Foradil ®

Active substance: (±)2'Hydroxy5'[(RS)1hydroxy2[[(RS)pmethoxy-a-methylphenethyl]amino] ethyl] formanilide fumarate dihydrate (= formoterol fumarate).

One capsule contains 12 micrograms formoterol fumarate.

Inhalation powder in capsules.

Foradil is indicated in asthma (including nocturnal asthma and exercise-induced symptoms) for those treated with inhaled corticosteroids who also require a long-acting beta agonist in accordance with current treatment guidelines.

Foradil is indicated for the relief of reversible airways obstruction in patients with chronic obstructive pulmonary disease (COPD) requiring long-term bronchodilatory therapy.

For use in adults (including the elderly)

Asthma

Regular maintenance therapy: 1 inhalation capsule (12 micrograms) to be inhaled twice daily. For more severe cases 2 inhalation capsules to be inhaled twice daily. This dosing regimen provides symptomatic relief throughout day and night.

Chronic Obstructive Pulmonary Disease

1 inhalation capsule to be inhaled twice daily.

For use in children aged 5 and above

Asthma

Regular maintenance therapy: 1 inhalation capsule (12 micrograms) to be inhaled twice daily. For more severe cases the dose may be increased to 2 inhalation capsules to be inhaled twice daily after assessment by a physician.

Foradil should be taken twice daily. The maximum daily dose is 24 micrograms b.i.d. (4 capsules).

Although Foradil has a rapid onset of action, current asthma management guidelines recommend that long-acting inhaled bronchodilators should be used for maintenance bronchodilator therapy. They further recommend that in the event of an acute attack, a beta -agonist with a short duration of action should be used.

In accordance with the current management guidelines, long-acting beta 2-agonists may be added to the treatment regimen in patients experiencing problems with high dose inhaled steroids. Alternatively, where regular symptomatic treatment of asthma is required in addition to inhaled steroids, then long-acting beta 2-agonists can be used. Patients should be advised not to stop or change their steroid therapy when Foradil is introduced.

If the symptoms persist or worsen, or if the recommended dose of Foradil fails to control symptoms (maintain effective relief), this is usually an indication of a worsening of the underlying condition.

Chronic Obstructive Pulmonary Disease

Not appropriate.

Children under 5 yearsForadil is not recommended in children under the age of 5 years.

Renal and hepatic impairment

There is no theoretical reason to suggest that Foradil dosage requires adjustment in patients with renal or hepatic impairment, however no clinical data have been generated to support its use in these groups.

Hypersensitivity to formoterol fumarate or lactose.

In the treatment of asthma

Foradil should not be used (and is not sufficient) as the first treatment for asthma.

Asthmatic patients who require regular therapy with a beta 2-agonist should also receive regular and adequate doses of an inhaled anti-inflammatory agent (e.g. corticosteroids, and/or sodium cromoglicate) or oral corticosteroids. Whenever Foradil is prescribed, patients should be evaluated for the adequacy of the anti-inflammatory therapy they receive. Patients must be advised to continue taking anti-inflammatory therapy unchanged after the introduction of Foradil, even when their symptoms improve. Should symptoms persist, or should the number of doses of Foradil required to control symptoms increase, this usually indicates a worsening of the underlying condition and warrants a reassessment of asthma therapy by a physician.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Foradil. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Foradil should be used.

Although Foradil may be introduced as add-on therapy when inhaled anti-inflammatory agents (e.g. corticosteroids) do not provide adequate control of asthma symptoms, patients should not be initiated on Foradil during an acute severe asthma exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Serious asthma-related adverse events and exacerbations may occur during treatment with Foradil. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled, or worsen, after initiation on Foradil.

Concomitant conditions

Special care and supervision, with particular emphasis on dosage limits, is required in patients receiving Foradil when the following conditions may exist:

Ischaemic heart disease, cardiac arrhythmias, especially third degree atrioventricular block, severe cardiac decompensation, idiopathic subvalvular aortic stenosis, hypertrophic obstructive cardiomyopathy, thyrotoxicosis, known or suspected prolongation of the QT interval (QTc> 0.44 sec.; see section 4.5).

Caution should be used when co-administering theophylline and formoterol in patients with pre-existing cardiac conditions.

Due to the hyperglycaemic effect of beta 2stimulants, additional blood glucose controls are recommended in diabetic patients.

Hypokalaemia

Potentially serious hypokalaemia may result from beta 2-agonist therapy. Particular caution is advised in severe asthma as this effect may be potentiated by hypoxia and concomitant treatment (see section 4.5). It is recommended that serum potassium levels be monitored in such situations.

