Document: Fenorol inhalation powder hard capsule ENG SmPC change

• Fenorol inhalation powder, hard capsule SmPC
• Fenorol inhalation powder hard capsule ENG SmPC

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

Fenorol 12 mikrogram Inhalationspulver, hård kapsel

One hard capsule contains 12 micrograms formoterol fumarate dihydrate.

This is equivalent to a delivered dose (ex actuator) of 10 microgram of formoterol fumarate dihydrate.

Excipient(s) with known effect:

Lactose monohydrateup to 25 mg per metered dose.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Inhalation powder, hard capsule

Hard and colourless capsule of approximately 16 mm long containing white coloured powder

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

4.2 Posology and method of administration

Use of doses above those normally required by the individual patient on more than 2 days per week is a sign of suboptimal disease control and maintenance treatment should be reassessed.

Fenorol 12 mikrogram Inhalationspulver, hård kapsel is not recommended for use in children below 6 years due to insufficient data on safety and efficacy.

Asthma

In asthma, Fenorol 12 mikrogram Inhalationspulver, hård kapsel can be used once or twice daily (‘regular dosage’), and as ‘relief medication’ to relieve acute broncho-obstructive symptoms.

Adults aged > 18 years:

Relief medication: 1 inhalation for the relief of acute broncho-obstructive symptoms.

Regular dosage: 1 inhalation once or twice daily. Some patients may need 2 inhalations once or twice daily.

Prevention of exercise-induced bronchoconstriction: 1 inhalation before exercise.

The daily dose for regular use should not exceed 4 inhalations. If required, an additional 1 to 2 capsules per day may be used for the relief of typical symptoms, provided the recommended daily maximum dose of 48 micrograms per day is not exceeded.

Children and adolescents, 6 years and older:

Relief medication: 1 inhalation for the relief of acute broncho-obstructive symptoms.

Regular dosage: 1 inhalation once or twice daily.

Prevention of exercise-induced bronchoconstriction: 1 inhalation before exercise.

The daily dose should not exceed 2 inhalations.

No more than 1 inhalation should be taken on any single occasion.

Children should only use this product under the supervision of an adult.

COPD:

Regular dosage: 1 inhalation once or twice daily.

The daily dose for regular use should not exceed 2 inhalations.

If required, additional inhalations above those prescribed for regular therapy may be used for relief of symptoms, up to a maximum total daily dose of 4inhalations, (regular plus as required). More than 2 inhalations should not be taken on any single occasion.

Special patient groups: There are no special dosing requirements for elderly patients. There are no data available for use of Fenorol 12 mikrogram Inhalationspulver, hård kapselin patients with hepatic or renal impairement (see also section 5.2).

Method of administration

For inhalation use

In order to ensure correct use of the inhaler, patients should receive thorough instructions on how to use the device.

The patient should upload the device with only one capsule, then should press the bottoms sited in both sides performing the capsules with the needles and therefore inhales trough mouthpiece

Lately put away the capsule used

Fenorol 12 mikrogram Inhalationspulver, hård kapselis inspiratory flow driven which means that, when the patient inhales through the mouthpiece, the substance will follow the inspired air into the airways.

Note! It is important to instruct the patient to breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is obtained.

It is important to instruct the patient never to chew or bite on the mouthpiece and never to use the inhaler if it has been damaged or if the mouthpiece has become detached.

The patient may not taste or feel any medication when using Fenorol 12 mikrogram Inhalationspulver, hård kapseldue to the small amount of drug dispensed.

Detailed instructions for use are packed together with each inhaler.

4.3 Contraindications

Hypersensitivity to Formoterol or to any of the excipients listed in section 6.1

4.4 Special warnings and precautions for use

Fenorol 12 mikrogram Inhalationspulver, hård kapselshould not be used (and is not sufficient) as the first treatment for asthma.

