CORE BROMHEXINE PRODUCT INFORMATION

Product description This section should include: a description of the dosage form; a list of the active ingredients expressed quantitatively; and a list of the excipients expressed qualitatively

QUALITATIVE AND QUANTITATIVE COMPOSITION Bromhexine Hydrochloride 4mg/5ml Syrup, colourless liquid

PHARMACEUTICAL FORM Syrup

Pharmacology

Therapeutical indications As assistant agent for the liquefaction of the mucous secretions of the respiratory passageway in cases of acute and chronic bronchopulmonary diseases (bronchitis, emphysema, chronic asthmatic bronchitis) During acute exacerbations of bronchitis it must be administered in combination with the appropriate antibiotic. Therapeutic indications As a mucolytic in the management of viscid mucoid secretions associated with bronchitis, bronchiectasis, sinusitis. Dosage Oral. Adults and children over 12 years: Children 5 - 12 years: Children 2 - 5 years: 2 5 ml three times daily to 3 5 ml four times daily. 1 5 ml four times daily. 1 5 ml twice daily.

BISOLVON Oral Solution is sugar free and therefore suitable for diabetics. Pharmacodynamics

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Bromhexine is an agent that regulates the mucus, which is useful in the decrease of the tenacity of the bronchial secretions. When it is administered orally, it is absorbed rapidly and its action appears 30 minutes to 1 hour later. When it is administered in inhalation form its action appears in 10-15 minutes. The immediate action of bromhexine appears with an increase in the quantity of the sputum, which appears 23 days after the initiation of the treatment. By the cleavage of the fibers of the acid mucopolysaccharides the bronchial secretion is diluted and the expectoration is facilitated. Bromhexine also ameliorates the efficiency of the bronchodilators.

Pharmacokinetics: Bromhexine hydrochloride is rapidly absorbed from the gastrointestinal tract and undergoes extensive first-pass metabolism in the liver. Its oral bioavailability is stated to be only about 20%. It is widely distributed to body tissues and is highly bound to plasma proteins. About 85 to 90% of a dose is excreted in the urine mainly as metabolites. It has a terminal elimination half-life of up to about 12 hours. Bromhexine crosses the blood brain barrier and small amounts cross the placenta. Bromhexine hydrochloride is rapidly absorbed by the gastrointestinal tract and about 85-90% of the administered dose is excreted in the urine mainly in metabolite form. The maximum concentration in plasma appears after about an hour later. The half-life time is about 6.5 hours. Bromhexine is strongly bound to the plasma proteins in a percentage 95-98%. The bioavailiability is about 20-25% of the administered dose because of the phenomenon of the first passage in the liver. Absorption Bromhexine is rapidly and completely absorbed from the gastrointestinal tract. After oral administration solid and liquid formulations show similar bioavailability. The absolute bioavailability of bromhexine hydrochloride was about 22.2 8.5 % and 26.8 13.1 % for BISOLVON tablets and solution, respectively. The first pass metabolism amounts to about 75-80%. Concomitant food leads to an increase of bromhexine plasma concentrations. Distribution After intravenous administration bromhexine was rapidly and widely distributed throughout the body with a mean volume of distribution (Vss) of up to 1209 206 L (19 L/kg). The distribution into lung tissue (bronchial and parenchymal) was investigated after oral administration of 32 mg and 64 mg bromhexine. Lung tissue concentrations two hours post dose 1.5 -4.5 times higher in bronchiolo-bronchial tissues and between 2.4 and 5.9 times higher in pulmonary parenchyma compared to plasma concentrations. Unchanged bromhexine is bound to plasma proteins by 95 % (non-restrictive binding). Metabolism Bromhexine is almost completely metabolised to a variety of hydroxylated metabolites and to dibromanthranilic acid. All metabolites and bromhexine itself are conjugated most probably in form of N-glucuronides and Oglucuronides. There are no substantial hints for a change of the metabolic pattern by a sulphonamide or oxytetracyclin. There is insufficient pharmacokinetic data to evaluate a possible drug-drug interaction between bromhexine and erythromycin. Elimination Bromhexine is a high extraction ratio drug after i.v. administration in the range of the hepatic blood flow, 843-1073 mL/min resulting in high inter- and intraindividual variability (CV > 30 %) After administration of radiolabelled bromhexine about 97.4 1.9 % of the dose were recovered as radioactivity in urine, with less than 1% as parent compound. Bromhexine plasma concentrations showed a multiexponential decline. After administration of single oral doses between 8 and 32 mg, the terminal elimination half-life ranged between 6.6 and 31.4 hours. The relevant half-life to

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predict the multiple dose pharmacokinetics is about 1 hour, thus no accumulation was seen after multiple dosing (accumulation factor 1.1). General Bromhexine shows dose proportional pharmacokinetics in the range of 8-32 mg following oral administration. There are no data for bromhexine pharmacokinetics in the elderly or in patients with renal or liver insufficiency. Bromhexine pharmacokinetics are not relevantly affected by co-administration of ampicillin or oxytetracycline. Interaction studies with oral anticoagulants or digoxin were not performed. Pharmacodynamics/Mechanism of action: Bromhexine is an oral mucolytic agent with a low level of associated toxicity. Bromhexine acts on the mucus at the formative stages in the glands, within the mucus-secreting cells. Bromhexine disrupts the structure of acid mucopolysaccharide fibres in mucoid sputum and produces a less viscous mucus, which is easier to expectorate.

