Symptoms
Volunteers receiving single oral doses of 50 mg commonly experienced sedation.
Management
The elimination half-life of zolmitriptan is 2.5 to 3 hours, and therefore monitoring of patients after overdose with Zomig Rapimelt should continue for at least 15 hours or while symptoms or signs persist.
There is no specific antidote to zolmitriptan. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.
It is unknown what effect haemodialysis or peritoneal dialysis has on the serum concentrations of zolmitriptan.
3 years.
Not applicable.
The following excipients are contained in each Zomig Rapimelt as indicated:
Aspartame (E951)
Citric Acid Anhydrous
Silica Colloidal Anhydrous
Crospovidone
Magnesium stearate
Mannitol (E421)
Microcrystalline Cellulose
Orange Flavour SN027512
Sodium Hydrogen Carbonate
An oral teratology study of zolmitriptan has been conducted. At the maximum tolerated doses, 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.
Five genotoxicity tests have been performed. It was concluded that Zomig Rapimelt 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.
Pharmacotherapeutic group: Selective serotonin (5HT1) agonists. ATC code: N02CC03
Mechanism of action
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 5HT1D receptor is predominately 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.
Clinical efficacy and safety
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.
Following oral administration of Zomig conventional tablets zolmitriptan is rapidly and well absorbed (at least 64%) in man. The mean absolute bioavailability of the parent compound is approximately 40%. There is an active metabolite (183C91, the N-desmethyl metabolite) which is also a 5HT IB/1D agonist and is 2 to 6 times as potent, in animal models, as zolmitriptan.
In healthy subjects, when given as a single dose, zolmitriptan and its active metabolite 183C91, display dose-proportional AUC and Cmax over the dose range 2.5 to 50 mg. Absorption is rapid with 75% of Cmax achieved within 1 hour and plasma concentrations are sustained subsequently for 4 to 6 hours. Zolmitriptan absorption is unaffected by the presence of food. There is no evidence of accumulation on multiple dosing of zolmitriptan.
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-desmethylated metabolite (183C91) is active whilst the others are not. 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 Rapimelt. 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 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.
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.
In a small group of healthy individuals there was no pharmacokinetic interaction with ergotamine. Concomitant administration of zolmitriptan with ergotamine/caffeine was well tolerated and did not result in any increase in adverse events or blood pressure changes as compared with zolmitriptan alone.
Following the administration of rifampicin, no clinically relevant differences in the pharmacokinetics of zolmitriptan or its active metabolite were observed.
Selegiline, an MAO-B inhibitor, and fluoxetine (a selective serotonin reuptake inhibitor; SSRI) had no effect on the pharmacokinetic parameters of zolmitriptan.
Zomig Rapimelt was demonstrated to be bioequivalent with the conventional tablet in terms of AUC and Cmax for zolmitriptan and its active metabolite 183C91. Clinical pharmacology data show that the tmax for zolmitriptan can be later for the orally dispersible tablet (range 0.6 to 5h, median 3h) compared to the conventional tablet (range 0.5 to 3h, median 1.5h). The tmax for the active metabolite was similar for both formulations (median 3h).
Renal impairment
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.
Elderly
The pharmacokinetics of zolmitriptan in healthy elderly subjects were similar to those in healthy young volunteers.
18th January 2017
AstraZeneca UK Ltd
600 Capability Green
Luton LU1 3LU
United Kingdom
Do not store above 30°C.
PVC aluminium/aluminium blister pack of 2 tablets (sample pack)* or 6 tablets (3 strips of 2 tablets).
Not all pack sizes may be marketed.
PL 17901/0076
The blister pack should be peeled open as shown on the foil (tablets should not be pushed through the foil). The Zomig Rapimelt tablet should be placed on the tongue, where it will dissolve and be swallowed with the saliva.
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
20 JUNE 2001