Asthmatic patients who require therapy with long-acting ₂-agonists, should also receive optimal maintenance anti-inflammatory therapy with corticosteroids. Patients must be advised to continue taking their anti-inflammatory therapy after the introduction of Fenorol 12 mikrogram Inhalationspulver, hård kapseleven when symptoms decrease. Should symptoms persist, or treatment with ₂-agonists need to be increased, this indicates a worsening of the underlying condition and warrants a reassessment of the maintenance therapy. Although Fenorol 12 mikrogram Inhalationspulver, hård kapsel may be introduced as add-on therapy when inhaled corticosteroids do not provide adequate control of asthma symptoms, patients should not be initiated on Fenorol 12 mikrogram Inhalationspulver, hård kapselduring 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 Fenorol 12 mikrogram Inhalationspulver, hård kapsel. Patients should be asked to continue treatment but seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Fenorol 12 mikrogram Inhalationspulver, hård kapsel. Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Fenorol 12 mikrogram Inhalationspulver, hård kapsel. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Fenorol 12 mikrogram Inhalationspulver, hård kapselshould be used.

The maximum daily dose should not be exceeded.

The long-term safety of regular treatment at higher doses than 4 inhalations per day in adults with asthma, 2 inhalations per day in children with asthma and 2 inhalations per day in patients with COPD, has not been established.

Frequent need of medication (i.e. prophylactic treatment e.g. corticosteroids and long-acting ₂-agonists) for the prevention of exercise-induced bronchoconstriction several times every week, despite an adequate maintenance treatment, can be a sign of suboptimal asthma control, and warrants a reassessment of the asthma therapy and an evaluation of the compliance.

Caution should be observed when treating patients with thyrotoxicosis, phaeochromocytoma, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heart failure. An adjustment of the dose of formoterol may be considered.

Formoterol may induce prolongation of the QTc-interval. Caution should be observed when treating patients with prolongation of the QTc-interval and in patients treated with drugs affecting the QTc-interval (see 4.5).

Due to the hyperglycaemic effects of ₂-agonists, additional blood glucose monitoring is recommended initially in diabetic patients.

Potentially serious hypokalaemia may result from ₂-agonist therapy. Particular caution is recommended in acute severe asthma as the associated risk may be augmented by hypoxia. The hypokalaemic effect may be potentiated by concomitant treatment with xanthine-derivatives, steroids and diuretics. The serum potassium levels should therefore be monitored. Special caution is advised if theophylline and formoterol are used concomitantly in patients with pre-existing cardiac disease.

As with other inhalation therapy, the potential for paradoxial bronchospasm should be considered. If this occurs the patient will experience an immediate increase in wheezing and shortness of breath after dosing which should be treated straightaway with a fast-acting inhaled bronchodilator. Fenorol 12 mikrogram Inhalationspulver, hård kapsel , treatment should be discontinued immediately, the patient should be assessed and, if necessary, an alternative therapy started (See section 4.8).

Fenorol 12 mikrogram Inhalationspulver, hård kapselcontains lactose monohydrate, up to 25 mg per metered dose. This amount does not normally cause problems in lactose intolerant people. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Children up to the age of 6 years should not be treated with Fenorol 12 mikrogram Inhalationspulver, hård kapsel, as no sufficient experience is available for this group.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Concomitant use with oral corticosteroids might increase hyperglycaemic effects.

Administration of formoterol to patients being treated with monoamine oxidase inhibitors (or having been treated during the past 14 days) or tricyclic antidepressants should be performed with caution, since the action of β2-adrenergic stimulants on the cardiovascular system may be potentiated.

In addition L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards β2-sympathomimetics.

Concomitant treatment with other sympathomimetic substances such as other ₂-agonists or ephedrinemay potentiate the undesirable effects of Fenorol 12 mikrogram Inhalationspulver, hård kapseland may require titration of the dose.

Concomitant treatment with xanthine derivatives, steroids or diuretics such as thiazides and loop diuretics may potentiate a rare hypokalaemic adverse effect of ₂-agonists. Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.

There is a theoretical risk that concomitant treatment with other drugs known to prolong the QTc-interval may give rise to a pharmacodynamic interaction with formoterol and increase the possible risk of ventricular arrhythmias. Examples of such drugs include certain antihistamines (e.g. terfenadine, astemizole, mizolastine), certain antiarrhythmics (e.g. quinidine, disopyramide, procainamide), erythromycin and tricyclic antidepressants.

