Plot 1 Junaid Dosunmu Street,Central Business District, Alausa, P.0. Box 3560 Ikeja, Lagos, Nigeria.
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AstraZeneca, Silk Court, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, England
Dosage Form, Composition & NAFDAC Registration Number (NRN)
Tablet (NRN: 04-1838): Zafirlukast 20 mg; film-coated tablet.
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 receptors found in the human airway. Leukotriene production and receptor occupation have been implicated in the pathophysiology of asthma. Effects include smooth muscle contraction, airway oedema and altered cell activity associated with the inflammatory process, including eosinophil influx to the lung.
Accolate is a competitive highly selective and potent oral peptide leukotriene antagonist of LTC4, LTD4 and LTE4 components of slow-reacting substance of anaphylaxis. In vitro studies have shown that Accolate antagonises the contractile activity of all three peptide leukotrienes (leukotriene C4, D4 and E4) in human conducting airway smooth muscle to the same extent. Animal studies have shown Accolate to be effective in preventing peptide leukotriene-induced increases in vascular permeability, which give rise to oedema in the airways, and to inhibit peptide leukotriene-induced influx of eosinophils into airways.
The specificity of Accolate has been shown by its action on leukotriene receptors and not prostaglandin, thromboxane, cholinergic and histamine receptors.
In a placebo-controlled study where segmental broncho-provocation with allergen was followed by bronchoalveolar lavage 48 hours later, zafirlukast decreased the rise in basophils, lymphocytes and histamine, and reduced the stimulated production of superoxide by alveolar macrophages.
Accolate attenuated the increase in bronchial hyper-responsiveness that follows inhaled allergen challenge. Further, methacholine sensitivity was diminished by long-term dosing with Accolate 20 mg twice daily.
Further, in clinical trials evaluating chronic therapy with Accolate, the lung function measured when plasma levels were at trough showed sustained improvements over baseline.
Accolate shows a dose dependent inhibition of bronchoconstriction induced by inhaled LTD4. Asthmatic patients are approximately 10-fold more sensitive to the bronchoconstricting activity of inhaled LTD4. A single oral dose of Accolate can enable an asthmatic patient to inhale 100 times more LTD4 and shows significant protection at 12 and 24 hours.
Accolate inhibits the bronchoconstriction caused by several kinds of challenge, such as the response to sulphur dioxide, exercise and cold air. Accolate attenuates the early and late phase inflammatory reaction caused by various antigens such as grass, cat dander, ragweed and mixed antigens.
In asthmatic patients not adequately controlled by beta-agonist therapy (given as required), Accolate improves symptoms (reducing daytime and nocturnal asthmatic symptoms), improves lung function, reduces the need for concomitant beta-agonist medication and reduces incidence of exacerbation. Similarly, benefits have been seen in patients with more severe asthma receiving high dose inhaled steroids. In clinical studies, there was a significant first-dose effect on baseline bronchomotor tone observed within 2 hours of dosing, when peak plasma concentrations had not yet been achieved. Initial improvements in asthma symptoms occurred within the first week, and often the first few days, of treatment with Accolate.
Pharmacokinetic Properties: Peak plasma concentrations of zafirlukast are achieved approximately 3 hours after oral administration of Accolate.
Administration of Accolate with food increased the variability in the bioavailability of zafirlukast and reduced bioavailability in most (75%) subjects. The net reduction was approximately 40%.
Following twice-daily administration of Accolate (30 to 80 mg bid), accumulation of zafirlukast in plasma was low (not detectable - 2.9 times first dose values; mean 1.45; median 1.27). The terminal half-life of zafirlukast is approximately 10 hours. Steady-state plasma concentrations of zafirlukast were proportional to the dose and predictable from single-dose pharmacokinetic data.
