Source: Υπουργείο Υγείας (CY) Revision Year: 2017 Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
Pharmacotherapeutic group: Mucolytics
ATC code: R05CB06
Ambroxol hydrochloride, the active ingredient of Medovent, has been shown to increase respiratory tract secretion. It increases the secretion of surfactant in the lung and increases the ciliary activity. These actions result in improved mucus secretion and transport (mucociliary clearance). Mucociliary clearance improvement has been shown in clinical pharmacology studies. Stimulation of the secretion and mucociliary clearance facilitates expectoration and smoothes cough.
In patients suffering from COPD, long-term treatment (6 months) with ambroxol retard led to a significant reduction in exacerbations, which became evident after 2 months of treatment. Patients in the treatment group with ambroxol had significantly fewer sick days and days when they required treatment with antibiotics. Treatment with ambroxol retard induce a statistically significant improvement in symptoms (difficult expectoration, cough, dyspnea, signs identified by lung auscultation) as compared to placebo.
A local anesthetic effect was observed in the rabbit eye test, which can be explained by ambroxol properties of blocking the sodium channel. It has been shown in vitro that ambroxol hydrochloride blocks sodium channels in neurons; binding was reversible and dose dependent.
It has been demonstrated in vitro that cytokine released from blood mononuclear cells but also from polymorphonuclear cells and delineating tissue was significantly reduced by ambroxol hydrochloride.
In clinical trials in patients with angina, pharyngeal pain and redness were reduced significantly.
These pharmacological properties are consistent with additional observations from clinical trials regarding the efficacy of ambroxol hydrochloride on symptoms of upper respiratory tract, leading to rapid relief of pain and discomfort related to pain in ENT after inhalation.
Concomitant use of ambroxol hydrochloride and antibiotics (amoxicillin, cefuroxime, erythromycin) leads to an increase in the concentration of antibiotic in lung tissue (bronchopulmonary secretions and sputum).
Ambroxol hydrochloride is rapidly and completely absorbed after oral formulations whose mechanism of transfer/release is unchanged dose dependent. Peak plasma concentrations occurred approximately 1 to 2.5 hours after administration of immediate release pharmaceutical forms after an average of 6.5 hours after oral extended release pharmaceutical forms/modified. The absolute bioavailability after administration of a 30 mg tablet was 79%. Showed that the relative bioavailability of extended-release capsules was 95% compared to a total daily dose of 60 mg (30 mg twice daily) administered as immediate release tablets.
Distribution of ambroxol hydrochloride from blood to tissues is rapid and strong, the highest concentration of active substance is in the lung. The volume of distribution after oral administration was estimated at 552 l plasma protein binding is approximately 90% at therapeutic doses.
About 30% of the oral administrated substance dose is metabolized to first-pass metabolism/first metabolic passage. Otherwise, ambroxol hydrochloride is metabolised primarily in the liver by glucuronidation and a small portion is metabolised in dibromanthranilic acid (about 10% of dose), except for minor metabolites.
Studies in human liver cells microsomes have shown that CYP3A4 is the predominant isoform responsible for the metabolism of ambroxol hydrochloride in dibromanthranilic acid.
After 3 days of oral administration, approximately 6% of the dose is recovered unmodified, while about 26% of the dose is recovered in urine in conjugated form. Elimination half-life of ambroxol hydrochloride is approximately 10 hours. Total elimination has an average of 660 ml/min, while the renal clearance represents about 8% of the total clearance.
In patients with hepatic impairment, ambroxol hydrochloride elimination is reduced, resulting in higher plasmatic concentrations of 1.3 to 2 times. Because of the high therapeutic concentrations, no dose adjustment is required.
There is no evidence that age and sex affect from a clinically significant point of view the pharmacokinetics of ambroxol in significant and therefore there is no need for changing the dose.
There is no evidence that foods affect the bioavailability of ambroxol hydrochloride.
Ambroxol hydrochloride has a low acute toxicity.
After oral doses of 150 mg/kg/day administration (mice, 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) no adverse effect was seen, therefore the product was included in NOAEL class (“No Observed Adverse Effect Level - NOAEL”). For ambroxol, no target organ regarding toxicologically was found.
Four weeks studies with repeated toxic doses of intravenous ambroxol hydrochloride in rats (4, 14 and 64 mg/kg/day) and dogs (45, 90 and 120 mg/kg/day (3 hours infusion/day)) did not show the occurrence of severe local or systemic toxicity, including histopathology. All side effects were reversible.
There was no evidence that ambroxol hydrochloride may be embryotoxic or teratogenic in studies with oral administrated doses up to 3000 mg/kg/day in rats and up to 200 mg/kg/day in rabbits. At doses up to 500 mg/kg/day, fertility of male and female rats was not affected.
Dose without adverse effect level (“NOAEL”) during peri-and postnatal development was 50 mg/kg, whereas the dose of 500 mg/kg was slightly toxic to female and puppies, as resulted by delayed increase in weight and size reduction.
Ambroxol hydrochloride has no mutagenic properties, according to the studies of genotoxicity in vitro (Ames test and chromosomal aberration test) and in vivo (micronucleus test).
There is no evidence of carcinogenicity in mice studies (50, 200 and 800 mg/kg/day) and rats (65, 250 and 1000 mg/kg/day), after being subjects of a diet of 105 and 116 weeks respectively.
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