Combivent Metered Aerosol

C

1. Name Of The Medicinal Product

Combivent® Metered Aerosol.

2. Qualitative And Quantitative Composition

COMBIVENT Metered Aerosol is a combination of ipratropium bromide monohydrate and salbutamol sulphate. Each valve activation delivers 21 mcg of ipratropium bromide monohydrate (corresponds to 20 mcg ipratropium bromide anhydrous) and 120 mcg of salbutamol sulphate.

For excipients, see 6.1

3. Pharmaceutical Form

Pressurised inhalation, suspension.

Pressurised aluminium container closed with a metering valve containing a creamy-white suspension inserted into a grey plastic actuator (mouthpiece).

4. Clinical Particulars 4.1 Therapeutic Indications

COMBIVENT is indicated as a bronchodilator for the treatment of bronchospasm associated with chronic obstructive pulmonary disease in patients who require regular treatment with both ipratropium and salbutamol.

4.2 Posology And Method Of Administration

Adults (including elderly patients):

Two inhalations four times a day.

Children:

There is no experience of the use of COMBIVENT in children below the age of 12 years.

Administration

The correct operation of the metered aerosol apparatus is essential for successful therapy.

The aerosol should be shaken and the valve depressed once or twice before the apparatus is initially used.

Before each use the following rules should be observed:

1. Remove protective cap.

2. Shake the metered aerosol well before each use.

3. Breathe out deeply.

4. Hold the metered aerosol and close lips over the mouthpiece. The arrow and the base of the container should be pointing upwards.

5. Breathe in as deeply as possible, pressing the base of the container firmly at the same time, this releases one metered dose. Hold the breath for a few seconds, then remove the mouthpiece from the mouth and breathe out.

6. Replace the protective cap after use.

As the container is not transparent it is not possible to see when the contents are used up, but shaking the container will show if there is any remaining fluid.

The mouthpiece should always be kept clean and can be washed with warm water. If soap or detergent is used, the mouthpiece should be thoroughly rinsed in clear water.

4.3 Contraindications

COMBIVENT Metered Aerosol is contraindicated in patients with hypertrophic obstructive cardiomyopathy or tachyarrhythmia, and in patients with a history of hypersensitivity to any of its components, or to atropine or its derivatives.

COMBIVENT Metered Aerosol is also contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soya bean and peanut. For such patients COMBIVENT Unit Dose Vials without soya lecithin can be used.

4.4 Special Warnings And Precautions For Use

Immediate hypersensitivity reactions may occur after administration of COMBIVENT Metered Aerosol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm and oropharyngeal oedema.

There have been rare reports of ocular complications (i.e. mydriasis, blurring of vision, narrow-angle glaucoma, eye pain) when the contents of metered aerosols containing ipratropium bromide have been sprayed inadvertently into the eye. Care must be taken to prevent COMBIVENT from entering the eye, particularly in patients who may be pre-disposed to glaucoma. Such patients should be specifically warned to protect their eyes.

Eye pain or discomfort, blurred vision, visual halos or coloured images, in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately.

Patients must be instructed in the correct administration of COMBIVENT Metered Aerosol.

In the following conditions COMBIVENT should only be used after careful risk/benefit assessment: Insufficiently controlled diabetes mellitus, recent myocardial infarction and/or severe organic heart or vascular disorders, hyperthyroidism, pheochromocytoma, risk of narrow-angle glaucoma. prostatic hypertrophy or bladder-neck obstruction.

There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischaemia associated with salbutamol. Patients with underlying severe heart disease (e.g. ischaemic heart disease, tachyarrhythmia or severe heart failure) who are receiving salbutamol for respiratory disease, should be warned to seek medical advice if they experience chest pain or other symptoms of worsening heart disease.

The patient should be instructed to consult a doctor immediately in the event of acute, rapidly worsening dyspnoea. In addition, the patient should be warned to seek medical advice should a reduced response become apparent.

Potentially serious hypokalemia may result from beta2-agonist therapy. Particular caution is advised in severe asthma, as this effect may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics. Additionally, hypoxia may aggravate the effects of hypokalemia on cardiac rhythm, especially in patients receiving digoxin. It is recommended that serum potassium levels are monitored in such situations.

Patients with cystic fibrosis may be more prone to gastro-intestinal motility disturbances.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Beta-adrenergics, xanthine derivatives and corticosteroids may enhance the effect of COMBIVENT. The concurrent administration of other beta-mimetics, systemically absorbed anticholinergics and xanthine derivatives may increase the side effects.

A potentially serious reduction in effect may occur during concurrent administration of beta-blockers.

Beta-adrenergic agonists should be administered with caution in patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of beta-adrenergic agonists may be enhanced.

Inhalation of halogenated hydrocarbon anaesthetics such as halothane, trichloroethylene and enflurane may increase the susceptibility to the cardiovascular effects of beta-agonists.

Anticholinergic effects of other drugs can be enhanced.

4.6 Pregnancy And Lactation

Ipratropium bromide has been in general use for several years and there is no definite evidence of ill-consequence during pregnancy; animal studies have shown no hazard.

Salbutamol has been in widespread use for many years without apparent ill-consequence during pregnancy. There is inadequate published evidence of safety in the early stages of human pregnancy but in animal studies there has been evidence of some harmful effects on the foetus at very high dose levels.

As with all medicines, COMBIVENT should not be used in pregnancy, especially the first trimester, unless the expected benefit is thought to outweigh any possible risk to the foetus. Similarly, COMBIVENT should not be administered to breast-feeding mothers unless the expected benefit is thought to outweigh any possible risk to the neonate.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

The following side effects have been reported based on clinical trials involving 821 patients.

