4.1. Therapeutic indications

The management of bronchospasm in patients suffering from chronic obstructive pulmonary disease who require regular treatment with both ipratropium and salbutamol.

4.2. Posology and method of administration

COMBIVENT UDVs are intended for inhalation only and may be administered from a suitable nebuliser or an intermittent positive pressure ventilator. The single dose units must not be taken orally or administered parenterally.

Treatment should be initiated and administered under medical supervision, e.g. in the hospital setting. Home based treatment can be recommended in exceptional cases (severe symptoms or experienced patients requiring higher doses) when a low dose rapid acting beta-agonist bronchodilator has been insufficient in providing relief after consultation with an experienced physician.

The treatment with the nebuliser solution in UDVs should always be started with the lowest recommended dose (1 UDV). In very severe cases two unit dose vials may be required for symptom relief. Administration should be stopped when sufficient symptom relief is achieved.

The recommended dose is:

Adults (including elderly patients and children over 12 years):

1 single dose unit three or four times daily.

Children under 12 years:

There is no experience of the use of COMBIVENT UDVs in children under 12 years.

Administration:

Please refer to the patient information leaflet for instructions for use with a nebuliser.

Since the single dose units contain no preservatives, it is important that the contents are used immediately after opening and that a fresh vial is used for each administration to avoid microbial contamination. Partly used, open or damaged single dose units should be discarded.

It is strongly recommended not to mix COMBIVENT UDVs with other drugs in the same nebuliser.

4.3. Contraindications

COMBIVENT UDVs are contraindicated in patients with hypertrophic obstructive cardio- myopathy or tachyarrhythmia. COMBIVENT UDVs are also contraindicated in patients with a history of hypersensitivity to ipratropium bromide, salbutamol sulfate or to atropine or its derivatives.

4.4. Special warnings and precautions for use

Hypersensitivity

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

Paradoxical bronchospasm

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway. COMBIVENT should be discontinued immediately, the patient should be assessed and alternative therapy instituted if necessary.

Ocular complications

There have been rare cases of ocular complications (i.e. mydriasis, blurring of vision, narrow-angle glaucoma and eye pain) when the contents of metered aerosols containing ipratropium bromide have been sprayed inadvertently into the eye.

Patients must be instructed in the correct use of COMBIVENT UDVs and warned not to allow the solution or mist to enter the eyes. This is particularly important in patients who may be pre-disposed to glaucoma. Such patients should be warned specifically 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.

Systemic effects

In the following conditions COMBIVENT UDVs 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.

Cardiovascular effects

Cardiovascular effects may be seen with sympathomimetic drugs including COMBIVENT.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, arrhythmia 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. Attention should be paid to assessment of symptoms such as dyspnoea and chest pain, as they may be of either respiratory or cardiac origin.

Hypokalaemia

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

Gastro-intestinal motility disturbances

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

Dyspnoea

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.

Lactic acidosis

Lactic acidosis has been reported in association with high therapeutic doses of intravenous and nebulised short-acting beta-agonist therapy, mainly in patients being treated for an acute exacerbation of bronchospasm in severe asthma or chronic obstructive pulmonary disease (see Section 4.8 and 4.9). Increase in lactate levels may lead to dyspnoea and compensatory hyperventilation, which could be misinterpreted as a sign of asthma treatment failure and lead to inappropriate intensification of short-acting beta-agonist treatment. It is therefore recommended that patients are monitored for the development of elevated serum lactate and consequent metabolic acidosis in this setting.

Interference with laboratory tests or other diagnostic measures

The use of COMBIVENT may lead to positive results with regards to salbutamol in tests for non clinical substance abuse, e.g. in the context of athletic performance enhancement (doping).

4.5. Interaction with other medicinal products and other forms of interaction

The chronic co-administration of COMBIVENT with other anticholinergic drugs has not been studied. Therefore, the chronic co-administration of COMBIVENT with other anticholinergic drugs is not recommended.

The use of additional beta-agonists, xanthine derivatives and corticosteroids may enhance the effect of COMBIVENT UDVs. The concurrent administration of other beta-mimetics, systemically absorbed anticholinergics and xanthine derivatives may increase the severity of side effects. A potentially serious reduction in effect may occur during concurrent administration of beta-blockers.

Beta2-adrenergic agonists should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of beta2-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.

