Secretolytic therapy in acute and chronic bronchopulmonary diseases associated with impaired mucus formation and transport.

Posology
Children up to 2 years of age:
2.5 ml of solution twice daily (equivalent to 15 mg ambroxol hydrochloride per day)
Children from 2 to 5 years of age:
2.5 ml of solution three times daily (equivalent to 22.5 mg ambroxol hydrochloride per day)
Children from 6 to 12 years of age:
5 ml of solution 2 – 3 times daily (equivalent to 30 – 45 mg ambroxol hydrochloride per day)
Adults and adolescents over 12 years of age:
The usual dose is 10 ml of solution three times daily (equivalent to 90 mg ambroxol hydrochloride per day) for the first 2 – 3 days and 10 ml of solution twice daily (equivalent to 60 mg ambroxol hydrochloride per day) thereafter.
For adults and adolescents over 12 years of age, the therapeutic effect may be enhanced by increasing the dose to 20 ml of solution twice daily (equivalent to 120 mg ambroxol hydrochloride per day).

For adults and adolescents over 12 years of age the use of the higher-strength Mucosolvan cough syrup 30 mg/5 ml is recommended.
Under medical advice the duration of use is not limited. Patients are instructed in the package leaflet to not take Mucosolvan paediatric syrup 15 mg/5 ml for more than 4 – 5 days without medical advice.
Method of administration
Mucosolvan paediatric syrup 15 mg/5 ml can be taken with or without food and is dispensed with the aid of the measuring cup provided.
Notes:
Mucosolvan paediatric syrup 15 mg/5 ml is suitable for diabetics. 5 ml of the solution is equivalent to 0 carbohydrate units.
Mucosolvan paediatric syrup 15 mg/5 ml does not contain alcohol.

There have been reports of severe skin reactions such as erythema multiforme, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and acute generalised exanthematous pustulosis (AGEP) associated with the administration of ambroxol hydrochloride. If symptoms or signs of a progressive skin rash (sometimes associated with blisters or mucosal lesions) are present, ambroxol hydrochloride treatment should be discontinued immediately and medical advice should be sought.
In patients with impaired bronchial motility and copious secretions (as seen, for instance, in the rare syndrome of primary ciliary dyskinesia), Mucosolvan paediatric syrup 15 mg/5 ml must be used with caution because of the risk that it may promote accumulation of secretions.
In patients with impaired kidney function or severe liver disease, Mucosolvan should not be used except on medical advice. With ambroxol, as with any medicine that is metabolized hepatically and excreted renally, accumulation of the metabolites of ambroxol which are formed in the liver can be expected to occur in patients with severe renal failure.

Simultaneous use of Mucosolvan paediatric syrup 15 mg/5 ml and cough suppressants may lead to the development of a dangerous accumulation of secretions owing to the reduction of the cough reflex and should be undertaken only after a careful benefit/risk assessment.

Pregnancy
Ambroxol hydrochloride crosses the placental barrier. Non-clinical studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, labour and delivery or postnatal development. Extensive clinical experience after the 28th week of pregnancy has shown no evidence of harmful effects on the foetus. However, the usual precautions concerning the administration of any medicine during pregnancy should be observed. The use of Mucosolvan is not recommended during the first trimester of pregnancy in particular.

Breast-feeding
Ambroxol has been shown to pass into breast milk in animal studies. Use while breast-feeding is not recommended.
Fertility
Non-clinical studies do not indicate direct or indirect harmful effects with respect to fertility.

There is no evidence from postmarketing data for an effect on the ability to drive or use machines. Studies on the effects on the ability to drive and use machines have not been performed.

The following categories are normally used when reporting the frequencies of side effects:

Immune system disorders
Rare:
Hypersensitivity reactions
Not known:
Anaphylactic reactions including anaphylactic shock, angioedema and pruritus
Skin and subcutaneous tissue disorders
Rare:
Rash, urticaria
Not known:
Severe cutaneous adverse reactions (including erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis and acute generalized exanthematous pustulosis).
Nervous system disorders
Common:
Dysgeusia (e.g. changed taste)
Gastrointestinal disorders
Common:
Nausea, oral hypoaesthesia
Uncommon:
Vomiting, diarrhoea, dyspepsia, abdominal pain, dry mouth
Rare:
Dry throat
Very rare:
Sialorrhoea
Respiratory, thoracic and mediastinal disorders
Common:
Pharyngeal hypoaesthesia

Not known:
Dyspnoea (as a symptom of a hypersensitivity
reaction)
General disorders and administration site conditions
Uncommon:
Fever, mucous membrane reactions
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.
To report any side effect(s):
• Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 8002490000
o Calling: 19999
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

• Other GCC States:

− Please contact the relevant competent authority.

No specific symptoms of overdose have been reported to date. The symptoms observed in cases of accidental overdose or medication error are consistent with the known side effects at the recommended dose and may require symptomatic treatment.

