Leukotriene receptor antagonists.

Zafirlukast

White f-c tablet marked with company name, tablet name and strength.

Tablets, zafirlukast 20mg .

Treatment of asthma.

The dosage is one 20 mg tablet twice daily. This dosage should not be exceeded. Higher doses may be associated with elevations of one or more liver enzymes consistent with hepatotoxicity.

As food may reduce the bioavailability of zafirlukast, 'Accolate' should not be taken with meals.

Renal impairment:

No dosage adjustment is necessary in patients with mild renal impairment. However, experience is limited in patients with moderate to severe renal impairment so clear dose recommendations cannot be given; 'Accolate' should be used with caution in this patient group.

There is no clinical experience of the use of 'Accolate' in children under 12 years of age.

Until safety information is available, the use of 'Accolate' in children is contraindicated.

The clearance of zafirlukast is significantly reduced in elderly patients (over 65 years old), and C_max and AUC are approximately double those of younger adults. However, accumulation of zafirlukast is no greater than that seen in multiple-dose trials conducted in adult subjects with asthma, and the consequences of the altered kinetics in the elderly are unknown.

Clinical experience with 'Accolate' in the elderly (over 65 years) is limited and caution is recommended until further information is available.

'Accolate' should not be given to patients who have previously experienced hypersensitivity to the product or any of its ingredients.

'Accolate' is contraindicated in patients with hepatic impairment or cirrhosis; it has not been studied in patients with hepatitis or in long term studies of patients with cirrhosis.

'Accolate' is contraindicated in children under 12 years of age until safety information is available.

'Accolate' should be taken regularly to achieve benefit, even during symptom free periods. 'Accolate' therapy should normally be continued during acute exacerbations of asthma.

'Accolate' does not allow a reduction in existing steroid treatment.

As with inhaled steroids and cromones (disodium cromoglycate, nedocromil sodium), 'Accolate' is not indicated for use in the reversal of bronchospasm in acute asthma attacks.

'Accolate' has not been evaluated in the treatment of labile (brittle) or unstable asthma.

Cases of eosinophilic conditions, including Churg-Strauss Syndrome and eosinophilic pneumonia have been reported in association with Accolate usage. Presentations may involve various body systems including vasculitic rash, worsening pulmonary symptoms, cardiac complications or neuropathy. A causal relationship has neither been confirmed nor refuted. If a patient develops an eosinophilic condition, or a Churg-Strauss Syndrome type illness, Accolate should be stopped. A rechallenge test should not be performed and treatment should not be restarted.

Elevations in serum transaminases can occur during treatment with 'Accolate'. These are usually asymptomatic and transient but could represent early evidence of hepatotoxicity, and have very rarely been associated with more severe hepatocellular injury, fulminant hepatitis and liver failure, some of which resulted in a fatal outcome.. Extremely rarely, cases of fulminant hepatitis and liver failure have been reported in patients in whom no previous clinical signs or symptoms suggestive of liver dysfunction were reported.

If clinical symptoms or signs suggestive of liver dysfunction occur (e.g. anorexia, nausea, vomiting, right upper quadrant pain, fatigue, lethargy, flu-like symptoms, enlarged liver, pruritus and jaundice), Accolate should be discontinued. The serum transaminases, in particular serum ALT, should be measured immediately and the patient managed accordingly.

Physicians may consider the value of routine liver function testing. Periodic serum transaminase testing has not proven to prevent serious injury but is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug may enhance the likelihood of recovery. If liver function testing shows evidence of hepatotoxicity 'Accolate' should be discontinued immediately and the patient managed accordingly.

Patients in whom 'Accolate' was withdrawn because of hepatotoxicity should not be re-exposed to 'Accolate'.

'Accolate' may be administered with other therapies routinely used in the management of asthma and allergy. Inhaled steroids, inhaled and oral bronchodilator therapy, antibiotics and antihistamines are examples of agents which have been co-administered with 'Accolate' without adverse interaction.

'Accolate' may be administered with oral contraceptives without adverse interaction.

Co-administration with warfarin results in an increase in maximum prothrombin time by approximately 35%. It is therefore recommended that if 'Accolate' is co-administered with warfarin, prothrombin time should be closely monitored. The interaction is probably due to an inhibition by zafirlukast of the cytochrome P450 2C9 isoenzyme system.

In clinical trials co-administration with theophylline resulted in decreased plasma levels of zafirlukast, by approximately 30%, but with no effect on plasma theophylline levels. However, during post-marketing surveillance, there have been rare cases of patients experiencing increased theophylline levels when co-administered 'Accolate'.

Co-administration with terfenadine resulted in a 54% decrease in AUC for zafirlukast, but with no effect on plasma terfenadine levels.

Co-administration with acetylsalicylic acid ("aspirin", 650 mg four times a day) may result in increased plasma levels of zafirlukast, by approximately 45%.

Co-administration with erythromycin will result in decreased plasma levels of zafirlukast, by approximately 40%.

The clearance of zafirlukast in smokers may be increased by approximately 20%.

At concentrations of 10 microgram/ml and above, zafirlukast causes increases in the assay value for bilirubin in animal plasma. However, zafirlukast has not been shown to interfere with the 2,5-dichlorophenyl diazonium salt method of bilirubin analysis of human plasma.

The following have been reported in association with the administration of 'Accolate':

The above events have usually resolved following cessation of therapy. Headache and gastrointestinal disturbance are usually mild and do not necessitate withdrawal from therapy.

In placebo-controlled clinical trials, an increased incidence of infection has been observed in elderly patients given 'Accolate' (7.8% vs 1.4%). Infections were usually mild, predominantly affecting the respiratory tract.

AstraZeneca

(POM)

11 May 2012