Source: Health Products Regulatory Authority (IE) Revision Year: 2020 Publisher: Rowex Ltd, Newtown, Bantry, Co. Cork, Ireland
Pharmacotherapeutic group: Analagesics, selective serotonin (5HT1) agonists
ATC code: N02CC01
Sumatriptan is a specific and selective 5-hydroxytryptamine-1d receptor agonist, and has not demonstrated activity on the other 5HT (5HT2-5HT7) receptors.
The vascular 5HT1d receptor is found predominantly in the cranial blood vessels and has a vasoconstrictor effect. In experimental animals, it has been shown that sumatriptan causes vasoconstriction of the arterioles and the arteriovenous anastomata of the carotid vascular bed. This vascular bed provides the blood supply to the extracranial and intracranial tissues, such as the meninges. It has been proposed that dilatation of these arterial vessels, and the formation of oedema here, is the underlying cause of a migraine attack in humans. There is also evidence from animal experiments to suggest that sumatriptan inhibits the activity of the trigeminal nerve. Both effects (cranial vasoconstriction and inhibition of the activity of the trigeminal nerve) might contribute to the anti-migraine effect of sumatriptan in humans.
A clinical response occurs approximately 30 minutes after oral administration of a dose of 100 mg. The recommended oral dose for sumatriptan tablets is 50 mg. In clinical trials, doses of 25-100 mg have appeared to be more effective than placebo; however, 25 mg is less effective than 50 and 100 mg (statistically significant).
Sumatriptan is effective for the acute treatment of migraine attacks that occur during menstruation in women, i.e. in the period from 3 days before to 5 days after the beginning of menstruation.
The efficacy of sumatriptan tablets 50 mg and 100 mg have been demonstrated in two clinical trials in 2,696 people with moderate to severe migraine. The patients reported the time to pain reduction (defined as no pain or mild pain).
The percentage with pain reduction within 2 hours was 42% for placebo, 67% for the 50 mg tablet and 72% for the 100 mg tablet. Half of these respondents had pain reduction within 56 minutes.
The percentage of patients pain-free within 2 hours was 15% for placebo, 40% for the 50 mg tablet and 46% for the 100 mg tablet. Half of these patients were pain-free within 75 minutes.
A number of placebo-controlled clinical studies assessed the safety and efficacy of oral sumatriptan in approximately 800 children and adolescent migraineurs aged 10-17 years. These studies failed to demonstrate relevant differences in headache relief at 2 hours between placebo and any sumatriptan dose. The undesirable effects profile of oral sumatriptan in adolescents aged 10-17 years was similar to that reported from studies in the adult population.
Following oral administration sumatriptan is rapidly absorbed, the maximum concentration being reached after approx. 45 minutes. After oral administration of 100 mg the peak plasma concentration is on average 54 ng/ml. Absolute bioavailability after oral administration is on average 14%. This is partly due to presystemic metabolism and partly to incomplete absorption. In patients with hepatic insufficiency, presystemic clearance after oral administration is reduced, resulting in an increase in the plasma levels of sumatriptan.
Protein binding is low (14-21%) and the mean volume of distribution is 170 litres.
The elimination half-life is approximately 2 hours. Mean total clearance is 1160 ml/minute and mean renal clearance is approximately 260 ml/minute. Non-renal clearance is approximately 80% of total clearance, suggesting that sumatriptan is primarily cleared through oxidative metabolism mediated by monoamine oxidase A. The major metabolite, the indole acetic acid analogue of sumatriptan, is excreted in the urine as the acid or as the glucuronide conjugate. This metabolite has no known 5HT1 or 5HT2 activity. Minor metabolites have not been identified.
The pharmacokinetics of the oral administration of sumatriptan does not appear to be influenced by a migraine attack.
The kinetics in the elderly has not been sufficiently studied to permit a statement on possible differences in the kinetics between older 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 systemic exposure is almost doubled.
The pharmacokinetics in patients with severe hepatic impairment have not been studied (see sections 4.3 and 4.4).
Experimental studies on acute and chronic toxicity have not shown any evidence of toxic effects within the human therapeutic dosing range. In a fertility study in the rat, a reduction in the success of insemination was seen on exposure to concentrations higher than the maximum exposure in humans. In rabbits embryolethality was observed, without marked teratogenic effects.
Sumatriptan was devoid of genotoxic and carcinogenic activity in in-vitro systems and animal studies.
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