Ventek™

[Montelukast Sodium]

Ventek

Description / Properties

Ventek™ (Montelukast sodium) is a selective and orally active leukotriene receptor antagonist that specifically inhibits the cysteinyl leukotriene Cys LT1 receptor. The structural formula of montelukast sodium is: Each 10mg film coated Ventek™ tablet contains 10.4mg montelukast sodium, which is equivalent to 10mg of montelukast. Each 4mg and 5mg chewable Ventek™ tablet contains 4.16 and 5.2 mg montelukast sodium, respectively, which are equivalent to 4 and 5 mg of montelukast, respectively.

Clinical Pharmacology

MECHANISM OF ACTION The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids 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 airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. 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. Ventek™ (Montelukast Sodium) is orally active leukotriene receptor antagonist which acts selectevely, and specifically inhibits the cysteinyl leukotriene receptors.

SPHARMACOKINETICS ABSORPTION & DISTRIBUTION Montelukast is rapidly absorbed following oral administration. After administration of the 10mg film-coated tablet to fasted adults, the mean peak montelukast plasma concentration (Cmax ) is achieved in 3 to 4 hours (Tmax ). The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal in the morning. For the 5mg chewable tablet, the mean Cmax is achieved in 2 to 2.5 hours after administration to adults in the fasted state. The mean oral bioavailability is 73% in the fasted state versus 63% when administered with a standard meal in the morning. For the 4mg chewable tablet, the mean Cmax is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state. Montelukast is more than 99% bound to plasma proteiens.

Metabolism Montelukast is extensively metabolized in the liver by cytochrome P450, 3A4 and 2C9. Therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. rug Interaction.

Elimination The plasma clearance of montelukast averages 45 mL/min in healthy adults. Montelukast and its metabolites are excreted almost exclusively via the bile. The mean plasma half-life of montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg.

Indications

Elderly: The pharmacokinetic profile and the oral bioavailability of a single 10mg oral dose of montelukast are similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. No dosage adjustment in the elderly is required. Hepatic Insufficiency: Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in 41% higher mean montelukast area under the plasma concentration curve (AUC) following a single 10mg dose. The elimination of montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. Renal Insufficiency: Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients. Adolescents and Pediatric Patients: The plasma concentration profile of montelukast following administration of the 10mg tablet is similar in adolescents ? 15 years of age and young adults. The 10mg tablet is recommended for use in patients ??15 years of age. The mean systemic exposure of the 4mg chewable tablet in pediatric patients 2 to 5 years of age and and the 5mg chewable tablets in pediatric patients 6 to 14 years of age is similar to the mean systemic exposure of the 10mg tablets in adults. The 5mg chewable tablet should be used in pediatric patients 6 to 14 years of age and the 4mg chewable tablet shoud be used in pediatric patients 2 to 5 years of age.

Ventek™ is indicated in adults and pediatric patients 2 years of age and older for the prophylaxis and chronic treatment of asthma, including the prevention of day and night time symptoms, the treatment of aspirin-sensitive asthmatic patients, and prevention of exercise-induced bronchoconstriction. Ventek™ is indicated for the relief of symptoms of seasonal allergic rhinitis in adults and pediatric patients 2 years of age and older.

Contraindication

Hypersensitivity to any component of this product.

Drug Interactions

Montelukast at a dose of 10mg once daily dosed to pharmacokinetic steady state:

  • did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate).
  • did not change the pharmacokinetic profile of warfarin or influence the effect of a single 30mg oral dose of warfarin on protrhombin time or the INR (International Normalized Ratio).
  • did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin.
  • did not change the plasma concentration profile of terfenadine or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co- administration with terfenadine 60mg twice daily.

    Montelukast at doses of 100mg daily dosed to pharmacokinetic steady state:
  • did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1mg/ethinyl estradiol 35 mcg.
  • did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast apprximately 40% following a single 10mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast.

    Montelukast may inhibit the metabolism of drugs primarily metabolized by CYP 2C8 (e.g., paclitaxel, rosiglitazone, repaglinide); however, no in vivo interaction studies have been performed.