Pharmacotherapeutic group: Mucolytics ATC code: R05CB06
In preclinical investigations, ambroxol hydrochloride, the active substance in Mucosolvan, has been shown to increase the proportion of serous bronchial secretion. Ambroxol hydrochloride also increases the production of surfactant by acting directly on type II pneumocytes in the alveoli and Clara cells in bronchioles and simulating the activity of the cilia of the ciliated epithelium. These effects result in reduced viscosity of the mucus and improved transport (mucociliary clearance). Improved mucociliary clearance has been proven in clinical pharmacological studies.
The increased production and reduced viscosity of secretions and improved mucociliary clearance support expectoration and facilitate the coughing up of phlegm.
Long-term use (6 months) of Mucosolvan (Mucosolvan® prolonged-release capsules 75 mg) in COPD patients led to substantially reduced exacerbations after a treatment period of 2 months. Patients treated with Mucosolvan missed significantly fewer days of work due to illness and the duration of treatment with antibiotics was reduced. In comparison with a placebo, treatment with Mucosolvan prolonged-release capsules showed a statistically significant improvement in symptoms with regard to expectoration problems, coughing, dyspnoea and auscultatory signs.
The local anaesthetic effect of ambroxol hydrochloride was studied on the eyes of rabbits. It is likely due to its blocking effect on the sodium channels. Ambroxol hydrochloride blocks the hyperpolarized channels in cloned voltage-dependent neuronal sodium channels in vitro. The bond was reversible and concentration-dependent.
It was determined in vitro that ambroxol hydrochloride has an anti-inflammatory effect. Thus, ambroxol hydrochloride significantly reduced the cytokine release of mononuclear and polymorphonuclear cells in the blood and tissue.

Clinical studies in patients with a sore throat demonstrated that ambroxol hydrochloride administered as a 20 mg lozenge significantly reduced pain and redness in the throat.
These pharmacological properties are consistent with the additional observation of faster pain relief that was achieved with inhalative ambroxol treatment for upper respiratory conditions in clinical efficacy studies.
Concentrations of the antibiotics amoxicillin, cefuroxime, erythromycin and doxycycline in the sputum and bronchial secretions increase after the use of ambroxol hydrochloride. No clinical relevance has yet been derived from this.

Absorption:
Absorption of immediate release oral dosage forms of ambroxol hydrochloride is fast and complete, with dose linearity in the therapeutic range. Maximum plasma levels are reached within 1 to 2.5 hours after administration of the immediate-release formulation and after a median of 6.5 hours after administration of the slow-release formulation.
The absolute bioavailability after ingesting a 30 mg tablet is 79%. The prolonged-release capsule showed a relative availability of 95% (dose-normalized) in comparison to tablets with unchanged active substance release (60 mg daily dose, 30 mg twice daily).
Distribution:
Distribution of ambroxol hydrochloride from blood to tissue is rapid and pronounced, with the highest concentration of the active substance found in the lungs. The estimated volume of distribution after oral administration is 552 litres.
In the therapeutic range, the plasma protein binding is approx. 90%.
Metabolism and elimination:
About 30% of the orally administered dose is eliminated via first-pass metabolism.
Ambroxol hydrochloride is primarily metabolized in the liver through glucuronidation and cleavage to dibromoanthranilic acid (approx. 10% of the dose). Studies in human liver microsomes have shown that CYP3A4 is responsible for the metabolism of ambroxol hydrochloride to dibromoanthranilic acid.
After 3 days of oral administration, ambroxol hydrochloride is eliminated renally, approx. 6% unchanged and approx. 26% in the form of its conjugates.
The terminal elimination half-life of ambroxol hydrochloride is about 10 hours. Total clearance is in the range of 660 ml/min, with renal clearance accounting for approx. 8% of the total clearance. After 5 days an estimated 83% of the total dose (radioactively marked) is eliminated with the urine.
Special patient groups:
The elimination of ambroxol hydrochloride is reduced in patients with impaired liver function, resulting in plasma levels that are approx. 1.3 to 2 times higher. Due to the broad therapeutic range of the active substance, a dose adjustment is not necessary.
Age and gender were not found to influence the pharmacokinetics of ambroxol hydrochloride to a clinically relevant degree. Therefore, deviating from the recommended dose is not necessary.
Food was not found to have any effect on the bioavailability of ambroxol hydrochloride.

Ambroxol has a low index for acute toxicity.
Oral use: No toxicological target organs were discovered in repeated-dose studies in rats (52 and 78 weeks), rabbits (26 weeks), mice (4 weeks) or dogs (52 weeks). The “no observed adverse effect level” (NOAEL) was 50 mg/kg/day in rats, 40 mg/kg/day in rabbits, 150 mg/kg/day in mice and 10 mg/kg/day in dogs.
Intravenous use: Toxicity studies with ambroxol hydrochloride showed no severe local or systemic toxicity including histopathology over 4 weeks in rats (4, 16 and 64 mg/kg [infusions 3 hours/day]) or in dogs (45, 90 and 120 mg/kg/day [infusions 3 hours/day]). All adverse events were reversible.
Ambroxol hydrochloride was neither embryotoxic nor teratogenic at tested oral doses of up to 3,000 mg/kg/day in rats and up to 200 mg/kg/day in rabbits. Fertility in male and female rats was not impaired at doses of up to 1,500 mg/kg/day.
The NOAEL was 50 mg/kg/day in a study on perinatal and postnatal development.
Ambroxol hydrochloride was slightly toxic for mother animals and young animals at 500 mg/kg/day (delayed development of body weight and reduced litter size).
In vitro (Ames and chromosome aberration tests) and in vivo (micronucleus test in mice) studies on genotoxicity revealed no mutagenic potential for ambroxol hydrochloride.
Ambroxol hydrochloride showed no tumorigenic potential in studies on carcinogenicity in mice (50, 200 and 800 mg/kg/day) or rats (65, 250 and 1,000 mg/kg/day) when added to food over a period of 105 and 116 weeks respectively.

Benzoic acid, hydroxyethyl cellulose, sucralose, flavouring agents, purified water

Not applicable.

This medicine does not require any special storage conditions.

Amber glass bottle with a childproof screw closure and measuring cup

Pack sizes:
Pack with 100 ml Pack with 250 ml
Not all pack sizes may available in your country

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.