There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.

The bronchodilating effects can be enhanced by anticholinergic drugs.

Beta-adrenergic blockers can weaken or inhibit the effect of Fenorol 12 mikrogram Inhalationspulver, hård kapsel. Fenorol 12 mikrogram Inhalationspulver, hård kapselshould therefore not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons.

4.6 Fertility, pregnancy and lactation

Fertility

There are no clinical data of the effect of Fenorol 12 mikrogram Inhalationspulver, hård kapsel on fertility. However, a somewhat reduced fertility in male rats was observed at high systemic exposure to formoterol (see section 5.3).

Pregnancy

There are no adequate data from the use of formoterol in pregnant women. In animal studies formoterol has caused implantation losses as well as decreased early postnatal survival and birth weight. The effects appeared at considerably higher systemic exposures than those reached during clinical use of formoterol. Treatment with formoterol may be considered at all stages of pregnancy if needed to obtain asthma control and if the expected benefit to the mother is greater than any possible risk to the foetus. The potential risk for human is unknown.

Breast-feeding

There is insufficient information on the excretion of Formoterol in human milk

Available pharmacodynamic/toxicological data in animals have shown excretion of formoterol in milk (for details see 5.3). In rats, small amounts of formoterol have been detected in maternal milk.

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Fenorol 12 mikrogram Inhalationspulver, hård kapseltherapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman

4.7 Effects on ability to drive and use machines

Fenorol 12 mikrogram Inhalationspulver, hård kapsel has no influence on the ability to drive and use machines.

4.8 Undesirable effects

The most commonly reported adverse events of ₂-agonist therapy, such as tremor and palpitations, tend to be mild and disappear within days of treatment.

Adverse reactions, which have been associated with formoterol, are given below, listed by system organ class and frequency. Frequency are defined as: very common (1/10), common (1/100) and <1/10), uncommon (1/1 000 and < 1/100), rare (1/10 000 and < 1/1000) and very rare <1/10 000).

Organ System	Frequency	Adverse drug reaction
Blood and lymphatic system disorders	Very rare	Thrombopenia
Cardiac disorders	Common	Palpitations
	Uncommon	Tachycardia
	Rare	Cardiac arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia, extrasystoles.
	Very rare	Angina pectoris, Prolongation of QTc interval
Gastrointestinal disorders	Rare	Nausea
Immune system disorders	Rare	Hypersensitivity reactions, e.g. bronchospasm, exanthema, urticaria, pruritus, angioneurotic oedema
Metabolic and nutrition disorders	Rare	Hypokalemia
	Very rare	Hyperglycemia
Musculoskeletal, connective tissue and bone disorders	Uncommon	Muscle cramps, myalgia
Nervous system disorders	Common	Headache, tremor
	Very rare	Taste disturbances, , Nervousness
Psychiatric disorders	Uncommon	Agitation, restlessness, sleep disturbances, anxiety, dizziness
Vascular disorders	Very rare	Variations in blood pressure
Respiratory, thoracic and mediastinal disorders	Uncommon	oropharyngeal irritation

Central nervous system stimulating effects have been sporadically reported following inhalation of β2-agonists, manifesting hyperexcitability. These effects were mainly observed in children up to 12 years of age.

As with all inhalation therapy, paradoxical bronchospasm may occur in very rare cases.( see section 4.4).

Treatment with ₂-agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.

The excipient lactose contains small amounts of milk proteins. These may cause allergic reactions.

Reporting suspected adverse reactions after authorisation of the 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 the national reporting system listed in

[ To be completed nationally ]

4.9 Overdose

There is limited clinical experience on the management of overdose. An overdose would likely lead to effects that are typical of ₂-agonists: tremor, headache, palpitations. Symptoms reported from isolated cases are tachycardia, hyperglycaemia, hypokalaemia, prolonged QTc-interval, arrythmia, nausea and vomiting. Supportive and symptomatic treatment is indicated.

