Ambroxol 30 mg, Cetirizine 5 mg / 5 ml Syrup

Mechanism of Actions:Cetirizine, a human metabolite of hydroxyzine, is an antihistamine; its principal effects are mediated via selective inhibition of peripheral H 1receptors. The antihistaminic activity of cetirizine has been clearly documented in a variety of animal and human models. In vivoand ex vivoanimal models have shown negligible anticholinergic and anti-serotonergic activity. In clinical studies, however, dry mouth was more common with cetirizine than with placebo. In vitroreceptor binding studies have shown no measurable affinity for other than H 1receptors. Autoradiographic studies with radiolabeled cetirizine in the rat have shown negligible penetration into the brain. Ex vivoexperiments in the mouse have shown that systemically administered cetirizine does not significantly occupy cerebral H 1receptors.

Absorption:Cetirizine was rapidly absorbed with a time to maximum concentration (T max) of approximately 1 hour following oral administration of tablets or solution in adults. Comparable bioavailability was found between the tablet and solution dosage forms. When healthy volunteers were administered multiple doses of cetirizine (10 mg tablets once daily for 10 days), a mean peak plasma concentration (C max) of 311 ng/mL was observed. No accumulation was observed. Cetirizine pharmacokinetics were linear for oral doses ranging from 5 to 60 mg. Food had no effect on the extent of cetirizine exposure (AUC) but T maxwas delayed by 1.7 hours and C maxwas decreased by 23% in the presence of food.

Distribution: The mean plasma protein binding of cetirizine is 93%, independent of concentration in the range of 25–1000 ng/mL, which includes the therapeutic plasma levels observed.

Metabolism:A mass balance study in 6 healthy male volunteers indicated that 70% of the administered radioactivity was recovered in the urine and 10% in the feces. Approximately 50% of the radioactivity was identified in the urine as unchanged drug. Most of the rapid increase in peak plasma radioactivity was associated with parent drug, suggesting a low degree of first-pass metabolism. Cetirizine is metabolized to a limited extent by oxidative O-dealkylation to a metabolite with negligible antihistaminic activity. The enzyme or enzymes responsible for this metabolism have not been identified.

Elimination:The mean elimination half-life in 146 healthy volunteers across multiple pharmacokinetic studies was 8.3 hours and the apparent total body clearance for cetirizine was approximately 53 mL/min.

​ Interaction Studies — Pharmacokinetic interaction studies with cetirizine in adults were conducted with pseudoephedrine, antipyrine, ketoconazole, erythromycin and azithromycin. No interactions were observed. In a multiple dose study of theophylline (400 mg once daily for 3 days) and cetirizine (20 mg once daily for 3 days), a 16% decrease in the clearance of cetirizine was observed. The disposition of theophylline was not altered by concomitant cetirizine administration.

Ambroxol is a bromhexine metabolite with secretolytic and secretomotor activity described in the oral-solution product information. Its full mechanism is not completely established. The separate HPRA lozenge reference also describes sodium-channel blockade in laboratory studies, a mechanism related to local anesthetic activity.

The oral-reference studies summarized by HPRA report peak plasma levels after approximately 1–2.5 hours for immediate-release ambroxol, protein binding of about 90% and a terminal half-life of about 10 hours. Metabolism occurs mainly in the liver, including glucuronidation and CYP3A4-mediated pathways. Lozenge, syrup and modified-release formulations can produce different exposure.