Section 4.8 - update name and contact details of HA from IMB to HPRA.

Section 4.2 added:

"To ensure proper administration of the drug, a physician or other health professional should:

· Show the patient how to use the inhaler.

· Dispense the capsule only together with the inhaler.

· Instruct the patient that the capsules are only for inhalation use and not to be swallowed (see section 4.4 Special Warnings and precautions for use).

Detailed handling instructions are included in the package leaflet.

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

and

"Special populations
Renal impairment

Formoterol has not been studied in patients with renal impairment (see section 5.2 Pharmacokinetic properties).

Hepatic impairment

Formoterol has not been studied in patients with hepatic impairment (see section 5.2 Pharmacokinetic properties).

Geriatrics (older than 65 years)

The pharmacokinetics of formoterol has not been studied in the elderly population (See section 5.2 Pharmacokinetic properties). The available data from clinical trials performed in elderly patients do not suggest that the dosage should be different than in other adults (see section 5.2 Pharmacokinetic properties)."

Section 4.4 added:
"Incorrect route of administration

There have been reports of patients who have mistakenly swallowed Foradil capsules instead of placing the capsules in the Aerolizer inhalation device. The majority of these ingestions were not associated with side effects. Healthcare providers should discuss with the patient how to correctly use Foradil Aerolizer (see section 4.2 Posology and method of administration). If a patient who is prescribed Foradil Aerolizer does not experience breathing improvement, the healthcare provider should ask how the patient is using Foradil Aerolizer."

Section 4.5 moved the wording:
"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."

Section 4.6 added:
"There is limited data regarding the use of Foradil in pregnant women. Limited animal studies do not indicate Foradil has direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3 Pre-clinical safety data). "

and

"Fertility

There is no available data on the effect of formoterol on human fertility. No impairment of fertility was observed in studies performed in male and female rats (see section 5.3 Pre-clinical safety data)."

Section 4.8 added

Replaced "angioneurotic edema" and " exanthem" with "angioedema, rash"in rare immune disorders.
Revised frequency of "hypokalaemia" and "hyperglycaemia" from "rare" and "very rare" respectivley to "unknown".
Added "dry mouth" as uncommon gasatrintestinal disorder.
Changed "muscle cramps" to " muscle spasms".

Also added statement about reporting of side effects.

Section 5.1 added:
"Asthma

Twenty-seven internal clinical trials in a wide range of ages included pediatric, adult and elderly population. Well controlled clinical trials demonstrated the superiority of formoterol over placebo and salbutamol in the treatment of asthma with a treatment duration range of 1 day (single-dose) to 12 weeks. Moreover, 4 open-label, follow-up clinical trials including the pediatric, adult and elderly populations of these previous studies, were conducted demonstrating an acceptable efficacy and safety profile of Foradil for an additional 12 months of treatment. Below are described 3 of the major trials that have supported the indication for formoterol in asthma in children, adults and elderly respectively.

Study DP/PD2 was a double-blind, 12-week, parallel-group, multicentre trial that assessed formoterol dry powder 12 µg and 24 µg daily vs. salbutamol dry powder 1200 µg daily in 219 (age 5 – 13) children with asthma. The study concluded that formoterol dry powder 12 µg b.i.d. administered as dry powder capsules by inhalation through the Aerolizer^® device has superior bronchodilator effect when compared with salbutamol 400 µg t.i.d. dry powder after 12 weeks of therapy as assessed by PEFR. Regarding the safety, formoterol 12 µg b.i.d. was slightly better tolerated than salbumtamol 400 µg t.i.d. of formoterol 6 µg b.i.d. during 3 months of treatment.

Study DP/RD1 was a placebo-controlled, multi-centre, double-blind, between-patient trial that compared multiple doses of 12 µg formoterol dry powder with multiple doses of 400 µg salbutamol dry powder in 304 patients (age 19–72) with asthma during a 12-week active treatment period. The study concluded that formoterol 12 µg b.i.d. is statistically superior, both to salbutamol 400µg q.i.d. and placebo with regard to the primary outcome variable (morning PEFR before inhalation). Regarding the safety, formoterol 12 µg b.i.d. was equally well tolerated as salbutamol 400 µg q.i.d. or placebo during 3 months of treatment.

