Montelukast Sandoz

Montelukast sodium.

Each chewable tablet contains 5 mg montelukast.
Excipients/Inactive Ingredients: Mannitol, Microcrystalline cellulose, Croscarmellose sodium, Type EXF hydroxypropylcellulose, Cherry duarome, Aspartame, Cherry flavour, Ferric oxide red, Magnesium stearate.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airway diseases, leukotriene receptor antagonists. ATC code: R03DC03.
PHARMACOLOGY: Pharmacodynamics: The cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT₁) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction.
Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT₁ receptor. In clinical studies, montelukast inhibits bronchoconstriction due to inhaled LTD₄ at doses as low as 5 mg. Bronchodilation was observed within 2 hours of oral administration. The bronchodilation effect caused by a beta-agonist was additive to that caused by montelukast. Treatment with montelukast inhibited both early- and late-phase bronchoconstriction due to antigen challenge. Montelukast, compared with placebo, decreased peripheral blood eosinophils in adult and paediatric patients. In a separate study, treatment with montelukast significantly decreased eosinophils in the airways (as measured in sputum) and in peripheral blood while improving clinical asthma control.
Pharmacokinetics: Absorption: Montelukast is rapidly absorbed following oral administration.
For the 5-mg chewable tablet, the C_max is achieved in 2 hours after administration in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.
Distribution: Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8-11 l. Studies in rats with radiolabelled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabelled material after 24 hours were minimal in all other tissues.
Biotransformation: Montelukast is extensively metabolised. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and children.
In vitro studies using human liver microsomes indicate that cytochrome P450 3A4, 2A6 and 2C9 are involved in the metabolism of montelukast. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.
Elimination: The plasma clearance of montelukast averages 45 ml/min in healthy adults. Following an oral dose of radiolabelled montelukast, 86% of the radioactivity was recovered in 5-day faecal collections and <0.2% was recovered in the urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile.
Characteristics in patients: No dose adjustment is necessary for the elderly or mild to moderate hepatic insufficiency. Studies in patients with renal impairment have not been undertaken. Because montelukast and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in patients with renal impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic insufficiency (Child-Pugh score >9).
With high doses of montelukast (20- and 60-fold the recommended adult dose), decrease in plasma theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg once daily.
Toxicology: Preclinical safety data: In animal toxicity studies, minor serum biochemical alterations in ALT, glucose, phosphorus and triglycerides were observed which were transient in nature. The signs of toxicity in animals were increased excretion of saliva, gastrointestinal symptoms, loose stools and ion imbalance. These occurred at doses which provided >17-fold the systemic exposure seen at the clinical dose. In monkeys, the adverse effects appeared at doses from 150 mg/kg/day (>232-fold the systemic exposure seen at the clinical dose). In animal studies, montelukast did not affect fertility or reproductive performance at systemic exposure exceeding the clinical systemic exposure by greater than 24-fold. A slight decrease in pup body weight was noted in the female fertility study in rats at 200 mg/kg/day (>69-fold the clinical systemic exposure). In studies in rabbits, a higher incidence of incomplete ossification, compared with concurrent control animals, was seen at systemic exposure >24-fold the clinical systemic exposure seen at the clinical dose. No abnormalities were seen in rats. Montelukast has been shown to cross the placental barrier and is excreted in breast milk of animals.
No deaths occurred following a single oral administration of montelukast sodium at doses up to 5000 mg/kg in mice and rats (15,000 mg/m² and 30,000 mg/m² in mice and rats, respectively), the maximum dose tested. This dose is equivalent to 25,000 times the recommended daily adult human dose (based on an adult patient weight of 50 kg).
Montelukast was determined not to be phototoxic in mice for UVA, UVB or visible light spectra at doses up to 500 mg/kg/day (approximately >200-fold based on systemic exposure).
Montelukast was neither mutagenic in in vitro and in vivo tests nor tumorigenic in rodent species.