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Selective beta2-adrenoreceptor agonists, ATC code: R03AC13.

Formoterol is a selective ₂-adrenoceptor agonist that produces relaxation of bronchial smooth muscle. Formoterol thus has a bronchodilating effect in patients with reversible airways obstruction. The bronchodilating effect sets in rapidly, within 1-3 minutes after inhalation and has a mean duration of 12 hours after a single dose.

5.2 Pharmacokinetic properties

Absorption

Inhaled formoterol is rapidly absorbed. Peak plasma concentration is reached about 10 minutes after inhalation.

In studies the mean lung deposition of formoterol after inhalation via Turbuhaler ranged from 28-49% of the delivered dose (corresponding to 21-37% of the metered dose). The total systemic availability for the higher lung deposition was around 61% of the delivered dose (corresponding to 46% of the metered dose).

Distribution and metabolism:

Plasma protein binding is approximately 50%.

Formoterol is metabolised via direct glucuronidation and O-demethylation. The enzyme responsible for O-demethylation has not been identified. Total plasma clearance and volume of distribution has not been determined.

Elimination

The major part of the dose of formoterol is eliminated via metabolism. After inhalation 8-13% of the delivered dose (corresponding to 6-10% of the metered dose) of formoterol is excreted unmetabolised in the urine. About 20% of an intravenous dose is excreted unchanged in the urine. The terminal half-life after inhalation is estimated to be 17 hours.

Special populations:

The effect of decreased liver or kidney function on the pharmacokinetics of formoterol and the pharmacokinetics in the elderly is not known. As formoterol is primarily eliminated via liver metabolism an increased exposure can be expected in patients with severe liver cirrhosis.

5.3 Preclinical safety data

The effects of formoterol seen in toxicity studies in rats and dogs were mainly on the cardiovascular system and consisted of hyperaemia, tachycardia, arrhythmias and myocardial lesions. These effects are known pharmacological manifestations seen after the administration of high doses of ₂-agonists.

In animal reproductive toxicity studies, formoterol has caused implantation losses as well as decreased early postnatal survival and birth weight.A somewhat reduced fertility in male rats was observed at high systemic exposure to formoterol.

No genotoxic effects of formoterol have been observed in in-vitro or in vivo tests. In rats and mice a slight increase in the incidence of benign uterine leiomyomas has been observed. This effect is looked upon as a class-effect observed in rodents after long exposure to high doses of ₂-agonists.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate which contains milk proteins

6.2 Incompatibilities

Not applicable

6.3 Shelf life

Alu/Alu blister: 2 years.

HDPE bottle: 3 years.

6.4 Special precautions for storage

In Alu/Alu blisters: Store in the original package in order to protect from moisture

Do not store above 30 ºC.

In bottles: Store in the original package in order to protect from moisture.

This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

HDPE bottle screw-cap with a desiccant capsule containing silica gel and inviolable safety ring containing 60 hard hypromellose capsules and one inhaler

HDPE bottle screw-cap with a desiccant capsule containing silica gel and inviolable safety ring containing 120 hard hypromellose capsules and one inhaler

HDPE bottle screw-cap with a desiccant capsule containing silica gel and inviolable safety ring containing 180 hard hypromellosecapsules and one inhaler

The inhaler consists of a cap, mouthpiece, inhaler body, perforating system with 4 needles at each side. The push-bottoms are dark blue

Alu/Alu Blister of 10 hard hypromellose capsules and one inhaler

Alu/Alu Blister of 30hard hypromellose capsules and one inhaler

Alu/Alu Blister of 60hard hypromellose capsules and one inhaler

Alu/Alu Blister of 120 hard hypromellose capsules and one inhaler

Alu/Alu Blister of180 hard hypromellose capsules and one inhaler

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

The capsules should be removed from the blister strip onlyimmediately before use

7. MARKETING AUTHORISATION HOLDER

To be completed nationally

8. MARKETING AUTHORISATION NUMBER(S)

To be completed nationally

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

To be completed nationally

10. DATE OF REVISION OF THE TEXT

2014-12-10