Sumatriptan Succinate

SUMATRIPTAN SUCCINATE- sumatriptan succinate tablet
Medsource Pharmaceuticals

DESCRIPTION

Sumatriptan tablets USP contain sumatriptan (as the succinate), a selective 5-hydroxytryptamine 1 receptor subtype agonist. Sumatriptan succinate USP is chemically designated as 3-[2- (dimethylamino) ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure:

structure
(click image for full-size original)

The molecular formula is C 14 H 21 N 3 O 2 S•C 4 H 6 O 4 , representing a molecular weight of 413.5. Sumatriptan succinate USP is a white to off-white powder that is readily soluble in water and in saline. Each sumatriptan tablet USP for oral administration contains 35, 70, or 140 mg of sumatriptan succinate USP equivalent to 25, 50, or 100 mg of sumatriptan, respectively. Each tablet also contains the inactive ingredients croscarmellose sodium, lactose anhydrous, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, talc, titanium dioxide and triacetin.

CLINICAL PHARMACOLOGY

Mechanism of Action

Sumatriptan is an agonist for a vascular 5-hydroxytryptamine 1 receptor subtype (probably a member of the 5-HT 1D family) having only a weak affinity for 5-HT 1A , 5-HT 5A , and 5-HT 7 receptors and no significant affinity (as measured using standard radioligand binding assays) or pharmacological activity at 5-HT 2 , 5-HT 3 , or 5-HT 4 receptor subtypes or at alpha 1- , alpha 2- , or beta-adrenergic; dopamine 1 ; dopamine 2 ; muscarinic; or benzodiazepine receptors.

The vascular 5-HT 1 receptor subtype that sumatriptan activates is present on cranial arteries in both dog and primate, on the human basilar artery, and in the vasculature of human dura mater and mediates vasoconstriction. This action in humans correlates with the relief of migraine headache. In addition to causing vasoconstriction, experimental data from animal studies show that sumatriptan also activates 5-HT 1 receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels. Such an action may also contribute to the antimigrainous effect of sumatriptan in humans.

In the anesthetized dog, sumatriptan selectively reduces the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance. In the cat, sumatriptan selectively constricts the carotid arteriovenous anastomoses while having little effect on blood flow or resistance in cerebral or extracerebral tissues.

Pharmacokinetics

The mean maximum concentration following oral dosing with 25 mg is 18 ng/mL (range: 7 to 47 ng/mL) and 51 ng/mL (range: 28 to 100 ng/mL) following oral dosing with 100 mg of sumatriptan. This compares with a C max of 5 and 16 ng/mL following dosing with a 5 and 20 mg intranasal dose, respectively. The mean C max following a 6 mg subcutaneous injection is 71 ng/mL (range: 49 to 110 ng/mL). The bioavailability is approximately 15%, primarily due to presystemic metabolism and partly due to incomplete absorption. The C max is similar during a migraine attack and during a migraine-free period, but the t max is slightly later during the attack, approximately 2.5 hours compared to 2.0 hours. When given as a single dose, sumatriptan displays dose proportionality in its extent of absorption (area under the curve [AUC]) over the dose range of 25 to 200 mg, but the C max after 100 mg is approximately 25% less than expected (based on the 25 mg dose).

A food effect study involving administration of sumatriptan tablets 100 mg to healthy volunteers under fasting conditions and with a high-fat meal indicated that the C max and AUC were increased by 15% and 12 %, respectively, when administered in the fed state.

Plasma protein binding is low (14% to 21%). The effect of sumatriptan on the protein binding of other drugs has not been evaluated, but would be expected to be minor, given the low rate of protein binding. The apparent volume of distribution is 2.4 L/kg.

The elimination half-life of sumatriptan is approximately 2.5 hours. Radiolabeled 14 C-sumatriptan administered orally is largely renally excreted (about 60%) with about 40% found in the feces. Most of the radiolabeled compound excreted in the urine is the major metabolite, indole acetic acid (IAA), which is inactive, or the IAA glucuronide. Only 3% of the dose can be recovered as unchanged sumatriptan.

In vitro studies with human microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme, and inhibitors of that enzyme may alter sumatriptan pharmacokinetics to increase systemic exposure. No significant effect was seen with an MAO-B inhibitor (see CONTRAINDICATIONS,WARNINGS, and PRECAUTIONS: Drug Interactions).

Special Populations

Renal Impairment

Renal Impairment: The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined, but little clinical effect would be expected as sumatriptan is largely metabolized to an inactive substance.

Hepatic Impairment

The liver plays an important role in the presystemic clearance of orally administered sumatriptan. Accordingly, the bioavailability of sumatriptan following oral administration may be markedly increased in patients with liver disease. In 1 small study of hepatically impaired patients (N = 8) matched for sex, age, and weight with healthy subjects, the hepatically impaired patients had an approximately 70% increase in AUC and C max and a t max 40 minutes earlier compared to the healthy subjects (see DOSAGE AND ADMINISTRATION).

Age

The pharmacokinetics of oral sumatriptan in the elderly (mean age, 72 years; 2 males and 4 females) and in patients with migraine (mean age, 38 years; 25 males and 155 females) were similar to that in healthy male subjects (mean age, 30 years) (see PRECAUTIONS: Geriatric Use).

Gender

In a study comparing females to males, no pharmacokinetic differences were observed between genders for AUC, C max , t max , and half-life.

Race

The systemic clearance and C max of sumatriptan were similar in black (N = 34) and Caucasian (N = 38) healthy male subjects.

Drug Interactions

Monoamine Oxidase Inhibitors (MAO)

Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels (see CONTRAINDICATIONS and PRECAUTIONS).

Due to gut and hepatic metabolic first-pass effects, the increase of systemic exposure after coadministration of an MAO-A inhibitor with oral sumatriptan is greater than after coadministration of the monoamine oxidase inhibitors (MAOI) with subcutaneous sumatriptan. In a study of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan. Under the conditions of this experiment, the result was a 2-fold increase in the area under the sumatriptan plasma concentration x time curve (AUC), corresponding to a 40% increase in elimination half-life. This interaction was not evident with an MAO-B inhibitor.

A small study evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from a 25 mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure.

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