Boehringer Ingelheim Limited

Bisolvon^® 4 mg/5 ml Oral Solution

Each 5 ml contains bromhexine hydrochloride 4 mg.

Excipients: contains malitol liquid

For full list of excipients, see Section 6.1.

Oral Solution

A clear to almost clear, colourless to almost colourless solution with a fruity aromatic odour.

As a mucolytic in the management of viscid mucoid secretions associated with bronchitis, bronchiectasis, sinusitis.

Oral

BISOLVON Oral solution is sugar free and therefore suitable for diabetics.

BISOLVON Oral Solution should not be used in patients known to be hypersensitive to bromhexine or other components of the formulation.

In case of rare hereditary conditions that may be incompatible with an excipient of the product (please refer to “Special warnings and precautions”) the use of this product is contraindicated.

Bromhexine should be used with caution in patients with a history of, or existing, peptic ulceration.

There have been very rare reports of severe skin lesions such as Stevens Johnson syndrome and Lyell's syndrome in temporal association with the administration of mucolytic substances such as bromhexine. Mostly these could be explained by the severity of the underlying disease or concomitant medication. If new skin or mucosal lesions occur, medical advice should be sought immediately and treatment with bromhexine discontinued as a precaution.

As the product contains maltitol liquid, patients with rare hereditary problems of fructose intolerance should not take this medicine.

No clinically relevant unfavourable interactions with other medications have been reported.

Bromhexine crosses the placental barrier. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Clinical experience to date has shown no evidence of harmful effects on the foetus during pregnancy. Nonetheless the usual precautions regarding the use of drugs during pregnancy should be observed. Especially during the first trimester, the use of BISOLVON is not recommended.

Bromhexine is excreted in breast milk. Although unfavourable effects on breastfed infants would not be expected, BISOLVON is not recommended for use in nursing mothers.

None stated.

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

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.

Bromhexine is a synthetic derivative of the herbal active ingredient vasicine. Preclinically, it has been shown to increase the proportion of serous bronchial secretion. Bromhexine enhances mucus transport by reducing mucus viscosity and by activating the ciliated epithelium (mucociliary clearance).

In clinical studies, bromhexine showed a secretolytic and secretomotor effect in the bronchial tract area, which facilitates expectoration and eases cough.

Following the administration of bromhexine antibiotic concentrations (amoxycillin, erythromycin, oxytetracycline) in the sputum and bronchopulmonary secretions are increased.

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 (V_ss) 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 O-glucuronides. 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 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.

No details on schedule.

Maltitol liquid (E965)

Sucralose (E955)

Benzoic acid (E210)

Cherry aroma 96323-33

Chocolate aroma 96534-33

Levomenthol

Water, purified

Not applicable

Unopened: 3 years.

In-use: Use within 12 months of opening bottle.

Store in the original container.

Bisolvon Oral Solution is available in amber type III glass bottles with tamper-evident polyethylene caps with low density polyethylene liners. The registered pack sizes are 100 ml, 200 ml and 250 ml.

Not all pack sizes may be marketed.

A polypropylene measuring dish is provided.

No special requirements.

Boehringer Ingelheim Limited,

Ellesfield Avenue,

Bracknell,

Berkshire,

RG12 8YS,

United Kingdom.

PA 7/25/2

Date of first Authorisation:14^th November 1984

Date of Last Renewal: 01 April 2008

August 2011