Nimesulide

The concomitant use of nimesulide with corticosteroids requests caution because of an increased risk of bleeding or gastrointestinal ulceration.

The concomitant use of nimesulide with selective serotonin reuptake inhibitors (SSRIs) requests caution because of increased risk of gastrointestinal bleeding.

NSAIDs may enhance the effects of anti-coagulants, such as warfarin. Patients receiving
warfarin or similar anticoagulant agents or acetylsalicylic acid have an increased risk of bleeding complications, when treated with nimesulide. Therefore this combination is not recommended and is contraindicated in patients with severe coagulation disorders. If the combination cannot be avoided, anticoagulant activity should be monitored closely.

The concomitant use of nimesulide with antiplatelet drugs requests caution because of increased risk of gastrointestinal bleeding.

NSAIDs may reduce the efficacy of diuretics and that of other antihypertensive drugs. In some patients with reduced renal function (e.g. dehydrated patients or elderly subjects with impairment of renal function), concomitant administration of an ACE inhibitor and cyclo-oxygenase inhibitors may result in progression of the deterioration of renal function, including the possibility of acute renal insufficiency, which is normally reversible.

The occurrence of these interactions should be taken into consideration in patients who have to take nimesulide in association with ACE inhibitors or AIIA. Consequently, this drug association should be administered with precaution, especially in elderly patients. Patients should be properly hydrated, and the need for monitoring of renal function after starting the concomitant treatment and periodically after that should be analysed.

Due to their effect on renal prostaglandins, prostaglandin synthetase inhibitors like nimesulide may increase the nephrotoxicity of cephalosporins.

Nimesulide inhibits CYP2C9. The plasma concentrations of drugs that are substrates of this enzyme may be increased when nimesulide is used concomitantly.

The combined use of nimesulide with other non steroidal anti-inflammatory drugs, including acetylsalicylic acid given at anti-inflammatory doses (≥1g as single intake or ≥3g as total daily amount) is not recommended.

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.

In healthy subjects, nimesulide transiently decreases the effect of furosemide on sodium excretion and, to a lesser extent, on potassium excretion and reduces the diuretic response.

Co-administration of nimesulide and furosemide 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 Mesulid requires caution in susceptible renal or cardiac patients.

Non-steroidal anti-inflammatory drugs have been reported to reduce the clearance of lithium, resulting in elevated plasma levels and lithium toxicity. If nimesulide is prescribed for a patient receiving lithium therapy, lithium levels should be monitored closely.

Caution is required if nimesulide is used less than 24 hours before or after treatment with methotrexate because the serum level of methotrexate might increase and therefore, the toxicity of this drug might increase.

In vitro studies have shown displacement of nimesulide from binding sites by salicylic acid. However, despite a possible effect on plasma levels, these interactions have not demonstrated clinical significance.

In vitro studies have shown displacement of nimesulide from binding sites by valproic acid. However, despite a possible effect on plasma levels, these interactions have not demonstrated clinical significance.

In vitro studies have shown displacement of nimesulide from binding sites by tolbutamide. However, despite a possible effect on plasma levels, these interactions have not demonstrated clinical significance.

The use of nimesulide is contraindicated in the third trimester of pregnancy.

Like other NSAIDs nimesulide is not recommended in women attempting to conceive. As with other NSAIDs, known to inhibit prostaglandin synthesis, nimesulide may cause premature closure of the ductus arteriosus, pulmonary hypertension, oliguria, oligoamnios, increased risk of bleeding, uterine inertia and peripheral oedema. There have been isolated reports of renal failure in neonates born to women taking nimesulide in late pregnancy.

Studies in rabbits have shown an atypical reproductive toxicity and no adequate data from the use of nimesulide-containing medicinal products in pregnant women are available. Therefore, the potential risk for humans is unknown and prescribing the drug during the first two trimesters of pregnancy is not recommended.

There are no data relevant to the topical use of nimesulide gel in pregnant women. Therefore, nimesulide gel should not be used during pregnancy unless clearly necessary.

If nimesulide is used by a woman who is trying to conceive, or during the first and second trimesters of
pregnancy, the dose and duration of treatment should be kept as low as possible.

During the third trimester of pregnancy, all inhibitors of prostaglandin synthesis may expose

• the fetus to:
  • cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
  • renal dysfunction, which may progress to renal insufficiency with oligohydramnios;
• the mother and the newborn infant, at the end of pregnancy, to:
  • possible prolongation of bleeding time, and an antiplatelet effect which may occur even at very low doses;
  • inhibition of uterine contractions resulting in delay or prolongation of labour.

Consequently, nimesulide is contraindicated during the third trimester of pregnancy.

It is not known whether nimesulide is excreted in human milk. Nimesulide containing medicinal products are contraindicated when breastfeeding.

There are no data relevant to the topical use of nimesulide gel uring breastfeeding. Therefore, nimesulide gel should not be used during lactation unless clearly necessary.

No studies on the effect of nimesulide containing medicinal products on the ability to drive or use machines have been performed. However, patients who experience dizziness, vertigo or somnolence after receiving nimesulide should refrain from driving or operating machines.

Oral administration

General Description

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).

Oedema, hypertension, and cardiac failure have been reported in association with NSAID treatment. Very rare cases of bullous reactions including Stevens-Johnson Syndrom and Toxic Epidermal Necrolysis have been reported.

The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported following administration. Less frequently, gastritis has been observed.

List of adverse reactions

The following listing of undesirable effects is based on data from controlled clinical trials* (approximately 7,800 patients) and from post marketing surveillance with reporting rates classified as: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated cases.

Blood disorders

Rare: Anemia*, Eosinophilia*

Very rare: Thrombocytopenia, Pancytopenia, Purpura

Immune system disorders

Rare: Hypersensitivity*

Very rare: Anaphylaxis

Metabolism and nutrition disorders

Rare: Hyperkalemia*

Psychiatric disorders

Rare: Anxiety*, Nervousness*, Nightmare*

Nervous system disorders

Uncommon: Dizziness*

Very rare: Headache, Somnolence, Encephalopathy (Reye’s syndrome)

Eye disorders

Rare: Vision blurred*

Very rare: Visual disturbance

Ear and labyrinth disorders

Very rare: Vertigo

Cardiac disorders

Rare: Tachycardia*

Vascular disorders

Uncommon: Hypertension*

* frequency based on clinical trial

Topical application

The following side effects listing is based on reports from clinical studies, in a limited number of patients, where mild local reactions have been reported. The reporting rates are classified as: very common (>1/10); common (>1/100, <1/10), uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), including isolated cases.

Skin and subcutaneous tissue disorders

Common: Itching Erythema