Accoleit

Accoleit is indicated in adults and children aged 12 years and over for the treatment of asthma.

Accoleit should be taken continuously.

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, Accoleit should not be taken with meals. Each tablet should be swallowed whole with a drink of water.

Special populations

Elderly:

The clearance of zafirlukast is reduced in elderly patients (> 65 years old), such that C_max and AUC are approximately twice those of younger adults. However, accumulation of Accoleit 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, Accoleit should be used with caution in these patients.

Paediatric population:

The safety and efficacy of Accoleit in children under 12 years has not been established. The use of Accoleit in children under 12 years is contraindicated.

Accoleit 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.

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

General

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

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

Accoleit 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 Accoleit.

Eosinophilia including Churg-Strauss syndrome

Rarely, patients with asthma on anti-leukotriene medications, including Accoleit, 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 Accoleit, 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, Accoleit should be stopped. A rechallenge test should not be performed and treatment should not be restarted.

Hepatic effects

Elevations in serum transaminases can occur during treatment with Accoleit. 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), Accoleit 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 Accoleit should be discontinued immediately and the patient managed accordingly. Patients in whom Accoleit was withdrawn because of hepatotoxicity should not be re-exposed to Accoleit.

Lactose intolerance

Accoleit 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.

Accoleit has no or negligible influence on the ability to drive and use machines.

Tabulated list of adverse reactions

Administration of Accoleit 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)).

1 These events have usually resolved following cessation of therapy.

2 Frequency is based on post-marketing data.

Description of selected adverse events

Hepatic Effects:

Elevated serum transaminase levels have been observed in clinical trials with Accoleit. 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 Accoleit therapy.

Hyperbilirubinemia without elevated liver function tests has also been associated with the use of Accoleit.

During post-marketing experience there have been rare reports of symptomatic hepatitis, with and without hyperbilirubinemia, associated with the use of Accoleit. These cases have usually resolved following cessation of therapy with Accoleit. The predominate majority of cases have been reported in females.

Infection:

In placebo-controlled clinical trials, an increased incidence of infection has been observed in elderly patients given Accoleit. Infections were usually mild, predominantly affecting the respiratory tract and not necessitating withdrawal from therapy with Accoleit.

Reporting of suspected adverse reactions

Reporting 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

Limited information exists with regard to the effects of overdosage of Accoleit in humans.

Management

Management should be supportive. Gastric lavage and/or installation of charcoal may be considered in selected cases of the excessive overdose of Accoleit.

Pharmacotherapeutic Group: Leukotriene receptor antagonists, ATC code: R03D C01.

Mechanism of action

The 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.

Accoleit 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 Accoleit 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 Accoleit 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 Accoleit has been shown by its action on leukotriene receptors and not prostaglandin, thromboxane, cholinergic and histamine receptors.

Pharmacodynamic effects

In 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.

Accoleit attenuated the increase in bronchial hyperresponsiveness that follows inhaled allergen challenge. Further, methacholine sensitivity was diminished by long-term dosing with Accoleit 20 mg twice daily.

Further, in clinical trials evaluating chronic therapy with Accoleit, the lung function measured when plasma levels were at trough showed sustained improvements over baseline.

Accoleit 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 Accoleit can enable an asthmatic patient to inhale 100 times more LTD₄ and shows significant protection at 12 and 24 hours.

Accoleit inhibits the bronchoconstriction caused by several kinds of challenge, such as the response to sulphur dioxide, exercise and cold air. Accoleit attenuates the early and late phase inflammatory reaction caused by various antigens such as grass, cat dander, ragweed and mixed antigens.

Clinical efficacy and safety

In asthmatic patients not adequately controlled by beta-agonist therapy (given as required) Accoleit 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 Accoleit.

Absorption

Peak plasma concentrations of zafirlukast are achieved approximately 3 hours after oral administration of Accoleit.

Administration of Accoleit 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 Accoleit (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.

Distribution

Zafirlukast is approximately 99% protein bound to human plasma proteins, predominantly albumin, over the concentration range 0.25 to 4.0 microgram/ml.

Biotransformation

Zafirlukast 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.

Elimination

The 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-linearity

Steady state plasma concentrations of zafirlukast were proportional to the dose and predictable from single-dose pharmacokinetic data.

Special populations

Pharmacokinetic 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 C_max and AUC compared to normal subjects given the same doses of Accoleit.

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.

After multiple doses of greater than 40 mg/kg/day for up to 12 months, liver enlargement associated with degenerative/fatty change or glycogen deposition was seen in rats, mice and dogs. Histiocytic aggregates were seen in a number of tissues of dogs.

Male mice given 300 mg/kg zafirlukast daily had an increased incidence of hepatocellular adenomas compared to control animals. Rats given 2000 mg/kg zafirlukast daily had an increased incidence of urinary bladder papilloma compared to control animals. Zafirlukast was not mutagenic in a range of tests. The clinical significance of these findings during the long-term use of Accoleit in man is uncertain.

There were no other notable findings from the pre-clinical testing.

Not applicable.

No special requirements.