aggravate these conditions.
The use of indomethacin may impair female fertility and is not recommended for women attempting to conceive. This applies to all drugs that inhibit cyclooxygenase/prostaglandin synthesis.
In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of indomethacin should be considered.
Particular care should be taken with older patients who are more susceptible to side-effects from indomethacin.
The combinations of Indylon with the following should be avoided:
Warfarin: NSAID preparations inhibit the platelet aggregation and damage the mucous membrane in the gastrointestinal system, which increases the risk of gastrointestinal bleeding in patients on anticoagulants. Recent epidemiological studies show that the risk of bleeding ulcers is particularly high with the concurrent use of NSAIDs and warfarin. It has been shown that this interaction has also a metabolic effect of the NSAIDs to warfarin which is metabolized by the same enzyme, CYP 2C(NSAIDs inhibit the metabolism of this anticoagulant in vitro.
Other NSAID preparations: avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of serious NSAID related adverse effects.
Diflunisal: Co-administration of diflunisal with indomethacin increases the plasma level of indomethacin with a concomitant decrease in renal clearance. Thus the combination should not be used.
Aspirin and other salicylates: Use of indomethacin 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, co-administration of aspirin may decrease the blood concentration of indomethacin.
Methotrexate (high dose): NSAIDs inhibit the tubular secretion of methotrexate and a metabolic interaction which results to decreased clearance of methotrexate and consequently to the obvious risk of enhanced efficacy of methotrexate. The potent effect has resulted in bone marrow toxicity, skin ulceration in psoriasis and nephrotoxicity, possibly as a result of inhibition of prostaglandin synthesis in the kidney. In several cases, according to reports methotrexate and indomethacin may have additive renal toxicity. Two cases of acute renal insufficiency has been described for indomethacin treated patients who received methotrexate followed by 5-fluorouracil.
Ticlopidine: NSAID preparations should not be combined with ticlopidine because of additive inhibition of the function of the platelet.
The following combinations of Indylon may require adjustment of dosage:
Amikacin: Indomethacin increases the serum levels of aminoglycosides in newborn babies with patent ductus arteriosus.
Cyclosporin: Administration of NSAID concomitantly with cyclosporine is considered to increase the risk of nephrotoxicity due to decreased synthesis of prostacyclin in the kidney. In combination of the drugs, the renal function must be monitored closely.
Digoxin: Indomethacin reduces the clearance of digoxin in children (with a patent ductus arteriosus). Half dose of digoxin and frequent inspection of digoxin in plasma has been recommended. In a study of adult patients with heart failure resulted in treatment with indomethacin and digoxin concentration in plasma rose by over 40%,
Gentamicin: Indomethacin increases serum levels of amino-glycosides in newborn babies with a patent ductus arteriosus.
Hydralazine: Indomethacin can weaken the blood pressure lowering effect of hydralazine (only shown after single doses in healthy volunteers)
Lithium: Indomethacin may raise plasma lithium levels and reduce lithium clearance by approximately 30%. The combination should be avoided unless frequent monitoring of serum levels of lithium can be implemented and reduction in lithium dose can be made.
Methotrexate (low dose): In a few studies interaction has been found in some case reports which suggest potentiated effects of low dose methotrexate in psoriasis and rheumatoid arthritis. A possible interaction between NSAID preparations and methotrexate must be considered even at low dose to a reduced uptake of serotonin in platelets (see section 4.4).
Inhibition of prostaglandin synthesis may affect pregnancy and/or embryonic/foetal development in a negative way. Data from epidemiological studies suggest an increased risk of miscarriage and risk of cardiac malformation after ingestion of prostaglandin synthesis inhibitors during early pregnancy. The absolute risk of cardiovascular malformation rose from less than 1% to about 1.5%. The risk is believed to increase with higher dose and with duration of treatment. In animals the administration of prostaglandin synthesis inhibitors shown to lead to increased incidence of pre-and post-implantations loss and embryo/foetal death. Increased incidence of multiple malformations including cardiovascular have also been reported in animals exposed to a prostaglandin synthesis inhibitor in the organ-forming period. During the first and second trimester of pregnancy Indylon is not to be used unless absolutely necessary. If Indylon is being used by a woman who wished to become pregnant or during the first and second trimester of pregnancy this should be with a low dose for the shortest possible duration of treatment.
