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Pharmacology: Pharmacodynamics: Mechanism of Action: Sumatriptan has been demonstrated to be a selective vascular 5-hydroxytryptamine-1 (5-HT1D) receptor agonist with no effect at other 5HT-receptor (5-HT2-7) 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 meninges and dilatation and/or oedema formation in these vessels is thought to be the underlying mechanism of migraine in man. In addition, experimental evidence suggests that sumatriptan inhibits trigeminal nerve activity. Both these actions may contribute to the antimigraine action of sumatriptan in humans.
Pharmacodynamic Effects: Clinical response begins 10 to 15 minutes following a 6 mg subcutaneous injection, 15 minutes following a 20 mg dose given by intranasal administration and around 30 minutes following a 100 mg conventional tablet oral dose or 25 mg rectal dose.
Following administration of a 50 mg and 100 mg FDT, onset of pain relief began as early as 30 minutes and 20 minutes, respectively, in a small proportion of subjects and the percentage of responders continued to increase until 67% and 72% of subjects achieved pain relief over two hours, compared to 42% of placebo subjects. Onset of pain-free began as early as 33 minutes and 26 minutes, respectively, in a small proportion of subjects and the percentage of responders continued to increase until 40% and 47% of subjects achieved pain-free response over two hours, compared to 15% of placebo subjects (see Clinical Studies as follows).
Although the recommended dose of oral sumatriptan is 50 mg, migraine attacks vary in severity both within and between patients. Doses of 25 to 100 mg have shown greater efficacy than placebo in clinical trials, but 25 mg is statistically significantly less effective than 50 and 100 mg.
Sumatriptan is effective in the acute treatment of migraine including menstrually-associated migraine.
Clinical Studies: The time to onset of efficacy of sumatriptan 50 mg and 100 mg FDT was demonstrated in adults in two randomised, double-blind, placebo-controlled studies that were identical in design. The data from these studies were combined to obtain single results for each endpoint. Overall, 2696 subjects experiencing moderate to severe migraine pain reported time to pain relief and time to freedom from pain in the sumatriptan 50 mg, 100 mg and placebo groups. Time to pain relief (defined as a reduction in pain severity from moderate or severe to mild or no pain) curves were generated for sumatriptan and placebo for the two hour period after treatment. The time to onset of pain relief was defined as the earliest time point at which statistical significance was first achieved, compared with placebo, and maintained at all subsequent time points on the 0 to 2 hour curve. Freedom from pain (defined as a reduction in pain severity from severe or moderate to no pain) was evaluated using similar methods (see Pharmacodynamic Effects as previously mentioned).
The percentage of subjects achieving pain relief (Figure 1) or freedom from pain (Figure 2) within two hours after treatment was significantly higher among subjects receiving sumatriptan (FDT 50 mg or 100 mg) compared with those receiving placebo (p<0.001). (See Figure 1.)
Click on icon to see table/diagram/imageThe time to onset of pain relief for sumatriptan FDT 50 and 100 mg was 30 minutes and 20 minutes, respectively, based on the combined data. From this initial point onwards, the percentage of responders continued to increase until 67% and 72% of subjects achieved pain relief two hours after treatment for 50 and 100 mg, respectively, compared to 42% of subjects in the placebo group (Figure 1). (See Figure 2.)
Click on icon to see table/diagram/imageThe time to onset of the pain-free response for sumatriptan FDT 50 and 100 mg was 33 minutes and 26 minutes, respectively, based on the combined data. From this initial point onwards, the percentage of responders continued to increase until 40% and 47% of subjects achieved freedom from pain two hours after treatment for 50 and 100 mg, respectively, compared to 15% of subjects in the placebo group (Figure 2).
IMIGRAN FDT tablets have not been studied in adolescents, however, a number of placebo-controlled clinical studies assessed the safety and efficacy of oral sumatriptan standard tablets in over 650 child and adolescent migraineurs aged 10 to 17 years. These studies failed to demonstrate a statistically significant difference in headache relief at two hours between placebo and any sumatriptan dose. The undesirable effects profile of oral sumatriptan in children and adolescents aged 10 to 17 years was similar to that reported from studies in the adult population.
Pharmacokinetics: The pharmacokinetics of sumatriptan do not appear to be significantly affected by migraine attacks.
Absorption: After a 100 mg dose, the mean maximum plasma concentration is 54 nanograms/mL. Mean absolute oral bioavailability is 14% partly due to pre-systemic metabolism and partly due to incomplete absorption.
The Cmax of sumatriptan is increased by 15% following oral administration of the fast-disintegrating tablet with a high-fat meal.
Distribution: Plasma protein-binding is low (14 to 21%); the mean total volume of distribution is 170 litres.
Metabolism: 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.
Elimination: The elimination half-life is approximately two hours. The mean total plasma clearance is approximately 1,160 mL/min and the mean renal plasma clearance is approximately 260 mL/min.
Non-renal clearance accounts for about 80% of the total clearance. Sumatriptan is eliminated primarily by oxidative metabolism mediated by monoamine oxidase A.
Special Patient Populations: Hepatic Impairment: Following oral administration, pre-systemic clearance is reduced in patients with hepatic impairment resulting in increased plasma levels of sumatriptan (see Precautions).
Toxicology: Preclinical Safety Data: Carcinogenesis, mutagenesis: Sumatriptan was devoid of genotoxic and carcinogenic activity in in-vitro systems and animal studies.
Pregnancy and lactation: No teratogenic effects have been seen in rats or rabbits, and sumatriptan had no effect on the post-natal development of rats.
When administered to pregnant rabbits throughout the period of organogenesis, sumatriptan has occasionally caused embryolethality at doses that were sufficiently high to produce maternal toxicity.