Zafirlukast is extensively metabolised. Following a radiolabeled dose, the urinary excretion accounts for approximately 10% dose and faecal excretion for 89%. Zafirlukast is not detected in urine. The metabolites identified in human plasma were found to be at least 90-fold less potent than zafirlukast in a standard in vitro test of activity.
Zafirlukast is approximately 99% protein bound to human plasma proteins, predominantly albumin, over the concentration range 0.25 to 4.0 microgram/mL.
Pharmacokinetic studies in special populations have been performed in a relatively smaller number of subjects, and the clinical significance of the following kinetic data is not established.
Pharmacokinetics of zafirlukast in adolescents and adults with asthma were similar to those of healthy adult males. When adjusted for body weight, the pharmacokinetics of zafirlukast are not significantly different between men and women.
Elderly subjects and subjects with stable alcoholic cirrhosis demonstrated an approximately two-fold increase in Cmax and AUC compared to normal subjects given the same doses of Accolate.
There are no significant differences in the pharmacokinetics of zafirlukast in patients with mild renal impairment and in normal subjects. However, there are no conclusive data available in patients with moderate or severe renal impairment, hence the recommendation for caution is used in this patient population.
Accolate is indicated for the treatment of asthma.
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 exacerbation of asthma.
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. Inhaled and oral corticosteroids should not be stopped abruptly after initiation of Accolate.
Rarely, patients with asthma on anti-leukotriene medications, including Accolate, may present with systemic eosinophilia, eosinophilic pneumonia or with clinical features of systemic vasculitis, consistent with Churg-Strauss syndrome. Presentations may involve various body systems including vasculitic rash, worsening pulmonary symptoms, cardiac complications or neuropathy. These events have usually, but not always, been associated with reductions and/or withdrawal of steroid therapy. The possibility that leukotriene receptor antagonists, including Accolate, may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established. 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 (See also “Adverse Effects”).
If clinical symptoms or signs suggestive of liver dysfunction occur (e.g. 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 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.
Pregnancy and Lactation:
The safety of Accolate in human pregnancy has not been established. In animal studies, zafirlukast did not have any apparent effect on fertility and did not appear to have any teratogenic or selective toxic effect on the foetus. The potential risks should be weighed against the benefits of continuing therapy during pregnancy and Accolate should be used during pregnancy only if clearly needed.
Zafirlukast is excreted in human breast milk. Accolate should not be administered to mothers who are breastfeeding.
Effects on Ability to Drive and Use Machines:
There is no evidence that Accolate affects the ability to drive and use machinery.
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.
Administration of Accolate in clinical trials against placebo has been associated with headache (9.9% vs 9.0%) or gastro-intestinal disturbance (nausea 2.6% vs 2.2%, vomiting 1.2% vs 1.0%, diarrhoea 2.3% vs 1.8%, abdominal pain 1.6% vs 1.2%). These symptoms are usually mild and do not necessitate withdrawal from therapy.
Hypersensitivity reactions, including urticaria and angio-oedema have been reported. Rashes, including blistering, have also been reported. Infrequently, elevated serum transaminase levels have been observed in clinical trials against placebo with Accolate (increased ALT 1.0% vs 0.9%, increased AST 0.6% vs 0.6%); at recommended doses the incidence was equivalent to placebo. Rarely the transaminases profile has been consistent with drug-induced hepatitis which resolved following cessation of ‘Accolate’ 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.
Dosage & Administration
Accolate should be taken continuously.
Adults and Children aged 12 years and over: 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.
Elderly: The clearance of zafirlukast is significantly reduced in elderly patients (over 65 years old), such that Cmax 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.
Children: 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.
Renal Impairment: Experience is limited in patients with mild to severe renal impairment (See “Pharmacokinetics”) so clear dose recommendations cannot be given; therefore Accolate should be used with caution in this patient group.
Overdosage: No information exists with regard to the effect of overdosage of Accolate in humans.
Management should be supportive. Removal of excess medication by gastric lavage and/or instillation of charcoal may be helpful
Store below 30oC