SINTRINE Film-coated tablet Ref.[115334] Active ingredients: Montelukast

Patients should be advised never to use oral montelukast to treat acute asthma attacks and to keep their usual appropriate rescue medication for this purpose readily available. If an acute attack occurs, a short-acting inhaled β-agonist should be used. Patients should seek their doctors' advice as soon as possible if they need more inhalations of short-acting β-agonists than usual.

Patients should be advised to take SINTRINE 10 exactly as prescribed, even if they are asymptomatic.

SINTRINE 10 should also be used during periods of worsening asthma and patients should contact their healthcare practitioner if their asthma is not well controlled.

SINTRINE 10 should not be abruptly substituted for inhaled or oral corticosteroids. If appropriate, the dose of corticosteroids should be tapered gradually under medical supervision.

There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given concomitantly.

Eosinophilic conditions

In rare cases, patients on therapy with anti-asthma agents including montelukast may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg- Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These cases have been sometimes associated with the reduction or withdrawal of oral corticosteroid therapy. Although a causal relationship with leukotriene receptor antagonism has not been established, physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. Patients who develop these symptoms should be reassessed and their treatment regimens evaluated.

SINTRINE 10 should not be used as monotherapy for the treatment or management of exercise-induced bronchospasm. Patients should be advised to continue with the usual regimen of an inhaled beta-agonist for prophylaxis of exercise-induced bronchospasm and to have a short-acting inhaled beta-agonist available for rescue treatment.

While using SINTRINE 10, patients must seek medical attention if short-acting bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period is needed.

Patients with known hypersensitivity to aspirin should be advised to continue avoiding the use of aspirin or NSAIDs (non-steroidal anti-inflammatory agents) while taking SINTRINE 10.

Neuropsychiatric events such as behavioural changes, depression and suicidality have been reported in all age groups taking montelukast (see section 4.8). The symptoms may be serious and continue if the treatment is not withdrawn. Therefore the treatment with montelukast should be discontinued if neuropsychiatric symptoms occur during treatment.

Advise patients and/or caregivers to be alert for neuropsychiatric events and instruct them to notify their physician if these changes in behaviour occur.

Renal insufficiency

Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast was not evaluated in patients with renal sufficiency. No dosage adjustment is recommended in these patients.

Lactose

SINTRINE 10 contains lactose monohydrate. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take SINTRINE 10.

SINTRINE 10 contains lactose monohydrate which may have an effect on the glycaemic control of patients with diabetes mellitus.

SINTRINE 10 may be used together with other medicines used in the prophylaxis and chronic treatment of asthma. Montelukast does not significantly change the pharmacokinetics of theophylline, warfarin, digoxin, fexofenadine, oral contraceptives (containing 1 mg norethindrone and 35 μg ethinyl estradiol), prednisone or prednisolone.

Concurrent use of SINTRINE 10 and phenobarbital results in significant decreases (approximately 40%) in the area under the curve (AUC) for montelukast, as a result of induction of hepatic metabolism. No dosage adjustment is necessary. However, clinical monitoring is required when potent hepatic enzyme inducers such as phenytoin, phenobarbital or rifampicin are given with montelukast. Since montelukast is metabolised by CYP 3A4, 2C8, and 2C9, caution should be exercised, particularly in children, when montelukast is co-administered with inducers of CYP 3A4, 2C8, and 2C9, such as phenytoin, phenobarbital and rifampicin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of medicinal products primarily metabolized by CYP 2C8) demonstrated that montelukast does not inhibit CYP 2C8 in vivo. Therefore, montelukast is not anticipated to markedly alter the metabolism of medicinal products metabolised by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide). In vitro studies have shown that montelukast is a substrate of CYP 2C8, and to a less significant extent, of 2C9, and 3A4. In a clinical drug-drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) gemfibrozil increased the systemic exposure of montelukast by 4.4-fold. No routine dosage adjustment of montelukast is required upon co-administration with gemfibrozil or other potent inhibitors of CYP 2C8, but the physician should be aware of the potential for an increase in adverse reactions.

Based on in vitro data, clinically important drug interactions with less potent inhibitors of CYP 2C8 (e.g., trimethoprim) are not anticipated. Co-administration of montelukast with itraconazole, a strong inhibitor of CYP 3A4, resulted in no significant increase in the systemic exposure of montelukast.

The safety of the use of SINTRINE 10 in pregnant and lactating women has not yet been established. It is not known if SINTRINE 10 is excreted in human milk.

SINTRINE 10 should not be used in pregnancy and lactation (see “CONTRAINDICATIONS”).

SINTRINE 10 may cause side effects such as drowsiness and dizziness which may affect the ability to drive and operate machines safely.

Infections and infestations

Frequent: upper respiratory infection^†

Blood and lymphatic system disorders

Less frequent: Increased bleeding tendency, thrombocytopenia.

The following has been reported but frequency is unknown: bruising, agranulocytosis.

Immune system disorders

Less frequent: Anaphylaxis, angioedema, allergy, hypersensitivity reactions including rashes and urticaria, hepatic eosinophilic infiltration.

Endocrine disorders

The following has been reported but frequency is unknown: Pancreatitis.

Psychiatric disorders

Less frequent: Aggressive behaviour or hostility, agitation, hallucinations, dream abnormalities including nightmares, insomnia, drowsiness, irritability, restlessness, depression, suicidal thinking and behaviour (suicidality), somnambulism, anxiety, psychomotor hyperactivity (including irritability, restlessness, tremor^§), disturbance in attention, memory impairment, tic, obsessive-compulsive symptoms, dysphemia.

Nervous system disorders

Frequent: Headache

Less frequent: dizziness, drowsiness, paraesthesia/hypoesthesia, seizure.

Cardiac disorders

Less frequent: Palpitations.

Respiratory, thoracic and mediastinal disorders

Less frequent: Churg-Strauss Syndrome (see section 4.4) Nasal congestion, cough, influenza, increased incidence of respiratory tract infections, epistaxis, pulmonary eosinophilia

Gastrointestinal disorders

Frequent: Abdominal pain, diarrhoea^‡, nausea^‡, vomiting^‡.

Less frequent: Dyspepsia, gastroenteritis, dry mouth.

Hepato-biliary disorders

Frequent: elevated levels of serum transaminases (AST, ALT), symptomatic hepatitis

Less frequent: Elevated hepatic enzymes (AST, ALT), symptomatic hepatitis (including cholestatic, hepatocellular, and mixed-pattern liver injury) or hyperbilirubinaemia.

Skin and subcutaneous tissue disorders

Frequent: Skin rash^‡.

Less frequent: Pruritus, urticaria, bruising, angioedema, erythema nodosum, erythema multiforme

Musculoskeletal, connective tissue and bone disorders

Less frequent: arthralgia, myalgia including muscle cramps.

Renal and urinary disorders

The following has been reported but frequency is unknown: pyuria

Less frequent: enuresis in children

General disorders and administration site conditions

Less frequent: Asthenia, fatigue, dental pain, pyrexia^‡, malaise, Oedema

The following has been reported but frequency is unknown: generalised pain, fatalities.

^† This adverse experience, reported as Very Common in the patients who received montelukast, was also reported as Very Common in the patients who received placebo in clinical trials.
^‡ This adverse experience, reported as Common in the patients who received montelukast, was also reported as Common in the patients who received placebo in clinical trials.
^§ Frequency Category: Rare

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

Suspected adverse reactions can also be reported directly to the HCR via the website: https://pvi1j.solutions.iqvia.com or the e-mail address, adverse.event.sac@sandoz.com.

Not applicable.