This information is intended for use by health professionals

1. Name of the medicinal product

Accolate™ 20 mg film-coated tablets

2. Qualitative and quantitative composition

Each film-coated tablet contains 20 mg zafirlukast.

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.

3. Pharmaceutical form

Film-coated tablets.

White, round, biconvex, film-coated tablets intagliated with 'Accolate 20' on one side and plain on the reverse.

4. Clinical particulars
4.1 Therapeutic indications

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

4.2 Posology and method of administration

Accolate 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, Accolate 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 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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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.

4.4 Special warnings and precautions for use

General

Accolate 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 syndrome

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.

Hepatic effects

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 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 intolerance

Accolate 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.

4.5 Interaction with other medicinal products and other forms of interaction

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%.

Co-administration with fluconazole, a moderate CYP2C9 inhibitor, resulted in increased plasma levels of zafirlukast, by approximately 60%. The clinical significance of this interaction is unknown.

Co-administration with itraconazole, a strong CYP3A4 inhibitor, caused no change in plasma levels of zafirlukast.

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.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

In 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-feeding

Zafirlukast is excreted in human breast milk. Accolate should not be administered to mothers who are breast-feeding.

Fertility

In animal studies, zafirlukast did not have any apparent effect on fertility.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Tabulated list of adverse reactions

Administration 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

Not known

Agranulocytosis1,2

Immune system disorders

Uncommon

Hypersensitivity1

Angioedema1

Psychiatric disorders

Uncommon

Insomnia1

Not known

Nightmares

Nervous system disorders

Common

Headache

Not known

Hypoaesthesia/paraesthesia

Dizziness

Gastrointestinal disorders

Common

Nausea

Vomiting

Abdominal pain

Hepatobiliary disorders

Common

Elevations in transaminase levels

Uncommon

Hyperbilirubinemia

Rare

Hepatitis

Not known

Fulminant hepatitis2

Hepatic failure2

Skin and subcutaneous tissue disorders

Common

Rash1

Uncommon

Urticaria1

Pruritus1

Rare

Blister1

Musculoskeletal and connective tissue disorders

Common

Myalgia

Uncommon

Arthralgia

General disorders and administration site conditions

Uncommon

Oedema1

Malaise1

Injury poisoning and procedural complications

Rare

Bruising1

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 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 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

4.9 Overdose

Limited information exists with regard to the effects of overdosage of Accolate 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 Accolate.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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.

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 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.

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 safety

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 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.

5.2 Pharmacokinetic properties

Absorption

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 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 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.

5.3 Preclinical safety data

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 Accolate in man is uncertain.

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

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core

Croscarmellose sodium

Lactose Monohydrate

Magnesium Stearate E572

Microcrystalline Cellulose E460

Povidone

Film-coating

Hypromellose E464

Titanium Dioxide E171

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

Aluminium laminate/foil blister packs containing 56 or 100 tablets.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

AstraZeneca UK Limited,

600 Capability Green,

Luton, LU1 3LU, UK.

8. Marketing authorisation number(s)

PL 17901/0001

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 1st June 2000

10. Date of revision of the text

18th March 2016