Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Grünenthal Ltd, Regus Lakeside House, 1 Furzeground Way, Stockley Park East, Uxbridge, Middlesex, UB11 1BD, UK
Pharmacotherapeutic group: Selective serotonin (5HT1) agonists
ATC code: N02CC03
In pre-clinical studies, zolmitriptan has been demonstrated to be a selective agonist for the vascular human recombinant 5HT1B and 5HT1D receptor subtypes. Zolmitriptan is a high affinity 5HT1B/1D receptor agonist with modest affinity for 5HT1A receptors. Zolmitriptan has no significant affinity (as measured by radioligand binding assays) or pharmacological activity at 5HT2-, 5HT3-, 5HT4-, alpha1-, alpha2-, or beta1-, adrenergic; H1-, H2-, histaminic; muscarinic; dopaminergic1, or dopaminergic2 receptors.
The 5HT1B/1D receptor is predominantly located presynaptically at both the peripheral and central synapses of the trigeminal nerve and preclinical studies have shown that zolmitriptan is able to act at both these sites.
One controlled clinical trial in 696 adolescents with migraine failed to demonstrate superiority of zolmitriptan tablets at doses of 2.5 mg, 5 mg and 10 mg over placebo. Efficacy was not demonstrated.
Zolmitriptan, following intranasal administration, is rapidly absorbed with detectable levels in the plasma within 5 minutes of dosing. A proportion of the dose seems to be directly absorbed in the naso-pharynx. On average 40% of Cmax of the parent compound, zolmitriptan, is achieved within 15 minutes. The appearance in plasma of the active metabolite, 183C91, which is partly formed through first-pass metabolism, is delayed by 15 to 60 minutes post-dose. Cmax of the parent compound, zolmitriptan is achieved after 3 hours. Plasma concentrations are sustained for up to 4 to 6 hours. Elimination of zolmitriptan and the active metabolite 183C91 after oral and intranasal delivery appear similar; the mean elimination half-life (t½) for both zolmitriptan and 183C91 are approximately 3 hours. The bioavailability of intranasal relative to oral administration is 102%. In healthy volunteers after single and multiple intranasal doses, zolmitriptan and its active metabolite 183C91 display dose proportional AUC and Cmax over the range 1 to 5 mg. There is no evidence of accumulation of zolmitriptan after multiple intranasal dosing.
The plasma concentrations and elimination pharmacokinetics of zolmitriptan and the three major metabolites for the nasal spray and conventional tablet formulations are similar.
Following oral administration of Zomig conventional tablets, zolmitriptan is rapidly and well absorbed (at least 64%). The mean absolute bioavailability of the parent compound is approximately 40%.
Absorption is rapid with 75% of Cmax achieved within 1 hour and plasma concentrations are sustained subsequently for 4 to 6 hours. After oral administration zolmitriptan absorption is unaffected by the presence of food.
Zolmitriptan is eliminated largely by hepatic biotransformation followed by urinary excretion of the metabolites. There are three major metabolites: the indole acetic acid, (the major metabolite in plasma and urine), the N-oxide and N-desmethyl analogues. The N-desmethyl metabolite (183C91) is an active metabolite which is also a 5H 1B/1D agonist and is 2 to 6 times as potent, in animal models, as zolmitriptan. Plasma concentrations of 183C91 are approximately half those of the parent drug, hence it would therefore be expected to contribute to the therapeutic action of Zomig. Over 60% of a single oral dose is excreted in the urine (mainly as the indole acetic acid metabolite) and about 30% in faeces, mainly as unchanged parent compound.
A study using oral zolmitriptan to evaluate the effect of liver disease on the pharmacokinetics of zolmitriptan showed that the AUC and Cmax were increased by 94% and 50% respectively in patients with moderate liver disease and by 226% and 47% in patients with severe liver disease compared with healthy volunteers. Exposure to the metabolites, including the active metabolite, was decreased. For the 183C91 metabolite, AUC and Cmax were reduced by 33% and 44% in patients with moderate liver disease and by 82% and 90% in patients with severe liver disease.
The plasma half-life (T½) of zolmitriptan was 4.7 hours in healthy volunteers, 7.3 hours in patients with moderate liver disease and 12 hours in those with severe liver disease. The corresponding T½ values for the 183C91 metabolite were 5.7 hours, 7.5 hours and 7.8 hours respectively. No studies have been undertaken to characterise the pharmacokinetics of intranasally administered zolmitriptan in patients with hepatic impairment.
Following intravenous administration, the mean total plasma clearance is approximately 10 ml/min/kg, of which one third is renal clearance. Renal clearance is greater than glomerular filtration rate suggesting renal tubular secretion. The volume of distribution following intravenous administration is 2.4 L/kg. Plasma protein binding is low (approximately 25%). The mean elimination half-life of zolmitriptan is 2.5 to 3 hours. The half-lives of its metabolites are similar, suggesting their elimination is formation-rate limited.
Renal clearance of zolmitriptan and all its metabolites is reduced (7 to 8 fold) in patients with moderate to severe renal impairment compared to healthy subjects, although the AUC of the parent compound and the active metabolite were only slightly higher (16 and 35% respectively) with a 1 hour increase in half-life to 3 to 3.5 hours. These parameters are within the ranges seen in healthy volunteers. These findings originate from studies with zolmitriptan tablets.
In a small group of healthy individuals there was no pharmacokinetic interaction with ergotamine. Concomitant administration of Zomig with ergotamine/caffeine was well tolerated and did not result in any increase in adverse events or blood pressure changes as compared with Zomig alone (see Section 4.5). These findings originate from studies with zolmitriptan tablets.
Selegiline, an MAO-B inhibitor, and fluoxetine (a selective serotonin reuptake inhibitor; SSRI) had no effect on the pharmacokinetic parameters of zolmitriptan (see Section 4.4). These findings originate from studies with zolmitriptan tablets.
Following the administration of rifampicin, no clinically relevant differences in the pharmacokinetics of zolmitriptan or its active metabolite were observed. The findings originate from studies with zolmitriptan tablets.
The pharmacokinetics of zolmitriptan in healthy elderly subjects were similar to those in healthy young volunteers. These findings originate from studies with zolmitriptan tablets.
The absorption of zolmitriptan nasal spray in healthy volunteers was found unaltered when administered concomitantly with the sympathomimetic nasal decongestant, xylometazoline.
An oral teratology study of Zomig has been conducted. At the maximum tolerated doses of Zomig, 1200 mg/kg/day (AUC 605 μg/ml.h: approx. 3700 x AUC of the human maximum recommended daily intake of 15 mg) and 30 mg/kg/day (AUC 4.9 μg/ml.h: approx. 30 x AUC of the human maximum recommended daily intake of 15 mg) in rats and rabbits, respectively, no signs of teratogenicity were apparent.
A number of genotoxicity tests have been performed. It was concluded that Zomig is not likely to pose any genetic risk in humans.
Carcinogenicity studies in rats and mice were conducted at the highest feasible doses and gave no suggestion of tumorogenicity.
Reproductive studies in male and female rats, at dose levels limited by toxicity, revealed no effect on fertility.
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