Source: Υπουργείο Υγείας (CY) Revision Year: 2019 Publisher: CODAL-SYNTO Ltd, 21 Constantinoupoleos Street, 3011 Limassol, Cyprus
Nimesulide is contraindicated in patients with:
Concomitant use of NSAIDs, including selective inhibitors of cyclooxygenase-2 should be avoided. During treatment with Nimm patients should be advised to refrain from other analgesics.
Side effects may be minimised by using the lowest effective dose for the shortest duration necessary to control the symptoms (see section 4.2).
Treatment should be discontinued if no benefit is seen.
In rare cases, nimesulide has been reported to be associated with serious hepatic reactions, including some very rare fatal cases (see also section 4.8). Patients who experience symptoms of hepatic injury during treatment with (eg, anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine) or patients who develop abnormal liver function should discontinue the treatment. These patients should not use nimesulide.
Liver injury, reversible in the majority of cases, have been reported after short exposure to the drug. In the event that fever and / or flu-like symptoms occur, treatment should be discontinued.
Gastrointestinal bleeding, ulceration/perforation, which can be fatal, may occur at any time during treatment, with or without warning symptoms or a previous history of gastrointestinal events.
If gastrointestinal bleeding or ulceration occurs nimesulide should be discontinued.
The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing doses of NSAIDs 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 start treatment with the lowest dose available. Combination therapy with protective agents (eg. misoprostol or inhibitors proton pump) should be considered for these patients, and also for those who, concurrently use low-dose aspirin, or other drugs that may increase the risk of Gastrointestinal (events see below and section 4.5).
Patients with a history of gastrointestinal toxicity, particularly elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding), especially in the early stages of the treatment.
Gastrointestinal bleeding, ulceration/perforation, which can be fatal, may occur at any time during treatment, with or without warning symptoms or a previous history of gastrointestinal events. If gastrointestinal bleeding or ulceration occurs nimesulide should be discontinued.
Nimesulide should be administered with caution in patients with gastrointestinal disorders, including history of peptic ulcer, history of gastrointestinal bleeding, ulcerative colitis or Crohn’s disesase.
Caution should be recommended 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 used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated (see section 4.8)
The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal (see section 4.2). Therefore, an appropriate clinical monitoring is recommended on nimesulide use.
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 NSAIDs, particularly at high dose and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There is not sufficient evidence available which can exclude this risk associated with nimesulide.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with nimesulide after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, and smoking).
As nimesulide can interfere with platelet function, it should be used with caution in patients with bleeding diathesis (see also section 4.3). However, nimesulide is not a substitute for acetylsalicylic acid cardiovascular prophylaxis.
In patients with renal or cardiac impairment, caution is required since the use of nimesulide tablets can damage kidney function.
In this case, treatment should be discontinued (see also section 4.5).
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. Nimm should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
The use of nimesulide 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 nimesulide should be considered (see section 4.6).
Nimm contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Simultaneous use of nimesulide (see section 4.4) with other non-steroidal anti-inflammatory drugs, including acetylsalicylic acid given at anti-inflammatory doses (≥1 g as a single dose or ≥3 g as the total daily amount) is not recommended.
Increased risk of gastrointestinal ulceration or bleeding (see section 4.4).
Patients receiving warfarin or similar anticoagulant agents or acetylsalicylic acid have an increased risk of bleeding complications when treated with nimesulide (see section 4.4). Therefore this combination is not recommended and is contraindicated in patients with severe coagulation disorders (see also section 4.3). If the combination cannot be avoided, anticoagulant activity should be monitored closely.
Concomitant administration with corticosteroids, anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs) has an increased risk of gastrointestinal ulceration or bleeding (see section 4.4).
NSAIDs may reduce the effect of diuretics and that of others antihypertensive drugs. In some patients with impaired renal function (eg. Dehydrated patients or elderly patients with reduced renal function) the co-administration of an ACE inhibitor and of cyclooxygenase inhibitors may increase the impairment of renal function, including possibility of acute renal failure, which is usually reversible.
These interactions must be taken into consideration in patients who must take nimesulide in combination with ACE inhibitors or ARBs.
Therefore, administration of these drugs in combination with nimesulide should be undertaken with caution, especially in elderly patients. Patients should be adequately hydrated and consideration should be taken to monitor renal function after initiation of concomitant treatment and later on a periodic basis.
In healthy volunteers, the administration of nimesulide with furosemide transiently decreases the sodium-losing and – to a lesser extent- the potassium-losing effect and reduces the diuretic response. It also results in a decrease of about 20% of the AUC and cumulative excretion of furosemide, without affecting its renal clearance.
The concomitant use of furosemide and nimesulide requires caution in patients with renal or cardiac patients, as described in section 4.4.
NSAIDs have been reported to reduce lithium clearance, resulting in elevated plasma levels and lithium toxicity. If Nimm is prescribed to a patient receiving lithium therapy, lithium levels should be monitored closely.
