1 sustained release capsule contains 75 mg.
trans-4-[(2-amino-3,5-dibromo-benzyl)amino] cyclohexanol hydrochloride (=ambroxol hydrochloride).
Excipients/Inactive Ingredients: Sustained Release Capsule: crospovidone collidon CL, carnauba wax, stearyl alcohol, magnesium stearate.
Pharmacology: Preclinically ambroxol hydrochloride, the active ingredient of Mucosolvan, has been shown to increase respiratory tract secretion. It enhances pulmonary surfactant production and stimulates ciliary activity. These actions result in improved mucus flow and transport (mucociliary clearance).
Improvement of mucociliary clearance has been shown in clinical pharmacologic studies. Enhancement of fluid secretion and mucociliary clearance facilitates expectoration and eases cough.
In patients suffering from COPD, long-term treatment (6 months) with Ambroxol hydrochloride (Mucosolvan) Retard Capsule 75 mg resulted in a significant reduction of exacerbations that became evident after 2 months of treatment. Patients in the Ambroxol hydrochloride (Mucosolvan) treatment group lost significantly fewer days through illness and had fewer days when they needed antibiotic therapy. Treatment with Ambroxol hydrochloride (Mucosolvan) Retard Capsule 75 mg also induced a statistically significant improvement of symptoms (difficulty of expectoration, cough, dyspnea, auscultatory signs) compared with placebo.
A local anaesthetic effect of ambroxol hydrochloride has been observed in the rabbit eye model which may be explained by the sodium channel blocking properties. It was shown in vitro that ambroxol hydrochloride blocks cloned neuronal sodium channels; binding was reversible and concentration-dependent.
Cytokine release from blood but also tissue bound mononuclear and polymorphonuclear cells was found to be significantly reduced by ambroxol hydrochloride in vitro.
In clinical studies in patients with sore throat, pharyngeal pain and redness was significantly reduced.
These pharmacological properties are in accordance with the ancillary observation in clinical efficacy studies for the treatment with ambroxol hydrochloride of upper respiratory tract symptoms that leads to rapid relief of pain and pain related discomfort in the ear-nose-trachea region upon inhalation.
Following the administration of ambroxol hydrochloride antibiotic concentrations (amoxicillin, cefuroxime, erythromycin) in bronchopulmonary secretions and in the sputum are increased.
Antiviral properties in in vitro studies and in animal models in in vitro studies in human tracheal epithelial cells a reduction of rhinovirus replication has been observed. In a mouse airway model, a reduction of Influenza A virus replication was observed with ambroxol pretreatment.
Pharmacokinetics: Absorption: Absorption of all immediate release oral forms of ambroxol hydrochloride is rapid and complete, with dose linearity in the therapeutic range. Maximum plasma levels are reached within 1 to 2.5 hours following oral administration of the immediate-release formulation and after a median of 6.5 hours for the slow release formulation. The absolute bioavailability after a 30 mg tablet was found to be 79%. The slow release capsule showed a relative availability of 95% (dose-normalized) in comparison to a daily dose of 60 mg (30 mg twice daily) administered as immediate-release tablet.
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 volume of distribution following oral administration was estimated to be 552 L. In the therapeutic range, plasma protein binding was found to be approximately 90%.
Metabolism and elimination: About 30% of an orally administered dose is eliminated via first pass metabolism. Ambroxol hydrochloride is primarily metabolized in the liver by glucuronidation and some cleavage to dibromanthranilic acid (approximately 10% of dose) aside from some minor metabolites.
Studies in human liver microsomes have shown that CYP3A4 is responsible for the metabolism of ambroxol hydrochloride to dibromanthranilic acid. Within 3 days of oral administration, approximately 6% of the dose is found in free form, while approximately 26% of the dose is recovered in a conjugated form in the urine.
Ambroxol hydrochloride is eliminated with a terminal elimination half-life of approximately 10 hours. Total clearance is in the range of 660 mL/min, with renal clearance accounting for approximately 8% of the total clearance. It has been estimated that the amount of dose excreted in urine after 5 days represents about 83% of total dose (radioactivity).
Pharmacokinetics in special populations: In patients with hepatic dysfunction elimination of ambroxol hydrochloride is reduced, resulting in approximately 1.3 to 2-fold higher plasma levels. Due to the high therapeutic range of ambroxol hydrochloride, dose adjustments are not necessary.
