Mucum is a 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 other pharmaceutical dosage forms is recommended.

Under medical advice the duration of use is not limited. Patients are instructed in the package leaflet to not take Mucum for more than 4– 5 days without medical advice.

Method of administration

Mucum can be taken with or without food and is dispensed with the aid of the measuring cup provided.

There have been reports of severe skin reactions such as erythema multiforme, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and acute generalized  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), Mucum 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, Mucum 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.

This medicine contains benzoic acid that may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).

Simultaneous use of Mucum and cough suppressants may lead to the development of a dangerous accumulation of secretions in patients with pre-existing respiratory diseases such as cystic fibrosis or bronchiectasis who are affected by mucus hypersecretion, a reduced 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 Mucum 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 post marketing 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:

Side effects

Immune system disorders

Rare: Hypersensitivity reactions 

Not known: Anaphylactic reactions including anaphylactic shock, angioedema (rapidly developing swelling of the skin, subcutaneous, mucosa or submucosal tissues) 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 generalised exanthematous pustulosis). 

Nervous system disorders

Common: Dysgeusia (e.g. changed taste)

Gastrointestinal disorders

Common: Nausea, oral hypoaesthesia

Uncommon: Vomiting, diarrhoea, indigestion, 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

Healthcare professionals are asked to report any suspected adverse reactions via:

• UAE:

Pharmacovigilance and Medical Device Section

Drug Department - U.A.E MOHAP

Hotline: 80011111

Email: pv@mohap.gov.ae

P.O. Box: 1853 Dubai U.A.E.

• Oman:

Department of Pharmacovigilance & Drug Information

Directorate General of Pharmaceutical Affairs & Drug Control

Ministry of Health, Sultanate of Oman

Phone Nos. 0096822357687 / 0096822357686

Fax: 0096822358489

Email: dg-padc@moh.gov.om

Website: www.moh.gov.om

• Saudi Arabia:

The National Pharmacovigilance Centre (NPC):

- SFDA Call Centre: 19999

- E-mail: npc.drug@sfda.gov.sa

- Website: https://ade.sfda.gov.sa

• 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: mucolytic agents.

ATC code: R05CB06.

In preclinical investigations, ambroxol hydrochloride, the active substance in Mucum, 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 ambroxol hydrochloride in COPD patients led to substantially reduced exacerbations after a treatment period of 2 months. Patients treated with ambroxol hydrochloride 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 ambroxol hydrochloride 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 2.5hours 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 2times higher. Due to the broad therapeutic range ofthe 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 50mg/kg/day in rats, 40 mg/kg/day in rabbits, 150mg/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 to1,500 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, 200and 800 mg/kg/day) or rats (65, 250 and 1,000mg/kg/day) when added to food over a period of 105 and116 weeks respectively.

Not applicable

Store below 30°C.

100mL syrup packed in an amber glass bottle (USP Type III) labelled with a printed label with CRC cap, packed in a printed carton along with a leaflet and a measuring cap.

No special requirements