Informations for option: Copralineb 0.5 Mg/2.5 Mg Per 2.5 Ml Nebuliser Solution, show other option

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1. Copralineb 0.5 Mg/2.5 Mg Per 2.5 Ml Nebuliser Solution
2. Copralineb 0.5 Mg/2.5 Mg Per 2.5 Ml Nebuliser Solution

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Copralineb 0.5 mg/2.5 mg per 2.5 ml Nebuliser Solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 2.5ml ampoule contains 0.5mg ipratropium bromide (as 525 micrograms ipratropium bromide monohydrate) and 2.5mg salbutamol (as sulphate).

For the full list of excipients see section 6.1.

3    PHARMACEUTICAL FORM

Nebuliser Solution.

A polyethylene ampoule containing clear, colourless solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Copralineb is indicated for the management of bronchospasm in patients suffering from chronic obstructive pulmonary disease (COPD) who require regular treatment with both ipratropium bromide and salbutamol.

4.2 Posology and method of administration

For inhalation use.

The recommended dose is:

Adults (including elderly patients and children over 12 years): The content of one ampoule three or four times daily.

Children: Copralineb is not recommended in children below 12 years of age due to lack of data on safety and efficacy

Copralineb may be administered from a suitable nebuliser, e.g. PARI LC PLUS Nebuliser, jet nebulizer, or an intermittent positive pressure ventilator after the single dose ampoule has been opened and its contents transferred to the nebuliser chamber. The use of the solution for nebulization is not only limited to the given examples, but can also be based on the experience of the clinical professional. For full instructions on the use of the nebuliser the patient should be instructed to read the leaflet of the respective device carefully before starting the inhalation.

Drug delivery characteristics were studied in vitro using the PARI LC PLUS nebuliser device:

Droplet size distribution (micrometer)			Drug delivery rate (micrograms/ min)	Total drug delivered (micrograms /2,5 ml)
D 1 0	D 5 0	D 9 0
1	4	1 0	Salbutamol: 78.30 Ipratropium: 15.31	Salbutamol: 532.96 Ipratropium: 106.23

No information is available in respect of pulmonary inhalation and deposition patterns across nebuliser systems that have not been studied.

The use of an alternative untested nebuliser system may alter the pulmonary deposition of the active substances, this in turn may alter the efficacy and safety of the product and dose adjustment may then become necessary.

The nebuliser solution in the single dose ampoules is intended for inhalation use only and should not be taken orally or administered parenterally.

i. Prepare the nebuliser by following the manufacturer’s instructions and the advice of your doctor.

ii. Carefully separate a new ampoule from the strip. Never use an ampoule that has been opened already.

iii. Open the ampoule by simply twisting off the top always taking care to hold it in an upright position.

iv. Unless otherwise instructed by your doctor, squeeze all the contents of the plastic ampoule into the nebuliser chamber.

v. Assemble the nebuliser and use it as directed by your doctor. The duration of treatment for the inhalation of a complete dose is usually between five and 15 minutes.

vi. After nebulisation clean the nebuliser according to the manufacturer’s instructions. It is important that the nebuliser is kept clean.

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

Any nebuliser solution remaining in the nebuliser chamber should be discarded.

It is strongly recommended that Copralineb should not be mixed with other drugs in the same nebuliser

4.3 Contraindications

Patients with hypertrophic obstructive cardiomyopathy or tachyarrhythmia.

Patients with hypersensitivity to salbutamol, ipratropium bromide or to atropine or its derivatives.

4.4 Special warnings and precautions for use

Copralineb should not be used in children (see section 4.2).

Patients should be instructed to consult a doctor immediately in the event of acute, rapidly worsening dyspnoea or if a reduced response to treatment becomes apparent.

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

As with other inhalation therapy there is a risk of inhalation-induced bronchoconstriction or paradoxical bronchospasm. If this occurs the patient will experience an immediate increase in wheezing and shortness of breath after dosing, which should be treated straightaway with an alternative presentation or different fast-acting inhaled bronchodilator. Copralineb should be discontinued immediately, the patient should be assessed and, if necessary, alternative therapy instituted.