Others: Age and gender were not found to affect the pharmacokinetics of ambroxol hydrochloride to a clinically relevant extent, and thus there is no necessity for adjustment of dosage regimens. Food was not found to influence the bioavailability of ambroxol hydrochloride.
Toxicology: Ambroxol hydrochloride has a low index for acute toxicity. In repeated-dose studies, oral doses of 150 mg/kg/day (mouse, 4 weeks), 50 mg/kg/day (rat, 52 and 78 weeks), 40 mg/kg/day (rabbit, 26 weeks) and 10 mg/kg/day (dog, 52 weeks) were the no observed adverse effect levels (NOAELs).
No toxicological target organs were detected.
Four-week intravenous toxicity studies with ambroxol hydrochloride in rats (4, 16 and 64 mg/kg/day) and in dogs (45, 90 and 120 mg/kg/day (infusions 3 h/day)) showed no severe local and systemic toxicity including histopathology. All adverse effects were reversible.
Ambroxol hydrochloride was neither embryotoxic nor teratogenic when tested at oral doses 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 affected up to 500 mg/kg/day. The NOAEL in the peri- and post-natal development study was 50 mg/kg/ day. At 500 mg/kg/day, ambroxol hydrochloride was slightly toxic for dams and pups, as shown by a retarded body weight development and reduced litter size.
Genotoxicity studies in vitro (Ames and chromosome aberration test) and in vivo (mouse micronucleus test) did not reveal any mutagenic potential of ambroxol hydrochloride.
Ambroxol hydrochloride did not show any tumorigenic potential in carcinogenicity studies in mice (50, 200 and 800 mg/kg/day) and rats (65, 250 and 1000 mg/kg/day) when treated with a dietary admixture for 105 and 116 weeks, respectively.
Secretolytic therapy in acute and chronic bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport.
Adults: 1 capsule once daily.
The capsules should not be opened or chewed, but swallowed whole with ample liquid. The "carrier pellets" which are occasionally present in the stools have released the active substance during their passage through the digestive system and are therefore without significance.
General: In acute respiratory indication, medical advice should be sought if symptoms do not improve or worsen in the course of therapy.
Ambroxol hydrochloride (Mucosolvan) can be taken with or without food.
Signs and symptoms of overdose: 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 Ambroxol hydrochloride (Mucosolvan) at recommended doses and may need symptomatic treatment.
Ambroxol hydrochloride (Mucosolvan) should not be used in patients known to be hypersensitive to ambroxol hydrochloride 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 Precautions) the use of the product is contraindicated.
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 ambroxol hydrochloride. Mostly these could be explained by the severity of the patient's underlying disease and/or concomitant medication. In addition during the early phase of a Stevens-Johnson Syndrome or TEN a patient may first experience non-specific influenza-like prodromes like e.g. fever, aching body, rhinitis, cough and sore throat. Misled by these non-specific influenza-like prodromes it is possible that a symptomatic treatment is started with a cough and cold medication.
Therefore if new skin or mucosal lesions occur, medical advice should be sought immediately and treatment with ambroxol hydrochloride discontinued as a precaution.
In the presence of impaired renal function Ambroxol hydrochloride (Mucosolvan) may be used only after consulting a physician.
Effects on ability to drive and use machines: There is no evidence from postmarketing data for an effect on ability to drive and use machines. Studies on the effects on the ability to drive and use machines have not been performed.
Pregnancy: Ambroxol hydrochloride crosses the placental barrier.
Nonclinical studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Extensive clinical experience after the 28th week of pregnancy has shown no evidence of harmful effects on the foetus.
Nonetheless, the usual precautions regarding the use of drugs during pregnancy should be observed. Especially during the first trimester, the use of Ambroxol hydrochloride (Mucosolvan) is not recommended.
Lactation: Ambroxol hydrochloride is excreted in breast milk.
Although unfavourable effects on breastfed infants would not be expected, Ambroxol hydrochloride (Mucosolvan) is not recommended for use in nursing mothers.
Fertility: Nonclinical studies do not indicate direct or indirect harmful effects with respect to fertility.
Immune system disorder, Skin and subcutaneous tissue disorders:
Anaphylactic reactions including anaphylactic shock, angioedema, rash, urticaria, pruritus, and other hypersensitivity.
Nausea, vomiting, diarrhoea, dyspepsia and abdominal pain.
No clinically relevant unfavourable interaction with other medications has been reported.
Store at temperatures not exceeding 30°C.
R05CB06 - ambroxol ; Belongs to the class of mucolytics. Used in the treatment of wet cough.