Montelukast is indicated in adult and pediatric patients 6 months of age and older for prophylaxis and chronic treatment of asthma, including the prevention of day-and nighttime symptoms, the treatment of aspirin-sensitive asthmatic patients, and the prevention of exercise-induced bronchoconstriction.
Montelukast is indicated for the relief of daytime and nighttime symptoms of allergic rhinitis (seasonal allergic rhinitis in adults and pediatric patients 2 years of age and older, perennial allergic rhinitis in adults and pediatric patients 6 months of age and older).

The dose for paediatric patients 6-14 years of age is one 5 mg chewable tablet daily to be taken in the evening. If taken in connection with food, montelukast should be taken 1 hour before or 2 hours after food. No dose adjustment within this age group is necessary.
Method of administration: For oral use.
General recommendations: The therapeutic effect of montelukast on parameters of asthma control occurs within one day. Patients should be advised to continue taking montelukast even if their asthma is under control, as well as during periods of worsening asthma.
No dose adjustment is necessary for patients with renal insufficiency, or mild to moderate hepatic impairment. There are no data on patients with severe hepatic impairment. The dose is the same for both male and female patients.
Montelukast as an alternative treatment option to low-dose inhaled corticosteroids for mild persistent asthma: Montelukast is not recommended as monotherapy in patients with moderate persistent asthma. The use of montelukast as an alternative treatment option to low-dose inhaled corticosteroids for children with mild persistent asthma should only be considered for patients who do not have a recent history of serious asthma attacks that required oral corticosteroid use and who have demonstrated that they are not capable of using inhaled corticosteroids (see Indications/Uses). Mild persistent asthma is defined as asthma symptoms more than once a week but less than once a day, nocturnal symptoms more than twice a month but less than once a week, normal lung function between episodes. If satisfactory control of asthma is not achieved at follow-up (usually within one month), the need for an additional or different anti-inflammatory therapy based on the step system for asthma therapy should be evaluated. Patients should be periodically evaluated for their asthma control.
Therapy with montelukast in relation to other treatments for asthma: When treatment with montelukast is used as add-on therapy to inhaled corticosteroids, montelukast should not be abruptly substituted for inhaled corticosteroids (see Precautions).

In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to adult patients for 22 weeks and in short term studies, up to 900 mg/day to patients for approximately one week without clinically important adverse experiences.
There have been reports of acute overdose in post-marketing experience and clinical studies with montelukast. These include reports in adults and children with a dose as high as 1000 mg (approximately 61 mg/kg in a 42 month old child). The clinical and laboratory findings observed were consistent with the safety profile in adults and paediatric patients. There were no adverse experiences in the majority of overdose reports.
Symptoms of overdose: The most frequently occurring adverse experiences were consistent with the safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.
Management of overdose: No specific information is available on the treatment of overdose with montelukast.
It is not known whether montelukast is dialysable by peritoneal- or haemodialysis.

Hypersensitivity to the active substance or to any of the excipients.

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.
Montelukast should not be substituted abruptly for inhaled or oral corticosteroids.
There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given concomitantly.
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 usually, but not always, have been associated with the reduction or withdrawal of oral corticosteroid therapy. The possibility that leukotriene receptor antagonists may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor 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.
Treatment with montelukast does not alter the need for patients with aspirin-sensitive asthma to avoid taking aspirin and other non-steroidal anti-inflammatory agents.
Neuropsychiatric events have been reported in adults, adolescents, and children taking montelukast (see Adverse Reactions). Patients and physicians should be alert for neuropsychiatric events. Patients and/or caregivers should be instructed to notify their physician if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with montelukast if such events occur.
Effects on ability to drive and use machines: Montelukast has no or negligible influence on the ability to drive and use machines. However, individuals have reported drowsiness or dizziness.

Pregnancy: Animal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/foetal development.
Limited data from available pregnancy databases do not suggest a causal relationship between montelukast and malformations (i.e. limb defects) that have been rarely reported in worldwide post marketing experience.
Montelukast may be used during pregnancy only if it is considered to be clearly essential.
Breast-feeding: Studies in rats have shown that montelukast is excreted in milk (see PHARMACOLOGY: Toxicology: Preclinical safety data under Actions). It is unknown whether montelukast/metabolites are excreted in human milk.
Montelukast may be used in breast-feeding only if it is considered to be clearly essential.

