FORMULARY ADDITIONS

Montelukast, a selective leukotriene receptor antagonist, is indicated for the prophylaxis and chronic treatment of asthma in adults and children 6 years of age and older. Zafirlukast, the only other commercial drug available in this class is indicated for use in adults and children 12 years of age and older. Both drugs inhibit the cysteinyl leukotriene receptor (CyLT1) and are capable of preventing leukotriene (LTD₄)-induced airway effects.

Peak montelukast levels are reached within 2 to 2.5 hours after administration of the chewable tablet and 3 to 4 hours after oral administration of the 10 mg tablet. The mean plasma half-life is 2.7 to 5.5 hours. Montelukast is extensively metabolized primarily via the cytochrome P450 3A4 and 2C9 isoenzymes. Metabolism is reduced in patients with mild-to-moderate hepatic impairment and evidence of cirrhosis, resulting in an approximately 40% increase in the AUC. The half-life is also slightly prolonged. The pharmacokinetics of montelukast in patients with severe hepatic impairment or hepatitis have not been evaluated. Since montelukast and its metabolites are not renally eliminated, renal impairment should have no effect on the pharmacokinetics.

Montelukast is contraindicated in patients with hypersensitivity to the drug or any of the inactive ingredients. Montelukast is not indicated for the reversal of bronchospasm in acute asthma and should not be used to treat acute episodes of asthma, but it may be continued during acute exacerbations of asthma. It should not be used as monotherapy in patients with exercise-induced bronchospasm. Montelukast is classified in Pregnancy Category B. No teratogenicity was observed in animal studies. Animal studies indicate montelukast is excreted in breast milk. Therefore, it should be administered with caution in nursing mothers. The safety and efficacy of montelukast in children under 6 years of age have not been demonstrated.

The most common side effects in clinical trials occurring at a greater frequency than with placebo included headache, respiratory infections, dyspepsia, abdominal pain and rash. Hepatic transaminase elevations have been reported during montelukast therapy, but not at an incidence greater than observed with placebo. Unlike zafirlukast, montelukast does not inhibit any of the cytochrome P450 isoenzymes. No interactions with theophylline, prednisone, prednisolone, oral contraceptives, terfenadine, digoxin or warfarin were observed. Phenobarbital reduced the AUC of montelukast by approximately 40%. Similar interactions are anticipated with other cytochrome P450 enzyme inducers including rifampin.

The dosage for adults and adolescents > 15 years of age is 10 mg once daily in the evening. The dosage for pediatric patients 6 to 14 years of age is 5 mg once daily in the evening. Montelukast can be administered without regard to meals. The relative efficacy of morning administration compared to evening dosing has not been evaluated. The 10 mg tablet is recommended for patients >15 years of age, while the 5 mg chewable tablets are recommended for children 6 to 14 years of age.

Because montelukast has the advantage of once daily dosing and a chewable tablet dosage form, it is the preferred agent in this class on the KUMC formulary. Zafirlukast was deleted from the KUMC formulary but is still stocked in the KUMC Outpatient Pharmacy.

Tolcapone, a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), is indicated as adjunctive treatment for Parkinson’s Disease. It’s precise mechanism of action is unknown, but is believed to be related to its ability to inhibit COMT and alter plasma pharmacokinetics of levodopa. When given with levodopa and carbidopa, plasma levels of levodopa are more sustained than after administration of either agent alone. Sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater therapeutic effects. Also, an increase in adverse effects of levodopa may occur, usually requiring a dosage reduction.

MAO and COMT are the two major enzyme systems involved in the metabolism of catecholamines. Theoretically, it is possible that the combination of tolcapone and a nonselective MAOI (e.g., phenelzine and tranylcypromine) would inhibit the majority of pathways responsible for catecholamine metabolism. Thus, patients receiving a non-selective MAO inhibitor should receive concurrent tolcapone therapy, but concurrent therapy with a selective MAO-B inhibitor (e.g., selegiline) does not appear to be a problem. Because tolcapone enhances levodopa bioavailability, reductions of levodopa dosages by 20% to 25% may be needed.

The most commonly observed adverse effects associated with tolcapone include dyskinesia, nausea, sleep disorder, dystonia, dreaming excessive, anoxeria, muscle cramps, orthostatic complaints, somnolence, diarrhea, confusion, headache and dizziness. Although tolcapone is highly protein bound it does not displace other drugs from their binding sites (i.e., warfarin, phenytoin, tolbutamide, and digitoxin). Tolcapone has a FDA pregnancy rating of C. It is not known if this drug is excreted into human milk and should be used with caution in women who are nursing.

Tolcapone therapy should be initiated at 100 mg to 200 mg three times daily, always as adjunctive therapy to levodopa/carbidopa therapy. Initial treatment with 100 mg TID may be warranted to reduce the potential for increased dopaminergic side effects and necessary dosage adjustments in carbidopa/levodopa.

Alesse is a low dose monophasic estrogen/progestin combination oral contraceptive product indicated for the prevention of pregnancy. Multicenter open label trials demonstrate that this product provides similar contraceptive efficacy when compared to higher dosed oral contraception while maintaining a comparable safety and side effect profile. Results showed an overall pregnancy rate of 0.6% with a cumulative life table pregnancy rate of 0.0041 per woman entering the six cycle. This product shares similar contraindications, warnings and precautions as with other combination estrogen/progestin oral contraceptives. All oral contraceptives have a FDA pregnancy rating of X.

Mometasone nasal spray is indicated for the prophylaxis and treatment of nasal symptoms associated with seasonal allergic rhinitis and perennial allergic rhinitis in adults and children 12 years of age and older. In patients with established seasonal allergies, prophylaxis with this agent should begin approximately two to four weeks prior to the start of the pollen season. This once daily nasal corticosteroid has a similar efficacy and side effect profile as other available agents in this class. The most frequently cited adverse effects included headache, epistaxis, nasal burning, irritation and pharyngitis. Clinical studies have not demonstrated the development of hypothalamic pituitary adrenal axis suppression with the use of this agent. The recommended dose of prophylaxis and treatment of nasal symptoms is one to two sprays in each nostril once daily.

Fluticasone propionate, a locally active trifluorinated corticosteroid with potent anti-inflammatory activity, is a new inhalation aerosol indicated for the maintenance treatment of asthma as prophylactic therapy in adults and children greater than 12 years of age. It is also indicated for use in patients requiring oral corticosteroid therapy for asthma. This agent is more lipophilic than triamcinolone acetonide, which may be associated with slower dissolution in the airways, increased deposition in lung tissue and increased affinity for the glucocorticoid receptor. The majority of fluticasone delivered to the lungs is absorbed with a bioavailability of 30% of the dose delivered from the actuator. Thus, to minimize hypothalamic-pituitary-adrenal (HPA) suppression, this lowest effective dose should be used and recommended doses should not be exceeded.

Adverse reactions to inhaled fluticasone are similar to those reported with other inhaled corticosteroids including, pharyngitis, dysphonia and oral candidasis. The use of a spacer may increased systemic absorption and systemic effects of the drug. Patients should be monitored for systemic corticosteroid effects and growth of adolescents should be closely monitored.

Recommended dosing is provided in the following table:

* Starting dose above 88 mcg twice daily may be considered for patients wither poorer asthma control or in those who have previously required doses of inhaled corticosteroids that are in the higher range for that specific agent.

** For patients receiving chronic oral corticosteroid therapy: the prednisone dose should be decreased no faster than 2.5 mg/day on a weekly basis, beginning after at least one week of fluticasone therapy. Once prednisone reduction is complete, the dosage of fluticasone should be reduced to the lowest effective dose.