POM: Prescription only medicine
This information is intended for use by health professionals
Excipient with known effect:Each tablet contains 45 mg lactose monohydrate (see section 4.4).For the full list of excipients, see section 6.1.
Posology: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. Each tablet should be swallowed whole with a drink of water.
Elderly:The clearance of zafirlukast is reduced in elderly patients (> 65 years old), such that Cmax and AUC are approximately twice those of younger adults. However, accumulation of Accolate is not evident in elderly patients. In clinical trials, elderly patients receiving a dose of 20 mg twice daily were not associated with an increase in the overall incidence of adverse events or withdrawals because of adverse events. Therapy may be initiated at 20 mg twice daily and adjusted according to clinical response.
Patients with renal impairment:Experience is limited in patients with mild to severe renal impairment, so clear dose recommendations cannot be given. Therefore, Accolate should be used with caution in these patients (see section 5.2).
Paediatric population:The safety and efficacy of Accolate in children under 12 years has not been established. The use of Accolate in children under 12 years is contraindicated.
GeneralAccolate should be taken regularly to achieve benefit, even during symptom free periods. Accolate therapy should normally be continued during acute exacerbations 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.
Eosinophilia including Churg-Strauss syndromeRarely, 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.
Hepatic effectsElevations 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 section 4.8).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.
Lactose intoleranceAccolate 20 mg contains 45 mg lactose monohydrate in each tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp Lactase deficiency or glucose-galactose malabsorption, should not take this medicine.
PregnancyIn animal studies, zafirlukast did not appear to have any teratogenic or selective toxic effect on the foetus. However, the safety of Accolate in human pregnancy has not been established. 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.
Breast-feedingZafirlukast is excreted in human breast milk. Accolate should not be administered to mothers who are breast-feeding.
FertilityIn animal studies, zafirlukast did not have any apparent effect on fertility.
Tabulated list of adverse reactionsAdministration of Accolate may be associated with the following undesirable effects. The reactions are classified according to frequency (Very common ≥1/10, Common ≥1/100 to <1/10; Uncommon ≥1/1,000 to <1/100; Rare ≥1/10,000 to <1/1,000; Very rare <1/10,000; Not known (cannot be estimated from available data)).
|System Organ Class||Frequency||Undesirable Effect|
|Infections and infestations||Very common||Infection|
|Blood and lymphatic system disorders||Rare||Bleeding disorders including menorrhagia, thrombocytopenia1|
|Immune system disorders||Uncommon||Hypersensitivity1|
|Nervous system disorders||Common||Headache|
|Not known||Hypoaesthesia/paraesthesia Dizziness|
|Gastrointestinal disorders||Common||Nausea Vomiting Abdominal pain|
|Hepatobiliary disorders||Common||Elevations in transaminase levels|
|Not known||Fulminant hepatitis2 Hepatic failure2|
|Skin and subcutaneous tissue disorders||Common||Rash1|
|Musculoskeletal and connective tissue disorders||Common||Myalgia|
|General disorders and administration site conditions||Uncommon||Oedema1 Malaise1|
|Injury poisoning and procedural complications||Rare||Bruising1|
Description of selected adverse events
Hepatic Effects:Elevated serum transaminase levels have been observed in clinical trials with Accolate. The changes usually resolved during continued treatment or following cessation of therapy. Rarely the transaminase profile has been consistent with a drug-induced hepatitis, which resolved following cessation of Accolate therapy.Hyperbilirubinemia without elevated liver function tests has also been associated with the use of Accolate.During post-marketing experience there have been rare reports of symptomatic hepatitis, with and without hyperbilirubinemia, associated with the use of Accolate. These cases have usually resolved following cessation of therapy with Accolate. The predominate majority of cases have been reported in females (see section 4.4).
Infection:In placebo-controlled clinical trials, an increased incidence of infection has been observed in elderly patients given Accolate. Infections were usually mild, predominantly affecting the respiratory tract and not necessitating withdrawal from therapy with Accolate.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard
Mechanism of actionThe cysteinyl leukotrienes (LTC4, LTD4 and 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 has 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.
Pharmacodynamic effectsIn a placebo-controlled study where segmental bronchoprovocation 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 hyperresponsiveness 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.
Clinical efficacy and safetyIn 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 exacerbations. Similar 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.
AbsorptionPeak 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 bd), accumulation of zafirlukast in plasma was low (not detectable - 2.9 times first dose values; mean 1.45; median 1.27).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.
DistributionZafirlukast is approximately 99% protein bound to human plasma proteins, predominantly albumin, over the concentration range 0.25 to 4.0 microgram/ml.
BiotransformationZafirlukast is extensively metabolised. 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.
EliminationThe terminal half-life of zafirlukast is approximately 10 hours. Following a radiolabelled dose of zafirlukast approximately 10% of the radioactivity was recovered in the urine and 89% was recovered in the faeces.
Linearity/non-linearitySteady state plasma concentrations of zafirlukast were proportional to the dose and predictable from single-dose pharmacokinetic data.
Special populationsPharmacokinetic studies in special populations have been performed in a relatively small number of subjects, and the clinical significance of the following kinetic data is not established.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.
Tablet coreCroscarmellose sodium Lactose Monohydrate Magnesium Stearate E572 Microcrystalline Cellulose E460 Povidone
Film-coatingHypromellose E464Titanium Dioxide E171
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