Study DP/RD3 was a multi-centre, double-blind, parallel-group trial that compared the 3-month efficacy and tolerability of inhaled formoterol 12 µg and 24 µg b.i.d. dry powder and salbutamol 400 µg q.i.d. dry powder in 262 (age 64–82) elderly patients suffering from asthma. The study concluded that formoterol 12 µg and 24 µg b.i.d. are statistically superior to salbutamol 400 µg q.i.d. with regard to the primary outcome variable (morning PEFR before inhalation) over 3 months. Regarding the safety, formoterol was slightly better tolerated than salbutamol.

Prophylaxis of bronchospasm induced by inhaled allergens, cold air, or exercise

Four clinical studies were performed with formoterol in patients treated for the prophylaxis of bronchospasm induced by exercise and 2 studies were performed in patients for the prophylaxis of bronchospasm induced by inhaled allergen. Three major studies supporting the Foradil indication in the prophylaxis of bronchospasm induced by inhaled allergens, cold air or exercise are described below.

Prophylaxis of exercise-induced bronchoconstriction

A single-dose, randomized, double-blind, double-dummy, 4-way crossover trial compared 12 µg and 24 µg of formoterol dry powder capsules, 180 µg albuterol metered-dose inhaler versus placebo in 17 patients (age 13–50) for the prevention of exercise-induced bronchoconstriction. The study concluded that a single dose of formoterol 12 µg or 24 µg provides significantly greater protection against exercise-induced bronchoconstriction as assessed by FEV₁ compared with placebo at 15 minutes and 4, 8 and 12 hours after dosing. Both doses of formoterol provided significantly greater protection than albuterol at 4, 8 and 12 hours post-dose. No significant difference in efficacy was identified between formoterol 12 µg and 24 µg. There were less adverse events reported with formoterol 24 µg.

Prophylaxis of allergen-induced bronchoconstriction

A randomized, placebo-controlled, within-patient, multicentre clinical trial assessed the efficacy and tolerability of a single dose of inhaled formoterol 24 µg in protecting 24 patients (age 17–40) with asthma against allergen-induced bronchoconstriction evaluated between 3 and 32 hours after the inhalation of the trial medication. The study concluded that formoterol led to a significant and long-lasting protection against allergen-induced bronchoconstriction as assessed by FEV₁. Regarding the safety, formoterol had an excellent tolerability profile.

Prophylaxis of cold-air-induced bronchoconstriction

In a controlled study, the duration of the effect of inhaled formoterol (24 µg) was compared with that of a placebo and that of inhaled albuterol (200 µg) in 12 adult asthmatic subjects who underwent hyperventilation tests with cold dry air (-20 °C) on 4 study days. On the control day, they were subjected to four hyperventilation tests to ensure functional stability. On the 3 remaining days, after a first hyperventilation test, they inhaled placebo, albuterol, or formoterol in randomized, double-blind fashion. The hyperventilation test was repeated 1, 4, and 8 h and, if the blocking effect was still present, 12 and 24 h after the drug had been administered. The study concluded that the protection against bronchoconstriction, as assessed by FEV₁, induced by hyperventilation of unconditioned air in asthmatic subjects is significantly more prolonged after formoterol than after albuterol.

COPD

Two large multinational, multicenter, randomized, double-blind, parallel group, controlled trials have been carried out in the target population of patients with COPD (studies 25827 02 056 and 25827 02 058). Both were placebo-controlled and included an active comparator arm. The primary objective in both trials was to assess the efficacy of eformoterol 12 mg and 24 mg twice daily by Aerolizer^® device compared with placebo. In both trials further analysis was made of patients classified as “reversible” or “irreversible” at baseline based on a cut-off of 15% increase in FEV₁ 30 minutes after inhalation of 200 mg salbutamol. Approximately 50% of patients had reversible COPD in both trials.