There are also rare reports of a number of ocular complications when aerosolised ipratropium bromide, either alone or in combination with a beta2-adrenergic agonist, has been inadvertently sprayed into the eye. Patients must therefore be instructed in the correct use of Copralineb with their nebuliser and must be warned not to allow the nebuliser solution or mist to enter the eyes. To avoid inadvertent entry of drug into the eye, it is preferable to administer the nebulised suspension using a mouthpiece rather than a face mask.

Such ocular complications may include acute angle glaucoma, mydriasis, blurring of vision, increased intraocular pressure, eye pain and narrow-angle glaucoma. Patients who may be susceptible to glaucoma should be warned specifically about the need for ocular protection. Antiglaucoma therapy is effective in the prevention of acute narrow-angle glaucoma in susceptible individuals.

Eye pain or discomfort, blurred vision, visual halos or coloured spots together with red eyes from conjunctival congestion or corneal oedema may be manifestations of acute narrow-angle glaucoma. If a combination of these symptoms develops, treatment with miotic eye drops should be initiated and the patient should seek specialist advice immediately.

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

Caution should be exercised when Copralineb is used by patients with cardiac disease (severe heart disease, ischaemic disease, arrhythmias). Patients should be advised if they experience chest pain and or dyspnoea that they should contact their emergency services.

Cardiovascular effects may be seen with sympathomimetic drugs, including salbutamol. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischaemia associated with beta-agonists. Patients with underlying severe heart disease (e.g. ischaemic heart disease, arrhythmias or severe heart failure) who are receiving salbutamol 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 either respiratory or cardiac in origin.

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, diuretics and steroids.

Hypokalaemia can bring about increased sensitivity to arrhythmias in patients being treated with digoxin. Additionally, hypoxia may aggravate the effects of hypokalaemia on cardiac rhythm. It is recommended that serum levels of potassium are monitored in such situations.

Patients with cystic fibrosis may be more prone to disturbances in gastrointestinal motility and therefore ipratropium bromide, as with other anticholinergics, should be used with caution in these patients.

If it is necessary to use higher doses than recommended to control the symptoms of bronchoconstriction (or bronchospasm) the patient’s treatment plan should be reassessed.

Dental caries has been reported with salbutamol use. It is recommended, particularly in children, to pay attention to proper oral hygiene and perform regular dental checkups.

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent use of additional beta₂-agonists, corticosteroids, anticholinergics and xanthine derivatives may enhance the effect of Copralineb on airway function and may increase the severity of side effects. Due to opposing pharmacodynamic interaction with the salbutamol element, a potentially serious reduction in effect may occur during concurrent administration of beta-blockers such as propranolol.

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

Inhalation of anaesthetics containing halogenated hydrocarbons, e.g. halothane, trichloroethylene and enflurane, may increase the susceptibility to cardiovascular side effects of beta₂-agonists, which should therefore be monitored closely. Alternatively discontinuation of Copralineb prior to surgical operation should be considered.

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, diuretics and steroids. Potentially serious arrhythmias may occur during concomitant administration of digoxin and Copralineb. The interaction risk is aggravated by hypokalaemia and should be monitored regularly. Hypokalaemia can bring about increased sensitivity to arrhythmias in patients being treated with digoxin.

The effect of other anticholinergic products may be potentiated.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of ipratropium bromide and salbutamol together in pregnant women (in early stages of pregnancy). In animal studies there has been evidence of some harmful effects on the foetus at very high dose levels. The potential risk for humans is unknown. Copralineb should not be used during pregnancy unless clearly necessary and caution should be exercised when prescribing to pregnant women (especially in the first trimester).

Lactation

It is unknown whether ipratropium bromide is excreted into human breast milk. Salbutamol is excreted in human breast milk. There is insufficient/limited information on the excretion of Copralineb in human or animal breast milk. A risk to the suckling child cannot be excluded. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with Copralineb should be made taking into account the benefit of breast-feeding to the child and the benefit of Copralineb to the mother.