Overdosage Treatment Until now the symptoms of the bromhexine poisoning are not known. If they appear, symptomatic therapy is recommended.

Indications This section must contain the indications of the product as specified in the ARTG. If the indications are not specified in the ARTG (e.g. for a non-validated grandfathered product), the indications must be as specified on the product label.

Dosage This section must contain the current dosage instructions of the registered product, as specified on the product label.

Contraindications

Bromhexine is contraindicated for use in patients with known hypersensitivity or idiosyncratic reaction to bromhexine hydrochloride (or any of the other ingredients in the product).

Precautions Since mucolytics may disrupt the gastric mucosal barrier, bromhexine should be used with caution in patients with a history of gastric ulceration. Clearance of bromhexine or its metabolites may be reduced in patients with severe hepatic or renal impairment.

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Use in pregnancy Category A: Bromhexine has been taken by a large number of pregnant women and women of child bearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed.

Lactation It is not known whether bromhexine is excreted in breast milk or whether it has a harmful effect on the breastfeeding infant. Therefore it is not recommended for breastfeeding mothers unless the potential benefits to the patient are weighed against the possible risk to the infant. Pregnancy and lactation By experiments realized in animals there is no evidence that the drug has any effect on fetal development. As the studies in humans are limited so as to have safe conclusions, its use must be avoided during pregnancy and lactation. Bromhexine and Pregnancy Category A: Bromhexine has been taken by a large number of pregnant women and women of child bearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed. Bromhexine and Lactation It is not known whether bromhexine is excreted in breast milk or whether it has a harmful effect on the breastfeeding infant. Therefore it is not recommended for breastfeeding mothers unless the potential benefits to the patient are weighed against the possible risk to the infant. Special warnings and special precautions on use It must be administered with caution to patients with active duodenal ulcer, active tuberculosis or severe hepatic lesions. During the use of the drug an increase of the volume of the liquefied bronchial secretions may be induced and if they are not removed by the cough, special support may be needed in order to keep the respiratory passageways open. Attention in the administration: The drug must not be administered simultaneously to antitussive agents or to drugs with atropinic activity. BRONCHOTUSSINE contains Sorbitol E420. Therefore, patients with rare hereditary problems of fructose intolerance should not take this medicine without physicians advice. The probability of allergic reactions due to the presence of Methyl paraben E218 and Propyl paraben E216 should be considered while taking this medication. BRONCHOTUSSINE contains Ethanol 2,4% vol (alcohol) i.e. up to 100mg per dose (5ml), equivalent to 2,5ml beer, 1ml wine per dose. It is harmful for those suffering from alcoholism. To be taken into account in pregnant or breast feeding women, children and high risk groups such as patients with liver disease, or epilepsy. Bromhexine should be used with caution in patients with a history of, or existing, peptic ulceration. There have been very few reports of severe skin lesions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) in temporal association with the administration of expectorants such as bromhexine. Mostly these could be explained by the patient's underlying disease and/or concomitant medication. In addition during the early phase of a Stevens-Johnson syndrome or TEN a patient can first experience non-specific influenza-like prodomes e.g. fever, aching body, rhinitis, cough and sore throat. Misled by these non-specific influenza-like prodomes it is possible that a symptomatic treatment is started with a cough and cold medication. Therefore, if skin or mucosal lesions occur, medical advice should be sought immediately and treatment with bromhexine discontinued as a precaution.

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Interaction with other medicines There are no known significant interactions with other medicines. Interactions with other drugs and other forms of interaction The administration of the bromhexine simultaneously to antibiotics (amoxicillin, cefuroxime, erythromycine, doxycycline) leads to an increase of the bronchopulmonar distribution (penetration) of the antibiotics. No relevant negative clinical side effect has been reported with other drugs.

Adverse reactions Gastrointestinal side effects may occur occasionally with bromhexine and a transient rise in serum aminotransferase values has been reported. Other reported adverse effects include headache, vertigo (dizziness), sweating and allergic reactions. Gastrointestinal symptoms (epigastric discomfort, nausea, vomiting, diarrhea) may be present, which generally are mild and sometimes transient increase of the transaminases. Rarely allergic skin reactions have been reported. atau The following side effects have been reported based on clinical trials involving 3,992 patients 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 cannot be estimated from the available data Immune system disorders Hypersensitivity Anaphylactic reaction* Anaphylactic shock* Rare Not known Not known

Respiratory, thoracic and mediastinal disorders Bronchospasm* Gastro-intestinal disorders Abdominal pain upper Nausea Uncommon Uncommon Not known

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Vomiting Diarrhoea

Uncommon Uncommon

Skin and subcutaneous tissue disorders Rash Angioedema* Urticaria* Pruritus* Rare Not known Not known Not known

*This adverse reaction has been observed in post-marketing experience. With 95 % certainty, the frequency category is not greater than rare (3/3,992), but might be lower. A precise frequency estimation is not possible as the adverse drug reaction did not occur in a clinical trial database of 3,992 patients.

Overdosage In case of overdose, immediately contact the Poisons Information Centre (in Australia, call 13 11 26; in New Zealand call 0800 764 766) for advice. No specific overdose symptoms have been reported in man to date. Based on accidental overdose and/or medication error reports the observed symptoms are consistent with the known side effects of Bisolvon at recommended doses and may need symptomatic treatment.

Presentation Information should be included on: the presentation, including dosage form and pack sizes; identifying details (eg. colour, shape, identifying markings); poisons schedule details; and name and address of the sponsor.

Include the date of approval as the date on which the notification application is lodged

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