Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Glaxo Wellcome UK Ltd Trading as GlaxoSmithKline UK, 980 Great West Road, Brentford, Middlesex, TW8 9GS
Pharmacotherapeutic group: Selective 5-HT1 receptor agonists
ATC code: N02CC01
Sumatriptan is a selective vascular 5-hydroxytryptamine-1-(5-HT1d) receptor agonist with no effect on other 5-HT receptor (5-HT2 - 5-HT7) subtypes. The vascular 5-HT1d receptor is found predominantly in cranial blood vessels and mediates vasoconstriction. In animals, sumatriptan selectively constricts the carotid arterial circulation, but does not alter cerebral blood flow. The carotid arterial circulation supplies blood to the extracranial and intracranial tissues such as the meninges and dilatation and/or oedema formation in these vessels is thought to be the underlying mechanism of migraine in man. In addition, evidence from animal studies suggests that sumatriptan inhibits trigeminal nerve activity. Both cranial vasoconstriction and inhibition of trigeminal nerve activity may contribute to the anti-migraine action of sumatriptan in humans.
Clinical response begins 15 minutes following a 20 mg dose given by intranasal administration.
Because of its route of administration, Imigran Nasal Spray may be particularly suitable for patients who suffer nausea and vomiting during a migraine attack.
The magnitude of treatment effect is smaller in adolescents compared with adults.
After intranasal administration, sumatriptan is rapidly absorbed, median times to maximum plasma concentrations being 1.5 (range: 0.25-3) hours in adults and 2 (range: 0.5-3) hours in adolescents. After a 20 mg dose, the mean maximum concentration is 13ng/mL. Mean intranasal bioavailability, relative to subcutaneous administration is about 16%, partly due to pre-systemic metabolism.
Plasma protein binding is low (14–21%) and the mean volume of distribution is 170L. The elimination half-life is approximately 2 hours. The mean total plasma clearance is approximately 1160mL/min and the mean renal plasma clearance is approximately 260mL/min.
A pharmacokinetic study in adolescent subjects (12–17 years) indicated that the mean maximum plasma concentration was 13.9ng/mL and mean elimination half-life was approximately 2 hours following a 20 mg intranasal dose. Population pharmacokinetic modelling indicated that clearance and volume of distribution both increase with body size in the adolescent population resulting in higher exposure in lower bodyweight adolescents.
Non-renal clearance accounts for about 80% of the total clearance. Sumatriptan is eliminated primarily by oxidative metabolism mediated by monoamine oxidase A. The major metabolite, the indole acetic acid analogue of sumatriptan, is mainly excreted in urine, where it is present as a free acid and the glucuronide conjugate. It has no known 5-HT1 or 5-HT2 activity. Minor metabolites have not been identified. The pharmacokinetic profile of intranasal sumatriptan does not appear to be significantly affected by migraine attacks.
The kinetics in the elderly have been insufficiently studied to justify a statement on possible differences in kinetics between elderly and young volunteers.
Sumatriptan pharmacokinetics after an oral dose (50 mg) and a subcutaneous dose (6 mg) were studied in 8 patients with mild to moderate hepatic impairment matched for sex, age, and weight with 8 healthy subjects. Following an oral dose, sumatriptan plasma exposure (AUC and Cmax) almost doubled (increased approximately 80%) in patients with mild to moderate hepatic impairment compared to the control subjects with normal hepatic function. There was no difference between the patients with hepatic impairment and control subjects after the s.c. dose. This indicates that mild to moderate hepatic impairment reduces presystemic clearance and increases the bioavailability and exposure to sumatriptan compared to healthy subjects.
Following oral administration, pre-systemic clearance is reduced in patients with mild to moderate hepatic impairment and plasma exposure, measured by Cmax and AUC, almost doubled. Since a portion of the nasal spray dose is swallowed, patients with mild to moderate hepatic impairment could also have higher exposures, but to a lesser extent than observed after oral dosing. (see Section 4.4, Warnings and Precautions).
The pharmacokinetics of sumatriptan in patients with severe hepatic impairment have not been studied (see Section 4.3 Contraindications and Section 4.4 Warnings and Precautions).
In non-clinical studies carried out to test for local and ocular irritancy, following administration of sumatriptan nasal spray, there was no nasal irritancy seen in laboratory animals and no ocular irritancy observed when the spray was applied directly to the eyes of rabbits.
Experimental studies of acute and chronic toxicity showed no evidence of toxic effects within the human therapeutic dose range. In a rat fertility study a reduction in success of insemination was seen at exposures sufficiently in excess of the maximum human exposure. In rabbits, embryo-lethality without marked teratogenic defects was seen.
Sumatriptan was devoid of genotoxic and carcinogenic activity in in-vitro systems and animal studies.
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