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 Copralineb. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Undesirable effects

Based on the MedDRA system organ class and frequencies, adverse events are listed in the table below.

Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1 000 to < 1/100), rare (>1/10 000 to <1/1 000), very rare (<1/10 000) and not known (cannot be estimated from the available data).

System organ class	Symptom	Frequency
Immune system	Anaphylactic reaction, angioedema of the face,	Rare
disorders	lips and throat
Metabolism and nutritional disorders	Hypokalaemia	Rare
Psychiatric disorders	Restlessness, memory disorders, anxiety, hyperactivity in children	Rare
Nervous system	Headache	Common
disorders	Dizziness, feeling nervous	Uncommon
	Depression, sweating,	Rare
Eye disorders	Accommodation disorders	Common
	Closed-angle glaucoma, increased intraocular pressure, pain in the eye, mydriasis	Rare
Cardiac disorders	Palpitations, tachycardia	Common
	Increased systolic blood pressure, arrhythmias	Uncommon
	Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles), coronary ischaemic disease, decrease in diastolic blood pressure, peripheral vasodilatation.	Rare

4.9 Overdose

Acute effects of overdose with ipratropium bromide are unlikely due to its poor systemic absorption after either inhalation or oral administration. Any effects of overdose are therefore likely to be related to the salbutamol component.

Symptoms

Manifestations of overdose with salbutamol may include anginal pain, hypertension, hypotension, hypokalaemia, tachycardia, arrhythmia, chest pain, tremor, flushing, restlessness and dizziness. Patients should therefore be monitored closely for the potential unwanted effects from overdose of salbutamol. Hypokalaemia may occur following overdose with salbutamol and therefore serum potassium levels should be monitored.

Treatment

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

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Adrenergics and other drugs for obstructive airway diseases ATC code: R03A K04.

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

Salbutamol is a beta₂-adrenergic agonist, 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.

Copralineb provides the simultaneous delivery of ipratropium bromide and salbutamol sulphate producing effects on both muscarinic and beta2-adrenergic receptors in the lung. This provides enhanced bronchodilation over that provided by each agent singly.

5.2 Pharmacokinetic properties

Ipratropium bromide is poorly absorbed after inhalation and systemic bioavailability is estimated to be less than 10% of the administered dose. Renal excretion is 46% of the dose and terminal elimination half-life is about 1.6 hours after intravenous administration. The half-life is 3.6 hours for total drug and metabolites after radiolabelling. Ipratropium bromide does not cross the blood-brain barrier.

Salbutamol is rapidly and completely absorbed following inhalation. Peak plasma salbutamol concentrations are seen within three hours of administration and the drug is excreted unchanged in the urine after 24 hours. The elimination half-life is 37 hours. Salbutamol will cross the blood-brain barrier reaching concentrations about 5% of plasma concentrations.

Co-nebulisation of ipratropium bromide and salbutamol sulphate does not potentiate the systemic absorption of either component. The increased pharmacodynamic activity of Copralineb is due to the combined local effect of both drugs on the lung.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, carcinogenic potential or toxicity to reproduction.

6.1 List of excipients

Sodium chloride

Sulfuric acid (for pH adjustment) Water for injections

6.2    Incompatibilities

Not applicable

6.3    Shelf life

2 years

After first opening the ampoules:

Use immediately, discard any unused contents

6.4 Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze.

Keep ampoules in the outer pouch or carton in order to protect from light.

6.5 Nature and contents of container

The pack is a Plastic Form fill Seal (FFS) ampoule (made of low-density polyethylene) containing 2.5 ml of nebuliser solution, 5 of which are over wrapped in a triple laminated pouch (polyester film/aluminium foil/ polyethylene film) and then packed into cardboard cartons.

Pack sizes: 10, 20, 30, 40, 50, 60, 80, 100, 120 and 150 ampoules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

For single use only. Use immediately after first opening the ampoule.

Discard immediately after first use.

Partly used, opened or damaged ampoules should be disposed in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Sandoz Ltd

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 04416/1296

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/01/2013

10    DATE OF REVISION OF THE TEXT

16/05/2013