Study 25827 02 056 was a randomized, double-blind, between-patient trial that compared two doses of inhaled formoterol fumarate dry powder (12 and 24 µg b.i.d.) with placebo and ipratropium bromide MDI (40 µg q.i.d.) for 12 weeks in 698 patients (age 40–87) with COPD. The study concluded that formoterol fumarate (12 and 24 µg b.i.d.) produced statistically and clinically significant improvements in lung function, as measured by FEV₁ area under the curve, when compared to placebo after 12 weeks of treatment. Formoterol fumarate also improved the quality of life of patients and was more effective than ipratropium bromide (40 µg q.i.d.) with similar satisfactory tolerability.

Study 25827 02 058 was a randomized, between-patient trial that compared two doses of inhaled formoterol fumarate dry powder (12 µg b.i.d. and 24 µg b.i.d.) with placebo (double-blind) and with oral slow release theophylline (200–400 mg) at individual doses based on serum levels (open-label), each administered twice daily for one year in 725 patients (age 34–88) with COPD. The study concluded that formoterol fumarate at both 24 µg and 12 µg b.i.d. produced statistically and clinically significant improvements in lung function, as measured by FEV, area under the curve, when compared to placebo after 12 weeks of treatment. Formoterol fumarate also improved the quality of life of patients and was more effective than theophylline with superior tolerability."

Section 5.3 added:

"Formoterol was evaluated for its effects on fertility and general reproductive performance in sexually mature male and female rats. No impairment of fertility or effect on early embryonic development was observed at doses up to 60 mg/kg/day administered orally to rats (approximately 12,000 times the maximum recommended daily inhalation powder dose in human on a mg/m² basis)."

Section 2 has been updated to include: Excipients with known effect: contains lactose monohydrate (25mg).
Section 4.4 has been updated to include: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Section 6.1 has been updated to remove "25mg per capsule, which contains milk protein".

Section 4.2 has been revised to change the age of children from 5 to 6 years and to include a statement that children up to the age of 6 years should not be treated with Foradil.
Section 4.3 has been revised to specify the excipient lactose as a contra-indication.
Section 4.4 has been extensively revised to include the updated core safety profile information arising from PSUR worksharing.
Section 4.5 has been revised to include examples of antihistamines (terfenadine, astemizole and mizolastine) and the following statement has been added: Concomitant treatment with other sympathomimetic substances such as β₂-agonists or ephedrine may potentiate the undesirable effects of Foradil and may require titration of the dose.
Section 4.6 has been revised to include the following: In animal studies formoterol has caused implantation losses as well as decreased early postnatal survival and birth weight.
Section 4.8 has been extensively revised to include the updated core safety profile information from PSUR worksharing.
Section 4.9 has been revised to include prolonged QTc-interval,
Section 6.1 has been revised to  include "(25mg / capsule, which contains milk proteins), gelatine" as excipients.

In section 4.4 added severe hypertension" under Concomitant conditions.
In section 4.8 added some cardiac and skin disorder side effects to reflect post-marketing findings.
In section 4.9 added "hypertension" as potential symptom of overdose with Foradil.

Updated SmPC with findings from the "formoterol" PSUR 14- WS:
Section 4.4 Added some concomitant condition for whcih special care and supervision is required - "sever hypertension, aneurysm, phaeochromocytoma"
Section 4.5 Added "macrolides" into Interactions section.  Alos added in text " There is an elevated risk of cardiac arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.  The bronchodilating effects of formoterol can be enhanced by anticholinergic drugs.
Section 4.8 Re-classifed hypokalaemia, hyperglcaemia and increased blood pressure as unknown.  Re-classified angina pectoris and electrocardiogram QT prolonged as rare.

Updated section 4.2  and 4.4 to re-emphasise that Foradil should only be used as an add-on therapy to an ICS in asthma patients.  Also added a recommendation that for asthma children 5-12 years a combination (LABA + ICS) product is preferred to make sure that the ICS will be used in this population.

Section 4.1 - Expanded on indication of propylaxis and treatment of brochoconstriction for aptients with asthma as an add-on to inhaled glucocorticosteroid therapy.
Section 4.2 Expanded that Foradil should not be used as a rescue therapy for acute symptoms of asthma attacks
Section 4.4 Further explained about reduction of Foradil dose once symptoms become controlled.  Also included data on asthma exacerbations in children
Section 4.8 added side effects under Respiratory disorders and gave more data on asthma exacerbations in children.

Update of SPC Section 2 to QRD template