APONIL Tablet Ref.[28116] Active ingredients: Nimesulide

Simultaneous use of NSAIDs including cyclooxygenase-2 selective inhibitors is not recommended. Patients should be advised to refrain from other analgesics. The risk of adverse reactions may be reduced by using Aponil for the shortest possible duration (see section 4.2).

Treatment should be discontinued if no benefit is seen.

Hepatic effects

Rarely nimesulide has been reported to be associated with serious hepatic reactions, including very rare fatal cases (see also section 4.8). Patients who experience symptoms compatible with hepatic injury during treatment with nimesulide (such as anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine) or patients who develop abnormal liver function tests should have treatment discontinued. These patients should not be re-challenged with nimesulide. Liver damage, in most cases reversible, has been reported following short exposure to the drug.

Patients receiving nimesulide who develop fever and/or flu-like symptoms should discontinue the treatment. (See section 4.3).

Gastrointestinal effects

Gastrointestinal bleeding, ulceration and perforation, which can be fatal have been reported with all NSAIDs and may occur at any time during treatment, with or without warning symptoms or a previous history of gastrointestinal events.

In elderly patients and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), the risk of gastrointestinal bleeding, ulceration or perforation is higher on increased NSAIDs doses.

In these patients, treatment should start with the lowest available dose.

This should also be applied in these patients and in patients receiving concomitant low dose aspirin or other medicines that increase the risk of gastrointestinal side effects (see section 4.5).

Concomitant use of protective drugs should be considered (eg. misoprostol or proton pump inhibitors).

Patients with a history of gastrointestinal toxicity, particularly when elderly, should inform their physician about any unusual symptom of abdominal injury (especially gastrointestinal bleeding), which may occur especially at the beginning of treatment.

Gastrointestinal bleeding or ulceration/perforation can occur at any time during treatment, with or without warning symptoms or a history of gastrointestinal events.

If gastrointestinal bleeding or ulceration occurs, nimesulide should be discontinued.

Nimesulide should be used with caution in patients with gastrointestinal disorders, including history of peptic ulcer, history of gastrointestinal haemorrhage, ulcerative colitis or Crohn’s disease.

Patients receiving concomitant oral medicines that may increase the risk of ulcer or gastrointestinal bleeding, such as corticosteroids, anticoagulants (warfarin), selective serotonin- reuptake inhibitors or anti-platelet agents such as aspirin should be closely monitored (see section. 4.5).

NSAIDs should be used with caution in patients with a history of gastrointestinal disease (ulcerative colitis or Crohn’s disease), as they may exacerbate these conditions (see section 4.8).

Elderly patients

In elderly, the adverse reactions to NSAIDs occur with increased frequency; especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2.). Therefore, appropriate clinical monitoring is advisable for this group of patients.

Cardiovascular and Cerebrovascular effects

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 the use of NSAIDs, particularly at high doses and in long term treatment may be associated with a small increase in risk for arterial thrombotic events (for example myocardial infarction or stroke). There is insufficient data to exclude such a risk for nimesulide.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with diclofenac 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). Nimesulide is not a substitute of acetylsalicylic acid for cardiovascular function.

Renal effects

In patients with renal or cardiac impairment the administration of Aponil should be performed with caution since the use of nimesulide in that group of patients may result in deterioration of renal function. In case of deterioration treatment should be discontinued (see section 4.5).

Skin reactions

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. Aponil should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Effects on fertility

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, discontinuation of nimesulide should be considered (see section 4.6).

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

Pharmacodynamic interactions

Other NSAIDs

Coadministration of Aponil (see section. 4.4) with other NSAIDs, including aspirin at doses with anti-inflammatory effect (≥ 1 g as a single dose or as total daily dose ≥3 g) is not recommended.

Corticosteroids

Increased risk of gastrointestinal bleeding and ulceration (see section 4.4).

Anticoagulants

Co-administration of NSAIDs increases the effect of anti-coagulants such as warfarin (see section 4.4).