Frequencies

Very common

Common

Uncommon

Rare

Very Rare

< 1/10,000

Not known

cannot be estimated from the available data

Immune system disorders:

Anaphylactic reaction

Not known

Hypersensitivity

Not known

Metabolism and nutrition disorders:

Hypokalaemia

Not known

Psychiatric disorders:

Nervousness

Uncommon

Mental disorder

Not known

Nervous system disorders:

Dizziness

Uncommon

Headache

Uncommon

Tremor

Uncommon

Eye disorders:

Angle closure glaucoma

Not known

Eye pain

Not known

Intraocular pressure increased

Not known

Mydriasis

Not known

Vision blurred

Not known

There have been isolated reports of ocular complications with symptoms mentioned above when aerosolised ipratropium bromide either alone or in combination with an adrenergic beta2-agonist, has escaped into the eyes

Cardiac disorders:

Palpitations

Uncommon

Tachycardia

Uncommon

Arrhythmia

Very rare

Atrial fibrillation

Very rare

Myocardial ischaemia

Very rare

Blood pressure diastolic decreased

Not known

Blood pressure systolic increased

Not known

Respiratory, thoracic and mediastinal disorders:

Cough

Uncommon

Dysphonia

Uncommon

Bronchospasm

Not known

Laryngospasm

Not known

Pharyngeal oedema

Not known

Throat irritation

Not known

Gastrointestinal disorders:

Dry mouth

Common

Nausea

Uncommon

Oedema mouth

Not known

Gastrointestinal motility disorder

Not known

Vomiting

Not known

Skin and subcutaneous tissue disorders:

Angioedema

Not known

Hyperhidrosis

Not known

Rash

Not known

Skin reaction

Not known

Urticaria

Not known

Musculoskeletal and connective tissue disorders

Muscle spasms

Not known

Muscular weakness

Not known

Myalgia

Not known

Renal and urinary disorders:

Urinary retention

Uncommon

General disorders and administration site conditions:

Asthenia

Uncommon

As with all beta2-agonists hyperactivity in children is possible.

4.9 Overdose

The effects of overdosage are expected to be primarily related to salbutamol because acute overdosage with ipratropium bromide is unlikely as it is not well absorbed systemically after inhalation or oral administration. Hypokalaemia may occur following overdose. Serum potassium levels should be monitored.

Manifestations of overdosage with salbutamol may include anginal pain, hypertension, hypokalaemia and tachycardia. The preferred antidote for overdosage with salbutamol is a cardioselective beta-blocking agent but due care and attention should be used in administering these drugs in patients with a history of bronchospasm.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Ipratropium bromide is an anticholinergic agent which inhibits vagally mediated reflexes by antagonising the action of acetylcholine, the transmitter agent released from the vagus nerve. The bronchodilation following inhalation of ipratropium bromide is primarily local and site specific to the lung and not systemic in nature.

Salbutamol sulphate is a beta2-adrenergic agent which acts on airway smooth muscle resulting in relaxation. Salbutamol relaxes all smooth muscle from the trachea to the terminal bronchioles and protects against all bronchoconstrictor challenges.

COMBIVENT Metered Aerosol provides the simultaneous release of ipratropium bromide and salbutamol sulphate allowing the synergistic efficacy on the muscarinic and beta2-adrenergic receptors in the lung to cause bronchodilation.

5.2 Pharmacokinetic Properties

Ipratropium bromide is not readily absorbed into the systemic circulation either from the surface of the lung or from the gastrointestinal tract as compared by blood level and renal excretion studies. The half-life elimination of drug and metabolites is about 3 - 4 hours after inhalation or intravenous administration. Ipratropium bromide does not penetrate the blood brain barrier.

Salbutamol sulphate is rapidly and completely absorbed following oral administration either by the inhaled or gastric route. Peak plasma salbutamol concentrations are seen within three hours of administration and the drug is excreted unchanged in the urine after 24 hours. Intravenous salbutamol will cross the blood brain barrier reaching concentrations amounting to about five percent of the plasma concentrations. From a pharmacokinetic perspective, the additive activity of COMBIVENT is due to the local effect of the fixed dose of the active components (ipratropium bromide and salbutamol sulphate) on the muscarinic and beta2-adrenergic receptors in the lung.

5.3 Preclinical Safety Data

The individual active ingredients ipratropium bromide and salbutamol sulphate have been extensively investigated in animal models and the safety concerns are not clinically significant when COMBIVENT is used as metered aerosol at the recommended dosage levels to patients.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Dichlorodifluoromethane

Dichlorotetrafluoroethane

Trichloromonofluoromethane

Soya lecithin

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Store below 25°C.

Protect from direct sunlight and frost.

The canister contains a pressurised liquid. Do not expose to temperatures higher than 50?C. Do not try to open, puncture or burn the canister even when apparently empty.

6.5 Nature And Contents Of Container

COMBIVENT Metered Aerosol is a creamy - white suspension of micronised substances in halogenated propellants filled in metal canisters with a metering valve, delivering 50 µl per actuation.

Pack size: 10 ml

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Boehringer Ingelheim Limited,

Ellesfield Avenue,

Bracknell,

Berkshire,

RG12 8YS,

United Kingdom.

8. Marketing Authorisation Number(S)

PL 00015/0191

9. Date Of First Authorisation/Renewal Of The Authorisation

22.03.94

10. Date Of Revision Of The Text

February 2009

Legal category

POM

Combivent Metered Aerosol

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