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 UDVs 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 UDVs 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

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as dizziness, accommodation disorder, mydriasis and blurred vision during treatment with COMBIVENT. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8. Undesirable effects

Summary of the safety profile

Many of the listed undesirable effects can be assigned to the anticholinergic and beta2 –sympathomimetic properties of COMBIVENT. As with all inhalation therapy COMBIVENT may show symptoms of local irritation.

The most frequent side effects reported in clinical trials were headache, throat irritation, cough, dry mouth, gastrointestinal motility disorders (including constipation, diarrhoea and vomiting), nausea and dizziness.

Tabulated summary of adverse reactions

The following adverse reactions have been reported during use of COMBIVENT in clinical trials and during the post-marketing experience.

Frequencies

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

Not known

Frequency cannot be estimated from the available data

MedDRA System Organ Class

Adverse reactions

Frequency

Immune system disorders

Anaphylactic reaction

Rare

Hypersensitivity

Rare

Angioedema of the tongue, lips and face

Rare

Metabolism and nutrition disorders

Hypokalaemia

Rare

Lactic acidosis (see section 4.4)

Not known

Psychiatric disorders

Nervousness

Uncommon

Mental disorder

Rare

Nervous system disorders

Dizziness

Uncommon

Headache

Uncommon

Tremor

Uncommon

Sleep disturbances

Rare

Eye disorders

Accommodation disorder

Rare

Corneal oedema

Rare

Glaucoma (1)

Rare

Eye pain (1)

Rare

Increased intraocular pressure (1)

Rare

Mydriasis (1)

Rare

Blurred vision

Rare

Conjunctival hyperaemia

Rare

Halo vision

Rare

Cardiac disorders

Palpitations

Uncommon

Tachycardia

Uncommon

Arrhythmia

Rare

Atrial fibrillation

Rare

Myocardial ischaemia

Rare

Supraventricular tachycardia

Rare

Respiratory, thoracic and mediastinal disorders

Cough

Uncommon

Dysphonia

Uncommon

Throat irritation

Uncommon

Bronchospasm

Rare

Paradoxical bronchospasm (2)

Rare

Dry Throat

Rare

Laryngospasm

Rare

Pharyngeal oedema

Rare

Gastrointestinal disorders

Dry mouth

Uncommon

Nausea

Uncommon

Gastrointestinal motility disorder

Rare

e.g. Diarrhoea

Rare

Constipation

Rare

Vomiting

Rare

Mouth oedema

Rare

Stomatitis

Rare

Skin and subcutaneous tissue disorders

Skin reactions

Uncommon

Hyperhidrosis

Rare

Rash

Rare

Urticaria

Rare

Pruritus

Rare

Musculoskeletal and connective tissue disorders

Muscle spasms

Rare

Muscular weakness

Rare

Myalgia

Rare

Renal and urinary disorders

Urinary retention (3)

Rare

General disorders and administration site conditions

Asthenia

Rare

Investigations

Systolic blood pressure increased

Uncommon

Diastolic blood pressure decreased

Rare

(1) ocular complications have been reported when aerolised ipratropium bromide, either alone or in combination with an adrenergic beta2-agonist, has come into contact with the eyes – see section 4.4.

(2) as with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway. COMBIVENT should be discontinued immediately, the patient should be assessed and alternative therapy instituted if necessary – see section 4.4

(3) the risk of urinary retention may be increased in patients with pre-existing urinary outflow tract obstruction.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Acute effects of overdosage with ipratropium bromide are mild and transient (such as dry mouth, visual accommodation disorders) due to its poor systemic absorption after either inhalation or oral administration. Any effects of overdosage are therefore likely to be related to the salbutamol component.

Manifestations of overdosage with salbutamol may include tachycardia, anginal pain, hypertension, palpitations, tremor, hypokalaemia, hypotension, widening of the pulse pressure, arrhythmias and flushing. Metabolic acidosis has also been observed with overdosage of salbutamol, including lactic acidosis which has been reported in association with high therapeutic doses as well as overdoses of short-acting beta-agonist therapy, therefore monitoring for elevated serum lactate and consequent metabolic acidosis (particularly if there is persistence or worsening of tachypnea despite resolution of other signs of bronchospasm such as wheezing) may be indicated in the setting of overdose.

Treatment with COMBIVENT should be discontinued. Acid base and electrolyte monitoring should be considered.

The preferred antidote for overdosage with salbutamol is a cardioselective beta-blocking agent, but caution should be used in administering these drugs to patients with a history of bronchospasm.