Patients taking warfarin or other anticoagulants are at increased risk of bleeding complications during treatment with Aponil. Therefore, this combination is not recommended (see also section 4.4.) and is contraindicated in patients with severe coagulation disorders (see also section 4.3). If this combination cannot be avoided, anticoagulant activity should be closely monitored.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding (see section 4.4).

Diuretics, angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists (ARBs)

NSAIDs may reduce the efficacy of diuretics and other antihypertensive drugs. In some patients with reduced renal function (e.g. dehydrated patients or elderly subjects with renal impairment), concomitant use of ACE inhibitors and a cyclo-oxygenase inhibitor may result in progressive deterioration of renal function, including acute renal failure, which is usually reversible.

The occurrence of these interactions should also be considered in patients who must concomitantly use Aponil with ACE inhibitors or ARBs.

Therefore, this combination should be administered with caution, especially in elderly patients. Proper hydration of patients and periodic monitoring of renal function after initiation of concomitant therapy is necessary.

Pharmacokinetic interactions

Nimesulide effect on the pharmacokinetics of other drugs

Furosemide:

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.

Coadministration of Aponil require caution in patients with renal or cardiac as described in section 4.4.

Lithium:

NSAIDs have been reported to reduce lithium clearance, resulting in elevated plasma levels and lithium toxicity. If Aponil 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. Caution should be taken with Aponil.

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 its effect on renal prostaglandins, prostaglandin synthase inhibitors nimesulide may increase cyclosporin nephrotoxicity.

Effects of other drugs on the pharmacokinetics of nimesulide

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.

Pregnancy

The use of nimesulide is contraindicated during the last trimester of pregnancy (see section 4.3).

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 embryonic development/fetal development. Results of epidemiological studies suggest an increased risk of miscarriage and cardiac malformation and gastroschisis after the use of a prostaglandin synthesis inhibitor in the first stage of pregnancy.

The absolute risk of cardiac malformation was increased from less than 1% to about 1.5%. The risk increases with increasing doses and duration of treatment.

In animals, it has been demonstrated that the administration of prostaglandin synthesis inhibitors causes growth of pre- and post-implantation embryonic loss and embryo-fetal mortality.

In addition, increased incidence of various malformations, including cardiovascular malformations, has been reported in animals to which prostaglandin synthesis inhibitors were administered during the organogenesis period.

Studies in rabbits have shown an atypical reproductive toxicity (see section 5.3); no data

Is available on the use of Aponil in pregnant women. Therefore, the potential risk for humans is unknown and Aponil use during the first two trimesters of pregnancy is not recommended, except where this is strictly necessary.

If Aponil is administrated to women attempting to conceive or during the first two trimesters of pregnancy, the dose and duration of treatment should be as small 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 lung hypertension);
  • Renal dysfunction, which may progress to renal failure with oligohydramnios;
• The mother and newborn baby at the end of pregnancy, to:
  • Possible prolongation of bleeding time, and antiplatelet effects that may occur even at very low doses;
  • Inhibition of uterine contractions that may cause delayed or prolonged birth.

Consequently, Aponil is contraindicated in the third trimester of pregnancy.

Breast-feeding

It is not known whether nimesulide is excreted in human milk. Aponil is contraindicated during lactation. (See section 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 Aponil should refrain from driving or operating machines.

a) Summary of the safety profile

Clinical and epidemiological data suggest that the use of certain NSAIDs (particularly at high doses and long-term treatment) may be associated with a small increase in risk of developing arterial thrombotic events (for example myocardial infarction or stroke). (See section 4.4).

Adverse reactions reported in association with NSAID therapy were: edema, hypertension blood pressure and heart failure.

Very rare bullous reactions have been reported including Stevens-Johnson syndrome and toxic epidermal necrolysis.

The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly may occur (see section 4.4).

Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Chron’s disease (see section 4.4) have been reported following oral administration. Less frequently, gastritis has been observed.

b) Tabulated list of adverse reactions

The following list of adverse reactions is based on controlled clinical trials* (approximately 7,800 patients) and post-marketing surveillance with reporting frequencies 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).

^* Frequency determined based on clinical trials

Reporting of suspected adverse reactions

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.

None known.