Paradoxical bronchospasm

As with other inhalation therapy, the potential for paradoxical bronchospasm should be kept in mind. If it occurs, the preparation should be discontinued immediately and alternative therapy substituted.

There are no clinical data to support the advice given below, but from consideration of first principles one might expect the following interactions:

Drugs such as quinidine, disopyramide, procainamide, phenothiazines, antihistamines, and tricyclic antidepressants may be associated with QT-interval prolongation and an increased risk of ventricular arrhythmia (see section 4.4).

Concomitant administration of other sympathomimetic agents may potentiate the undesirable effects of Foradil.

Administration of Foradil to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants should be performed with caution, since the action of beta 2-adrenergic stimulants on the cardiovascular system may be potentiated.

Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate a possible hypokalaemic effect of beta 2-agonists. Hypokalaemia may increase susceptibility to cardiac arrhythmias in patients treated with digitalis (see section 4.4).

Beta -adrenergic blockers may weaken or antagonise the effect of Foradil. Therefore Foradil should not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons for their use.

There were no teratogenic effects revealed in animal tests. However, until further experience is gained, Foradil is not recommended for use during pregnancy (particularly at the end of pregnancy or during labour) unless there is no more established alternative. As with any medicine, use during pregnancy should only be considered if the expected benefit to the mother is greater than any risk to the foetus. The substance has been detected in the milk of lactating rats, but it is not known whether formoterol passes into human breast milk, therefore mothers using Foradil should refrain from breast feeding their infants.

Patients experiencing dizziness or other similar side effects should be advised to refrain from driving or using machines.

Adverse reactions are ranked in descending order of frequency, as follows:

very common ( 1/10)

common ( 1/100, < 1/10)

uncommon ( 1/1,000, < 1/100)

rare ( 1/10,000, <1/1,000)

very rare ( < 1/10,000), including isolated reports.

Symptoms

There is no clinical experience to date on the management of overdose, however, an overdosage of Foradil would be likely to lead to effects that are typical of beta 2-adrenergic agonists: nausea, vomiting, headache, tremor, somnolence, palpitations, tachycardia, ventricular arrhythmias, metabolic acidosis, hypokalaemia, hyperglycaemia.

Treatment

Supportive and symptomatic treatment is indicated. Serious cases should be hospitalised.

Use of cardioselective beta-blockers may be considered, but only subject to extreme caution since the use of beta -adrenergic blocker medication may provoke bronchospasm.

Serum potassium should be monitored.

Formoterol is a potent selective beta 2-adrenergic stimulant. It exerts a bronchodilator effect in patients with reversible airways obstruction. The effect sets in rapidly (within 1-3 minutes) and is still significant 12 hours after inhalation.

In man, Foradil has been shown to be effective in preventing bronchospasm induced by exercise and methacholine.

Formoterol has been studied in the treatment of conditions associated with COPD, and has been shown to improve symptoms and pulmonary function and quality of life. Formoterol acts on the reversible component of the disease.

Foradil has a therapeutic dose range of 12 to 24 micrograms b.i.d. Data on the plasma pharmacokinetics of formoterol were collected in healthy volunteers after inhalation of doses higher than the recommened range and in COPD patients after inhalation of therapeutic doses. Urinary excretion of unchanged formoterol, used as an indirect measure of systemic exposure, correlates with plasma drug disposition data. The elimination half-lives calculated for urine and plasma are similar.

Absorption

Following inhalation of a single 120 microgram dose of formoterol fumarate by healthy volunteers, formoterol was rapidly absorbed into plasma, reaching a maximum concentration of 266 pmol/l within 5 minutes of inhalation. In COPD patients treated for 12 weeks with formoterol fumarate 12 or 24 micrograms b.i.d. the plasma concentrations of formoterol ranged between 11.5 and 25.7 pmol/L and 23.3 and 50.3 pmol/L respectively at 10 minutes, 2 hours and 6 hours post inhalation.

Studies investigating the cumulative urinary excretion of formoterol and/or its (R,R) and (S,S)-enantiomers, after inhalation of dry powder (12-96 micrograms) or aerosol formulations (12-96 micrograms), showed that absorption increased linearly with the dose.

After 12 weeks administration of 12 micrograms or 24 micrograms formoterol powder b.i.d., the urinary excretion of unchanged formoterol increased by 63-73% in adult patients with asthma, by 19-38% in adult patients with COPD and by 18-84% in children, suggesting a modest and self-limiting accumulation of formoterol in plasma after repeated dosing.