The following drug-related adverse reactions in clinical studies were reported commonly (≥1/100 to <1/10) in asthmatic patients treated with montelukast and at a greater incidence than in patients treated with placebo: Adult and adolescent patients 15 years and older (two 12-week studies; n=795): Nervous system disorders: Headache.
Gastrointestinal disorders: Abdominal pain.
Paediatric patients 6 to 14 years old (one 8-week study; n=201), (two 56-week studies; n=615): Nervous system disorders: Headache.
With prolonged treatment in clinical trials with a limited number of patients for up to 2 years for adults, and up to 12 months for paediatric patients 6 to 14 years of age, the safety profile did not change.
List of adverse reactions: Adverse reactions reported in post-marketing use are listed, by System Organ Class and specific adverse reaction, as follows. Frequency categories* were estimated based on relevant clinical trials.
Infections and infestations: Very common: Upper respiratory infection^†.
Blood and lymphatic system disorders: Rare: Increased bleeding tendency.
Very rare: Thrombocytopenia.
Immune system disorders: Uncommon: Hypersensitivity reactions including anaphylaxis.
Very rare: Hepatic eosinophilic infiltration.
Psychiatric disorders: Uncommon: Dream abnormalities including nightmares, insomnia, somnambulism, anxiety, agitation including aggressive behaviour or hostility, depression, psychomotor hyperactivity (including irritability, restlessness, tremor^§).
Rare: Disturbance in attention, memory impairment, tic.
Very rare: Hallucinations, disorientation, suicidal thinking and behaviour (suicidality), obsessive-compulsive symptoms and dysphemia.
Nervous system disorders: Uncommon: Dizziness, drowsiness, paraesthesia/hypoesthesia, seizure.
Cardiac disorders: Rare: Palpitations.
Respiratory, thoracic and mediastinal disorders: Uncommon: Epistaxis.
Very rare: Churg-Strauss Syndrome (CSS) (see Precautions), pulmonary eosinophilia.
Gastrointestinal disorders: Common: Diarrhoea^‡, nausea^‡, vomiting^‡.
Uncommon: Dry mouth, dyspepsia.
Hepatobiliary disorders: Common: Elevated levels of serum transaminases (ALT, AST).
Very rare: Hepatitis (including cholestatic, hepatocellular and mixed pattern liver injury).
Skin and subcutaneous tissue disorders: Common: Rash^‡.
Uncommon: Bruising, urticaria, pruritus.
Rare: Angioedema.
Very rare: Erythema nodosum, erythema multiforme.
Musculoskeletal, connective tissue and bone disorders: Uncommon: Arthralgia, myalgia including muscle cramps.
Renal and urinary disorders: Uncommon: Enuresis in children.
General disorders and administration site conditions: Common: Pyrexia^‡.
Uncommon: Asthenia/fatigue, malaise, oedema.
^*Frequency category: Defined for each adverse experience term by the incidence reported in the clinical trials data base: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000).
^†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.

Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma. In drug-interactions studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following medicinal products: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), terfenadine, digoxin and warfarin.
The area under the plasma concentration curve (AUC) for montelukast was decreased approximately 40% in subjects with co-administration of phenobarbital. Since montelukast is metabolised by CYP 3A4, 2C8, and 2C9, caution should be exercised, particularly in children, when montelukast is coadministered 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 metabolised 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 dose 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.

Incompatibilities: Not applicable.
Special precautions for disposal: No special requirements.

Do not store above 30°C.
Store in the original package in order to protect from moisture and light.

Antiasthmatic & COPD Preparations / Antihistamines & Antiallergics

R03DC03 - montelukast ; Belongs to the class of leukotriene receptor antagonists. Used in the systemic treatment of obstructive airway diseases.

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