During the third trimester of pregnancy all prostaglandin synthesis inhibitors expose the foetus to:
The mother and the foetus at the end of pregnancy to:
The above implied that Indylon is contraindicated during the third trimester of pregnancy.
Indomethacin is excreted in breast milk but the risk of impact oon the child seems unlikely with therapeutic doses.
Since indomethacin may produce dizziness, drowsiness, fatigue or visual disturbances, patients should be warned not to drive, or operate machinery, if they become affected.
The most common adverse reactions are headache (12%) and gastrointestinal effects.
Uncommon (>1/1000, <1/100): palpitations, congestive heart failure, arrhythmia
Uncommon (>1/1000, <1/100): Leucopenia, thrombocytopenia, secondary anaemia due to manifested or occulted bleeding. Disseminated intravascular coagulation
Rare (>1/10000, <1/1000): aplastic anaemia, haemolytic anaemia, agranulocytosis
Uncommon (>1/1000, <1/100): paraesthesia, peripheral neuropathy
Rare (>1/10000, <1/1000): weakness, involuntary muscle movements, aggravation of epilepsy and parkinsonism, convulsions, dysarthria
Rare (>1/10000, <1/1000): Blurred vision, double vision, corneal storage and retinal disorders (in long-term treatment of patients with rheumatoid arthritis)
Common (>1/100, <1/10): tinnitus
Uncommon (>1/1000, <1/100): hearing loss
Rare (>1/10000, <1/1000): deafness
Rare (>1/10000, <1/1000): rhinitis, asthma (see Contraindications) chest pain
Common (>1/100, <1/10): dyspepsia, nausea, vomiting, diarrhea, epigastric discomfort, abdominal pain, constipation
Uncommon (>1/1000, <1/100): flatulance, single or multiple ulceration of the oesophagus, stomach, duodenum, small intestine or colon, including perforation and bleeding. Intestinal ulceration associated with stenosis and obstruction. Also, bleeding without obvious ulceration and perforation of pre-existing sigmoid lesions (such as diverticulum or carcinoma). Melena. Haematemesis.
Rare (>1/10000, <1/1000): colitis, aggravation of ulcerative colitis, aggravation of Crohn’s disease, regional ileitis, ulcerative stomatitis, intestinal stricture, gastritis.
Uncommon (>1/1000, <1/100): haematuria, renal insufficiency including renal failure
Rare (>1/10000, <1/1000): proteinuria, interstitial nephritis, nephritic syndrome
Uncommon (>1/1000, <1/100): pruritus, urticaria, petechia, eccymosis, erythema nodosum. Hair loss.
Rare (>1/10000, <1/1000): exfoliative dermatitis, erythema multiforme. Bullosa reactions such as Stevens-Johnson’s syndrome, toxic epidermal necrolysis,
Rare (>1/10000, <1/1000): hyperglycaemia, glycosuria, hyperkalaemia
Rare (>1/10000, <1/1000): hypertension, hypotension, tachycardia
Common (>1/100, <1/10): headache, dizziness, fatigue
Uncommon (>1/1000, <1/100): loss of appetite, syncope, oedema, fluid retention, hot flushes, sweating, epistaxis
Rare (>1/10000, <1/1000): acute anaphylaxix, drowsiness, coma, shock like state, angioedema.
Uncommon (>1/1000, <1/100): jaundice
Rare (>1/10000, <1/1000): hepatitis (deaths have been reported)
Uncommon (>1/1000, <1/100): vaginal bleeding, breast enlargement or gynecomastia
Common (>1/100, <1/10): depression
Rare (>1/10000, <1/1000): anxiety, insomnia, psychiatric disorders including psychotic episodes, mental confusion, depersonalization
Gastroduodenal perforation of gastrointestinal bleeding can sometimes be fatal, especially in the elderly (see section 4.4).
Hypersensitivity reactions may include acute anaphylaxis, acute respiratory distress, shock-like state with rapid blood pressure cases, angioedema, pruritus, angitis,
Pulmonary edema has occurred in rare cases.
Clinical trials and epidemiological data suggest that the use of some NSAIDs (particularly at high doses and during long term treatment) may cause a small increased risk of arterial thrombotic event (e.g. myocardial infarction or stroke, see section 4.4.).
Laboratory values: elevated urea nitrogen values.
Reporting suspected adverse reactions is an important way to gather more information to continuously monitor the benefit / risk balance of the medicinal product. Any suspected adverse reactions should be reported to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy / phs Fax: + 357 22608649.
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