As reported for other inhaled drugs, it is likely that about 90% of formoterol administered from an inhaler will be swallowed and then absorbed from the gastrointestinal tract. This means that the pharmacokinetic characteristics of the oral formulation largely apply also to the inhalation powder. When 80 micrograms of ³H-labelled formoterol fumarate was orally administered to two healthy volunteers, at least 65% of the drug was absorbed.

Distribution

The plasma protein binding of formoterol is 61-64% (34% primarily to albumin).

There is no saturation of binding sites in the concentration range reached with therapeutic doses.

Biotransformation

Formoterol is eliminated primarily by metabolism, direct glucuronidation being the major pathway of biotransformation, with O-demethylation followed by further glucuronidation being another pathway. Minor pathways involve sulphate conjugation of formoterol and deformylation followed by sulphate conjugation. Multiple isozymes catalyze the glucuronidation (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2B15) and O-demethylation (CYP2D6, 2C19, 2C9, and 2A6) of formoterol, and so consequently the potential for metabolic drug-drug interaction is low. Formoterol did not inhibit cytochrome P450 isozymes at therapeutically relevant concentrations.The kinetics of formoterol are similar after single and repeated administration, indicating no auto-induction or inhibition of metabolism.

Elimination

In asthmatic and COPD patients treated for 12 weeks with 12 or 24 micrograms formoterol fumarate b.i.d., approximately 10% and 7% of the dose, respectively, were recovered in the urine as unchanged formoterol. In asthmatic children, approximately 6% of the dose was recovered in the urine as unchanged formoterol after multiple dosing of 12 and 24 micrograms. The (R,R) and (S,S)-enantiomers accounted, respectively, for 40% and 60% of urinary recovery of unchanged formoterol, after single doses (12 to 120 micrograms) in healthy volunteers and after single and repeated doses in asthma patients.

After a single oral dose of ³H-formoterol, 59-62% of the dose was recovered in the urine and 32-34% in the faeces. Renal clearance of formoterol is 150 mL/min.

After inhalation, plasma formoterol kinetics and urinary excretion rate data in healthy volunteers indicate a biphasic elimination, with the terminal elimination half-lives of the (R,R)- and (S,S)-enantiomers being 13.9 and 12.3 hours, respectively.

Approximately 6.4-8% of the dose was recovered in the urine as unchanged formoterol, with the (R,R) and (S,S)-enantiomers contributing 40% and 60% respectively.

Mutagenicity

Mutagenicity tests covering a broad range of experimental endpoints have been conducted. No genotoxic effects were found in any of the in vitro or in vivo tests performed.

Carcinogenicity

Two-year studies in rats and mice did not show any carcinogenic potential.

Male mice treated at very high dose levels showed a slightly higher incidence of benign adrenal subcapsular cell tumours, which are considered to reflect alterations in the physiological ageing process.

Two studies in rats, covering different dose ranges, showed an increase in mesovarial leiomyomas. These benign neoplasms are typically associated with long-term treatment of rats at high doses of 2-adrenergic drugs. Increased incidences of ovarian cysts and benign granulosa/theca cell tumours were also seen; beta -agonists are known to have effects on the ovary in rats in which are very likely specific to rodents. A few other tumour types noted in the first study using the higher doses were within the incidences of the historical control population, and were not seen in the lower-dose experiment.

None of the tumour incidences were increased to a statistically significant extent at the lowest dose of the second study, a dose leading to a systemic exposure 10 times higher than that expected from the maximum recommended dose of formoterol.

On the basis of these findings and the absence of a mutagenic potential, it is concluded that use of formoterol at therapeutic doses does not present a carcinogenic risk.

Reproduction toxicity

Animal tests showed no teratogenic effects; after oral administration, formoterol was excreted in the milk of lactating rats.

Lactose, gelatin.

None known.

2 years in Alu/Alu blisters

In Alu/Alu blisters: protect from moisture (store below 25°C).

Blister calendar packs of 60 capsules, with an inhaler device in each pack.

To ensure proper administration of the drug, the patient should be shown how to use the inhaler by a physician or other health professional.

It is important for the patient to understand that the gelatin capsule may very occasionally break up and small pieces of gelatin might reach the mouth or throat after inhalation. The patient may be reassured that gelatin is harmless and will soften in the mouth and can be swallowed. The tendency for the capsule to break up is minimised by not piercing the capsule more than once.

The capsules should be removed from the blister strip only immediately before use.

PL 00101/0494

20 March 2003

15 November 2006

POM