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Boehringer Ingelheim Limited

The Hyde Building, 4th Floor, The Park, Carrickmines, Dublin 18,
Telephone: +353 1 2959620
Fax: +353 1 2959624
Medical Information e-mail: Medinfo@dbl.boehringer-ingelheim.com


Summary of Product Characteristics last updated on medicines.ie: 17/06/2014
SPC Combivent UDVs



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1. NAME OF THE MEDICINAL PRODUCT

Combivent® UDVs® 500 micrograms/2.5 mg per 2.5 ml Nebuliser solution


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 2.5 ml single dose unit contains 500 micrograms ipratropium bromide (as the monohydrate) and 2.5 mg salbutamol (as the sulphate).

For a full list of excipients, see section 6.1.


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3. PHARMACEUTICAL FORM

Nebuliser solution.

Clear, colourless or almost colourless solution.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

COMBIVENT UDVs are indicated for the management of bronchospasm in patients suffering from chronic obstructive pulmonary disease who require regular treatment with both ipratropium and salbutamol.


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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 should not be taken orally or administered parenterally.

The recommended dose is:

Adults (including elderly patients):

1 vial three or four times daily.

Patients should be advised to consult a doctor or the nearest hospital immediately in the case of acute or rapidly worsening dyspnoea (difficulty in breathing).

Special Populations:

COMBIVENT has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in those patient populations.

Paediatric patients:

Because of insufficient information in children COMBIVENT is not indicated for paediatric patients.

Administration:

The dose of nebuliser solution may need to be diluted in order to obtain a final volume suitable for the particular nebuliser being used; if dilution is necessary use only sterile sodium chloride 0.9% solution.

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, opened or damaged single dose units should be discarded.

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


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4.3 Contraindications

COMBIVENT UDVs are contraindicated in patients with hypertrophic obstructive cardiomyopathy or tachyarrhythmia.

COMBIVENT UDVs are also contraindicated in patients with a history of hypersensitivity to ipratropium bromide, salbutamol sulphate or to atropine or its derivatives.


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4.4 Special warnings and precautions for use

Immediate hypersensitivity reactions may occur after administration of COMBIVENT UDVs, 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 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.

In the following conditions COMBIVENT UDVs should only be used after careful risk/benefit assessment:

Inadequately 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.

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 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.

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

Cardiovascular effects may be seen with sympathomimetic drugs, including COMBIVENT. There is some evidence from post-marketing data and published literature 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.

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).


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4.5 Interaction with other medicinal products and other forms of interaction

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.

Beta-adrenergic agonists should be administered with caution to 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.


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4.6 Fertility, pregnancy and lactation

The safety of COMBIVENT during human Pregnancy has not been established. The inhibitory effect of COMBIVENT on uterine contraction should be taken into account. The benefits of using COMBIVENT during a confirmed or suspected pregnancy must be weighed against possible hazards to the unborn child. The usual precautions regarding the use of drugs in pregnancy, especially during the first trimester, should be observed.

For ipratropium bromide, preclinical studies have shown no embryotoxic or teratogenic effects following inhalation or intranasal application at doses considerably higher than those recommended in man. For salbutamol sulphate, non-inhalation preclinical studies did not indicate direct or indirect harmful effects unless the inhalation Maximum Recommended Human Daily Dose (MRHDD) was exceeded.

It is not known whether ipratropium bromide and salbutamol sulphate are excreted in breast milk. Although lipid-insoluble quaternary cations pass into breast milk, it is considered unlikely that ipratropium bromide would reach the infant to an important extent, when administered by inhalation. However, because many drugs are excreted in breast milk, caution should be exercised when COMBIVENT is administered to nursing mothers.

No studies on the effect on human fertility have been conducted for COMBIVENT. Preclinical studies performed with ipratropium bromide and salbutamol showed no adverse effect on fertility.


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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. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.


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4.8 Undesirable effects

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. Adverse drug reactions were identified from data obtained in clinical trials and pharmacovigilance during post approval of the drug.

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

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

Immune system disorders:

Anaphylactic reaction

Rare

Hypersensitivity

Rare

Metabolism and nutrition disorders:

Hypokalaemia

Rare

Psychiatric disorders:

Nervousness

Uncommon

Mental disorder

Rare

Nervous system disorders:

Dizziness

Uncommon

Headache

Uncommon

Tremor

Uncommon

Eye disorders:

Accommodation disorder

Rare

Corneal oedema

Rare

Glaucoma

Rare

Eye pain

Rare

Intraocular pressure increased

Rare

Mydriasis

Rare

Vision blurred

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

Bronchospasm

Rare

Bronchospasm paradoxical

Rare

Dry throat

Rare

Laryngospasm

Rare

Pharyngeal oedema

Rare

Gastrointestinal disorders:

Dry mouth

Uncommon

Nausea

Uncommon

Throat irritation

Uncommon

Diarrhoea

Rare

Constipation

Rare

Gastrointestinal motility disorder

Rare

Oedema mouth

Rare

Stomatitis

Rare

Vomiting

Rare

Skin and subcutaneous tissue disorders:

Skin reactions (such as rash,pruritus, urticaria)

Uncommon

Angioedema

Rare

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

Rare

General disorders and administration site conditions:

Asthenia

Rare

Investigations:

Blood pressure systolic increased:

Uncommon

Blood pressure diastolic decreased:

Rare

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 preferably through the online reporting option accessible from the IMB homepage. A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’. Alternatively, the traditional post-paid ‘yellow card’ option may also continue to be used.

