Zafirlukast (Page 2 of 6)

Clinical Studies:

Three U.S. double-blind, randomized, placebo-controlled, 13-week clinical trials in 1380 adults and children 12 years of age and older with mild-to-moderate asthma demonstrated that zafirlukast improved daytime asthma symptoms, nighttime awakenings, mornings with asthma symptoms, rescue beta2 -agonist use, FEV1 , and morning peak expiratory flow rate. In these studies, the patients had a mean baseline FEV1 of approximately 75% of predicted normal and a mean baseline beta2 -agonist requirement of approximately 4-5 puffs of albuterol per day. The results of the largest of the trials are shown in the table below.

Mean Change from Baseline at Study End Point
*
p<0.05, compared to placebo
Zafirlukast 20 mg

twice daily

N=514

Placebo

N=248

Daytime Asthma symptom score

(0-3 scale)

-0.44*

-0.25

Nightime Awakenings

(number per week)

-1.27*

-0.43

Mornings with Asthma Symptoms

(days per week)

-1.32*

-0.75

Rescue β2 -agonist use

(puffs per day)

-1.15*

-0.24

FEV1 (L)

+0.15*

+0.05

Morning PEFR (L/min)

+22.06*

+7.63

Evening PEFR (L/min)

+13.12

+10.14

In a second and smaller study, the effect of zafirlukast on most efficacy parameters was comparable to the active control (inhaled cromolyn sodium 1600 mcg four times per day) and superior to placebo at end point for decreasing rescue beta2 -agonist use (figure below).

graph
(click image for full-size original)

In these trials, improvement in asthma symptoms occurred within one week of initiating treatment with zafirlukast. The role of zafirlukast in the management of patients with more severe asthma, patients receiving antiasthma therapy other than as-needed, inhaled beta2 -agonists, or as an oral or inhaled corticosteroid-sparing agent remains to be fully characterized.

INDICATIONS AND USAGE

Zafirlukast tablets are indicated for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.

CONTRAINDICATIONS

Zafirlukast tablets are contraindicated in patients who are hypersensitive to zafirlukast or any of its inactive ingredients.

WARNINGS

Hepatotoxicity:

Cases of life-threatening hepatic failure have been reported in patients treated with zafirlukast. Cases of liver injury without other attributable cause have been reported from post-marketing adverse event surveillance of patients who have received the recommended dose of zafirlukast (40 mg/day). In most, but not all post-marketing reports, the patient’s symptoms abated and the liver enzymes returned to normal or near normal after stopping zafirlukast. In rare cases, patients have either presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death. In extremely rare post-marketing cases, no clinical symptoms or signs suggestive of liver dysfunction were reported to precede the latter observations.

Physicians may consider the value of liver function testing. Periodic serum transaminase testing has not proven to prevent serious injury but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery.

Patients should be advised to be alert for signs and symptoms of liver dysfunction (eg, right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, and anorexia) and to contact their physician immediately if they occur. Ongoing clinical assessment of patients should govern physician interventions, including diagnostic evaluations and treatment.

If liver dysfunction is suspected based upon clinical signs or symptoms (eg, right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, anorexia, and enlarged liver), zafirlukast should be discontinued. Liver function tests, in particular serum ALT, should be measured immediately and the patient managed accordingly. If liver function tests are consistent with hepatic dysfunction, zafirlukast therapy should not be resumed. Patients in whom zafirlukast was withdrawn because of hepatic dysfunction where no other attributable cause is identified should not be re-exposed to zafirlukast (see PRECAUTIONS, Information for Patients and ADVERSE REACTIONS).

Bronchospasm:

Zafirlukast tablets are not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Therapy with zafirlukast can be continued during acute exacerbations of asthma.

Concomitant Warfarin Administration:

Coadministration of zafirlukast with warfarin results in a clinically significant increase in prothrombin time (PT). Patients on oral warfarin anticoagulant therapy and zafirlukast should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see PRECAUTIONS, Drug Interactions).

PRECAUTIONS

Information for Patients:

Patients should be told that a rare side effect of zafirlukast is hepatic dysfunction, and to contact their physician immediately if they experience symptoms of hepatic dysfunction (eg. right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, and anorexia). Liver failure resulting in liver transplantation and death has occurred in patients taking zafirlukast (see WARNINGS, Hepatotoxicity and ADVERSE REACTIONS).

Zafirlukast tablets are indicated for the chronic treatment of asthma and should be taken regularly as prescribed, even during symptom-free periods. Zafirlukast is not a bronchodilator and should not be used to treat acute episodes of asthma. Patients receiving zafirlukast should be instructed not to decrease the dose or stop taking any other antiasthma medications unless instructed by a physician. Patients should be instructed to notify their physician if neuropsychiatric events occur while using zafirlukast (see PRECAUTIONS, Neuropsychiatric Events).Women who are breast-feeding should be instructed not to take zafirlukast (see PRECAUTIONS, Nursing Mothers). Alternative antiasthma medication should be considered in such patients.

The bioavailability of zafirlukast may be decreased when taken with food. Patients should be instructed to take zafirlukast at least 1 hour before or 2 hours after meals.

Eosinophilic Conditions: In rare cases, patients with asthma on zafirlukast may present with systemic eosinophilia, eosinophilic pneumonia, or clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic steroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. These events have usually, but not always, been associated with the reduction and/or withdrawal of steroid therapy. The possibility that zafirlukast may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established (see ADVERSE REACTIONS).

Neuropsychiatric Events: Neuropsychiatric events have been reported in adult, adolescent and pediatric patients taking zafirlukast. Post-marketing reports with zafirlukast include insomnia and depression. The clinical details of some post-marketing reports involving zafirlukast appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with zafirlukast if such events occur (see ADVERSE REACTIONS).

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