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

Posology
Children from 6 to 12 years of age:
The usual dose is ½ a tablet 2 - 3 times daily (equivalent to 2 - 3 x 15 mg ambroxol hydrochloride per day).
Adults and adolescents over 12 years of age:
The usual dose is 1 tablet 3 times daily (equivalent to 3 x 30 mg ambroxol hydrochloride per day) for the first 2 - 3 days and 1 tablet twice daily (equivalent to 2 x 30 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 2 tablets twice daily (equivalent to 120 mg ambroxol hydrochloride per day).
There is no restriction in principle on the duration of use, although longer-term administration requires medical supervision. The package leaflet informs patients that Mucosolvan tablets 30 mg should not be taken for more than 4 - 5 days without medical advice.
Method of administration

The tablets can be taken with or without food and should be swallowed whole with sufficient amounts of liquid (e.g. water, tea or fruit juice).

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 tablets 30 mg should be used with caution be- cause of the risk that they may promote accumulation of secretions.
Mucosolvan must not be used in patients with impaired renal function or severe liver disease except on medical advice. With ambroxol, as with any active substance which is metabolised in the liver and then eliminated via the kidneys, accumulation of the metabolites which are formed in the liver can be expected to occur in patients with severe renal impairment.
Each tablet contains 171 mg lactose (equivalent to 684 mg if the maximum recommended daily dose is taken). Patients with the rare hereditary problems of galactose intolerance, lactase deficiency or gl- ucose-galactose malabsorption should therefore not take Mucosolvan tablets 30 mg.

Concomitant administration of Mucosolvan tablets 30 mg and cough suppressants may lead to the de- velopment of a dangerous accumulation of secretions owing to attenuation of the cough reflex and sh- ould be undertaken only after careful risk-benefit 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, parturition or post- natal 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 drug during pregnancy should be observed. The use of Mucosolvan is not recommended during the first trimester of pregnancy in particular.
Lactation
Ambroxol has been shown to be excreted in the milk in animal studies. Use during lactation is not re- commended.

Fertility
Non-clinical studies do not indicate direct or indirect harmful effects with respect to fertility.

There is no evidence of any effect on the ability to drive or use machines. No relevant studies have been performed.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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 via the National Pharmacovigilance and drug safety Center (NPC).
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, Ext: 2317-2356-2340.
o Toll free phone: 8002490000
o Reporting hotline: 19999
o E-mail: npc.drug@sfda.gov.sa
o Website:www.sfda.gov.sa/npc

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 undesirable effects which may occur at recommended doses and may require symptomatic treatment.

Pharmacotherapeutic group: Mucolytics ATC code: R05CB06
It has been shown in preclinical studies that ambroxol hydrochloride, the active substance of Mucoso- lvan, increases the serous component of bronchial secretions. It also increases surfactant production by virtue of a direct effect on type II pneumocytes in the alveoli and Clara cells in the small airways, as well as stimulating the activity of the ciliated epithelium. These actions result in decreased mucus viscosity and improved mucociliary clearance. The improvement in mucociliary clearance has been demonstrated in clinical pharmacology studies.
Increased production of serous secretions and enhanced mucociliary clearance facilitate expectoration and ease cough.
In patients with COPD who were given Mucosolvan prolonged-release capsules 75 mg for 6 months, there was a significant reduction in exacerbations, compared to placebo, by the end of the 2nd month of treatment. Patients in the Mucosolvan group lost significantly fewer days through illness and had fewer days when they needed antibiotic therapy. They also experienced a statistically significant im- provement in symptoms, measured as difficulty in expectoration, cough, dyspnoea and auscultatory signs, compared to placebo.
A local anaesthetic effect of ambroxol hydrochloride has been observed in the rabbit eye model and is probably due to the drug's sodium channel blocking properties. In-vitro tests showed that the drug
blocks cloned voltage-dependent neuronal sodium channels; binding was reversible and concentration- dependent.
Ambroxol hydrochloride has been found to have an antiinflammatory effect in vitro. In in-vitro tests, it significantly reduced cytokine release from circulating and tissue-bound mononuclear and polymor- phonuclear cells.
Clinical studies in patients with sore throat showed that ambroxol hydrochloride administered as a 20 mg lozenge significantly reduces pharyngeal pain and redness.
These pharmacological properties are consistent with the ancillary observation from clinical efficacy studies that inhaled ambroxol provides rapid relief of pain when used in the treatment of upper respir- atory tract disorders.
Administration of ambroxol hydrochloride increases the concentrations of the antibiotics amoxicillin, cefuroxime, erythromycin and doxycycline in sputum and bronchial secretions. To date, this has not been shown to have any clinical relevance.