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Ireland

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie


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4.9 Overdose

Acute effects of overdosage with ipratropium bromide are mild and transient in nature (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. 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.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In preclinical studies, it appears to inhibit vagally mediated reflexes by antagonising the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increase in intracellular concentration of Ca++ which is caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle. Ca++ release is mediated by the second messenger system consisting of IP3 (inositol triphosphate) and DAG (diacylglycerol).

The bronchodilation following inhalation of ipratropium bromide is primarily local and site specific to the lung and not systemic in nature.

Salbutamol 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 bronchoconstrictor challenges.

COMBIVENT UDVs provide the simultaneous delivery of ipratropium bromide and salbutamol sulphate allowing effects on both muscarinic and beta2-adrenergic receptors in the lung leading to increased bronchodilation over that provided by each agent singly.


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5.2 Pharmacokinetic properties

Ipratropium:

Cumulative renal excretion (0-24 hrs) of ipratropium (parent compound) is approximated to 46% of an intravenously administered dose, below 1% of an oral dose and approximately 3 to 4% of an inhaled dose. Based on these data, the total systemic bioavailability of oral and inhaled doses of ipratropium bromide is estimated at 2% and 7 to 28% respectively.

Taking this into account, swallowed dose portions of ipratropium bromide do not relevantly contribute to systemic exposure.

Kinetic parameters describing the disposition of ipratropium bromide were calculated from plasma concentrations after i.v. administration. A rapid biphasic decline in plasma concentrations is observed. The apparent volume of distribution at steady-state (Vdss) is approximately 176 L (≈ 2.4 L/kg). The drug is minimally (less than 20%) bound to plasma proteins. Preclinical studies with rats and dogs revealed that the quarternary amine ipratropium does not cross the blood-brain barrier.

The half-life of the terminal elimination phase is approximately 1.6 hours.

Ipratropium has a total clearance of 2.3 L/min and a renal clearance of 0.9 L/min. After intravenous administration approximately 60% of a dose is metabolised probably mainly in the liver by oxidation.

In an excretion balance study cumulative renal excretion (6 days) of drug-related radioactivity (including parent compound and all metabolites) accounted for 72.1% after intravenous administration, 9.3% after oral administration and 3.2% after inhalation. Total radioactivity excreted via the faeces was 6.3% following intravenous application, 88.5% following oral dosing and 69.4% after inhalation. Regarding the excretion of drug-related radioactivity after intravenous administration, the main excretion occurs via the kidneys. The half-life for elimination of drug-related radioactivity (parent compound and metabolites) is 3.6 hours. The main urinary metabolites bind poorly to the muscarinic receptor and have to be regarded as ineffective.

Salbutamol is rapidly and completely absorbed following oral administration either by the inhaled or the gastric route and has an oral bioavailability of approximately 50%. Mean peak plasma salbutamol concentrations of 492 pg/ml occur within three hours after inhalation of COMBIVENT. Following this single inhaled administration, approximately 27% of the estimated mouthpiece dose is excreted unchanged in the 24 hour urine.

Kinetic parameters were calculated from plasma concentrations after i.v. administration. The apparent volume of distribution (Vz) is approximately 156 L (≈ 2.5 L/kg). Only 8% of the drug is bound to plasma proteins. Salbutamol will cross the blood brain barrier reaching concentrations amounting to about 5% of the plasma concentrations. The mean terminal half life is approximately 4 hours with a mean total clearance of 480 mL/min and a mean renal clearance of 291 mL/min.

Salbutamol is conjugatively metabolised to salbutamol 4'-O-sulphate. The R(-)- enantiomer of salbutamol (levosalbutamol) is preferentially metabolised and is therefore cleared from the body more rapidly than the S(+) - enantiomer. Following intravenous administration, urinary excretion was complete after approximately 24 hours. The majority of the dose was excreted as parent compound (64.2) and 12.0% were excreted as sulphate conjugate. After oral administration urinary excretion of unchanged drug and sulphate conjugate were 31.8% and 48.2 of the dose, respectively.

Co-administration of ipratropium bromide and salbutamol sulphate does not potentiate the systemic absorption of either component and therefore the additive activity of COMBIVENT is due to the combined local effect on the lung following inhalation.


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5.3 Preclinical safety data

The individual active ingredients, ipratropium bromide and salbutamol sulphate, have been extensively investigated in animal models and there are no clinically relevant safety issues when COMBIVENT UDVs are used at the recommended doses by patients.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Sodium chloride

Hydrochloric acid

Purified water


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6.2 Incompatibilities

In the absence of compatibility studies, it is strongly recommended not to mix COMBIVENT UDVs with other drugs in the same nebuliser.


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6.3 Shelf life

2 years

As the product contains no preservatives, a fresh vial should be used for each administration and the vial should be opened immediately before administration. Any solution left in the vial should be discarded.


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6.4 Special precautions for storage

Do not store above 25°C. Do not freeze. Keep container in the outer carton.


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6.5 Nature and contents of container

Low density polyethylene (LDPE) vials containing 2.5 ml of solution, formed into strips of 10 and packed into cartons containing 10, 20 or 60 vials.

Not all pack sizes may be marketed.


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6.6 Special precautions for disposal and other handling

Not applicable.


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7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

United Kingdom


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8. MARKETING AUTHORISATION NUMBER(S)

PA 7/52/2


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 7 March 1997

Date of last renewal: 13 November 2005


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10. DATE OF REVISION OF THE TEXT

June 2014



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