    Side Effects

    Montelukast sodium is generally well tolerated. However, following are the adverse effects reported which usually were mild and did not require discontinuation of therapy:

  • Hypersensitivity reactions (including anaphylaxis, angioedema, rash, pruritus, urticaria and very rarely, hepatic eosinophillic infiltration).
  • Dream abnormalities, hallucinations, palpitations, drowsiness, irritability, restlessness, asthenia/fatigue, insomnia, increased sweating, dizziness, headache, mydriasis;
  • Nausea, vomiting, dyspepsia, diarrhea, abdominal pain, trauma;
  • Myalgia including muscle cramps;
  • Cough, influenza, pharyngitis, sinusitis, otitis, viral infection, nasal congestion;
  • ALT increase, AST increase, pyuria;
  • Increased bleeding tendency, bruising edema;
  • Tremor, dry mouth, vertigo, arthralgia.

    Warning and Precautions

    General:

  • Montelukast sodium is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. However the dose of inhaled corticosteroid may be reduced gradually under medical supervision.
  • Montelukast sodium should not be abruptly substituted for inhaled or oral corticosteroids. Although a casual relationship with leukotriene receptor antagonism has not been established, caution and appropriate clinical monitoring is recommended when systemic corticosteroid reduction is considered in patients receiving montelukast sodium.
  • Montelukast sodium should not be used as monotherapy for the treatment and management of exercise-induced bronchospasm. Patients who have exacerbations of asthma after exercise should continue to use their usual regimen of inhaled beta-agonists as prophylaxis and should have it available as and when required.
  • Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking Montelukast sodium. Although Ventek™ is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin- sensitive asthmatic patients.
  • In rare cases, patients with asthma on therapy with 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. A causal association between montelukast and these underlying conditions has not been established.

    Information for Patients:

  • Patients should be advised to take Ventek™ daily as prescribed, even when they are asymptomatic, as well as during periods of worsening asthma, and to contact their physicians if their asthma is not well controlled.
  • Patients should be advised that oral Ventek™ is not for the treatment of acute asthma attacks.
  • Patients should be advised that, while using VENTEK, medical attention should be sought if short-acting inhaled 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 are needed.
  • Patients receiving Ventek™ should be instructed not to decrease the dose or stop taking any other anti-asthma medications unless instructed by a physician.
  • Patients with known aspirin sensitivity should be advised to continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking VENTEK.
  • Patients who have exacerbations of asthma after exercise should be instructed to continue to use their usual regimen of inhaled beta agonists as prophylaxis unless otherwise instructed by their physician.

    Pregnancy

  • Montelukast sodium has not been studied in pregnant women. It should be used during pregnancy only if clearly needed.
  • In animal studies, no teratogenicity was observed at oral doses up to 400 mg/kg/day.

    Nursing Mothers
    It is not known if montelukast sodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ventek™ is given to a nursing mother.

    Pediatric Use
    Safety and efficacy of montelukast have been established in adequate and well-controlled studies in pediatric patients with asthma and seasonal allergic rhinitis.

    Geriatric Use
    In clinical studies , no overall differences in safety or effectiveness were observed in geriatrics, but greater sensitivity of some older individuals cannot be ruled out. No evidence of tumorigenicity, mutagenic or clastogenic activity is reported with montelukast.

    Overdosage
    No mortality occurred following single oral doses of montelukast up to 5000 mg/kg in mice (estimated exposure was approximately 250 times the AUC for adults and children at the maximum recommended daily oral dose) and rats (estimated exposure was approximately 170 times the AUC for adults and children at the maximum recommended daily oral dose).
    No specific information is available on the treatment of over dosage with montelukast. 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 a week without clinically important adverse experiences. In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. There were no adverse experiences reported in the majority of overdosage reports. The most frequent adverse experiences observed were thirst, somnolence, mydriasis, hyperkinesia, and abdominal pain.

    Dosage

    Ventek™ should be taken once daily. For asthma, the dose should be taken in the evening. For seasonal allergic rhinitis, the time of administration may be individualized to suit patient needs.

  • Adults and Adolescents 15 Years of Age and Older with Asthma or Seasonal Allergic Rhinitis: The dosage for adults and adolescents 15 years of age and older is one 10mg tablet daily.

  • Pediatric Patients 6 to 14 Years of Age with Asthma or Seasonal Allergic Rhinitis: The dosage for pediatric patients 6 to 14 years of age is one 5mg chewable tablet daily. No dosage adjustment within this age group is necessary.

  • Pediatric Patients 2 to 5 Years of Age with Asthma or Seasonal Allergic Rhinitis: The dosage for pediatric patients 2 to 5 years of age is one 4mg chewable tablet.

    Presentations Available

    4mg, 5mg, 10mg Chewable and Film Coated Tablets

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