Potential pharmacokinetic interactions with glibenclamide, theophylline, warfarin, digoxin, cimetidine and antacid preparations (such as the combination of aluminium and magnesium hydroxide) were also studied in vivo. No clinically significant interactions were observed.
Nimesulide inhibits CYP2C9. The plasma concentrations of drugs that are substrates of this enzyme may be increase when used concomitantly with nimesulide.
Nimesulide should be used cautiously 24 hours before or after methotrexate treatment, since methotrexate plasma levels may be increased. This may lead to increased methotrexate toxicity.
Due to the effect of nimesulide in renal prostaglandins the nephrotoxicity of cyclosporin may be increased.
In vitro studies have shown a displacement of nimesulide from binding sites by tolbutamide, salicylic acid and valproic acid. However, despite a possible effect on plasma levels, these interactions have not demonstrated clinical significance.
The use of nimesulide is contraindicated during the last trimester of pregnancy. As with other NSAIDs the use of nimesulide is not recommended in women trying to conceive (see section 4.4).
Inhibition of prostaglandin synthesis may have a negative impact on pregnancy and/or the embryo/fetal development. Results of epidemiological studies suggest an increased risk of miscarriage and cardiac malformation and gastroschisis after use, in the first stage of pregnancy.The absolute risk for cardiovascular malformation was increased from less than 1% to about 1.5%. It was considered that the risk increases with dose and duration of therapy.
In animals, the administration of inhibitors of prostaglandin synthesis has been shown to cause an increase in pre- and post-implantation loss and mortality embryo/fetus. Furthermore, an increasedincidence of various malformations, including cardiovascular, has been reported in animals to which inhibitors of prostaglandin synthesis were administered during the period of organogenesis.
Studies in rabbits have shown an atypical reproductive toxicity (see section 5.3); data from the use of nimesulide in pregnant women are not available. Consequently, the potential risk for the human being is unknown and nimesulide is not recommended during the first two trimesters of pregnancy unless not strictly necessary.
If Nimm is used by a woman trying to conceive, or during the first or second trimester of pregnancy, the dose and duration of treatment must be kept as low as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose:
the fetus to:
*Cardiopulmonary toxicity (with premature closure of the ductus arteriosus and hypertension lung);
the mother and the baby at the end of pregnancy:
Consequently nimesulide is contraindicated during the third trimester of pregnancy.
It is not known whether nimesulide is excreted in human milk. Nimm is contraindicated in women who are breastfeeding (see sections 4.3 and 5.3).
No studies on the effect of nimesulide on the ability to drive or use machines have been performed. However patients who experience dizziness, vertigo or somnolence after receiving Nimm should refrain from driving or operating machines.
Clinical studies and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a modest increase in the risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).
Edema, hypertension and heart failure have been reported in association with NSAIDs treatment.
There have been very rare reports of bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.
The most commonly observed adverse events are gastrointestinal in nature.
Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly may occur (see section 4.4). Also, the following have been reported: nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (see section 4.4).
Less frequently, gastritis has been observed.
The following adverse reactions were reported in controlled clinical trials conducted in 7800 patients and on pharmacovigilance data. They are classified as very common (1/10), common (1/100 to <1/10)>, uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000).
Rare: Anaemia*, eosinophilia*
Very rare: Thrombocytopenia, Pancytopenia, Purpura
Rare: Hypersensitivity*
Very rare: Anaphylaxis
Rare: Hyperkalaemia*
Rare: Anxiety*, Nervousness*, Nightmare*
Uncommon: Dizziness*
Very rare: Headache, Somnolence, Encephalopathy (Reye syndrome)
Rare: Blurred vision*
Very rare: Visual disturbances
Very rare: Vertigo
Rare: Tachycardia*
Uncommon: Hypertension*
Rare: Haemorrhage*, Blood pressure fluctuation*, Hot flushes*
Uncommon: Dyspnoea*
Very rare: Asthma, Bronchospasm
Common: Diarrhoea*, Nausea*, Vomiting*
Uncommon: Constipation*, Flatulence*, Gastrointestinal bleeding, Duodenal ulcer and perforation, Gastric ulcer and perforation
Very rare: Gastritis*, Abdominal pain, Dyspepsia, Stomatitis, Melaena
Common: Hepatic enzymes increased
Very rare: Hepatitis, Acute hepatitis (including fatal cases), Jaundice, Cholestasis
Uncommon: Pruritus*, Rash*, Increased sweating*
Rare: Erythema*, Dermatitis*
Very rare: Urticaria, Angioneurotic oedema, Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis
Rare: Haematuria*, Dysuria*
Very rare: Urinary retention*, Renal failure, Oliguria, Interstitial nephritis
Uncommon: Oedema*
Rare: Malaise*, Asthenia*
Very rare: Hypothermia
* Frequency based on clinical trial data
Reporting suspected adverse reactions after authorisation of the medicinal product is an important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.
None known.
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