Absorption:
Absorption of ambroxol hydrochloride from rapid-release oral dosage forms is rapid and complete and is dose-linear in the therapeutic range. Peak plasma levels are reached within 1 - 2.5 h following administration of immediate-release dosage forms and after a median of 6.5 h following administration of slow-release dosage forms.
Absolute bioavailability following administration of a 30-mg tablet is 79%. The dose-normalised rel- ative bioavailability of the prolonged-release capsule is 95% when compared to the non-modified-rel- ease tablet form (60 mg daily, given as 2 x 30 mg doses).
Distribution:
Distribution of ambroxol hydrochloride from the blood to the tissues is rapid and pronounced, with the highest concentrations being found in the lungs. The estimated distribution volume following oral ad- ministration is 552 l.
Plasma protein binding in the therapeutic range is approximately 90%.
Metabolism and elimination:
Approximately 30% of an orally administered dose is eliminated by first-pass metabolism.
Ambroxol hydrochloride is metabolised primarily in the liver by glucuronide conjugation and cleavage to dibromoanthranilic acid (the latter accounting for about 10% of the dose). Studies in human liver microsomes have shown that CYP3A4 is responsible for the metabolism of ambroxol hydrochloride to dibromoanthranilic acid.
Three days after oral administration, about 6% of the dose is eliminated in unchanged form and about 26% in conjugated form in the urine.
The terminal elimination half-life of ambroxol hydrochloride is about 10 h. 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.
Pharmacokinetics in special populations:
In patients with impaired hepatic function, elimination of ambroxol hydrochloride is reduced, resulting in an approximately 1.3- to 2-fold increase in plasma levels. In view of the high therapeutic index of the drug, adjustment of the dose is not necessary.
The pharmacokinetics of ambroxol hydrochloride are not modified to any clinically significant extent by either age or gender. No adjustments to the recommended dosage are therefore required.
The bioavailability of ambroxol hydrochloride is not affected by food consumption.

Ambroxol has a low acute toxicity index.
Oral use: Repeated-dose toxicity studies in rats (52 and 78 weeks), rabbits (26 weeks), mice (4 weeks) and dogs (52 weeks) did not identify any target organ toxicity. 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: Four-week toxicity studies which included a histopathological assessment were carr- ied out in rats using doses of 4, 14 and 64 mg/kg/day (infused for 3 h/day) and in dogs using doses of 45, 90 and 120 mg/kg/day (infused for 3 h/day). These studies revealed no serious local or systemic toxicity; all adverse effects were reversible.
Ambroxol hydrochloride was neither embryotoxic nor teratogenic when tested at oral doses of up to 3000 mg/kg/day in rats and up to 200 mg/kg/day in rabbits. The fertility of male and female rats was not impaired following doses of up to 1500 mg/kg/day.
The NOAEL in a study on peri- and postnatal development was 50 mg/kg/day.

A dose of 500 mg/kg/day was slightly toxic for both dams and young animals, causing delayed weight gain and reduced litter size.
In genotoxicity studies, no evidence of any mutagenic potential was found either in vitro (Ames test and chromosome aberration test) or in vivo (micronucleus test in mice).
In carcinogenicity studies, no evidence of any tumorigenic potential was seen when ambroxol hydr- ochloride was given as a dietary admixture to mice at doses of 50, 200 and 800 mg/kg/day over 105 weeks and to rats at doses of 65, 250 and 1000 mg/kg/day over 116 weeks.

Colloidal anhydrous silica, lactose monohydrate, maize starch, magnesium stearate

Not applicable

Store below 30ºC

Primary packaging: PVC/aluminium blisters Secondary packaging: Carton box
Pack sizes:
Pack containing 20 tablets Pack containing 50 tablets
Hospital pack containing 1000 tablets Not all pack sizes marketed

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