Sumatriptan

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

log Kow = 0.93

0.93

54mg/mL

40.3 [ug/mL] (The mean of the results at pH 7.4)

Breast Feeding; Lactation; Milk, Human; Serotonin Receptor Agonists; Serotonin 5-HT1 Receptor Agonists; Triptans; Vasoconstrictor Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Medicines for acute migraine attacks

169-170

169-171 °C

169 - 171 °C

9.5

4.9

Warning

H319 (33.3%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

P203, P264+P265, P273, P280, P305+P351+P338, P318, P337+P317, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 6 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl sumatriptan, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl sumatriptan succinate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sumatriptan succinate/

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Alcohol consumed 30 minutes prior to sumatriptan ingestion had no effect on the pharmacokinetics of sumatriptan.

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.

Sumatriptan tablets and any ergotamine-containing or ergot-type medication (like dihydroergotamine or methysergide) should not be used within 24 hours of each other, nor should sumatriptan and another 5-HT1 agonists.

A 65-year-old woman was referred with confusion, strange behavior, sinus tachycardia, hypertension and hyperthermia. She had been taking sumatriptan and paroxetine and recovered completely after discontinuation of these agents. The diagnosis was 'serotonin syndrome', a result of overstimulation of 5-HT(1A) receptors in the raphe nuclei of the brainstem. It is a complication of the use of serotonergic agents and is associated with the rapid onset of mental, autonomic and neurological symptoms. Treatment consists of discontinuation of the suspected medication and, in severe cases, providing symptomatic relief. ...

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 80(SRC), determined from a log Kow of 0.93(2) and a regression-derived equation(3), indicates that sumatriptan is expected to have high mobility in soil(SRC). However, aromatic amines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group(4,5), suggesting that mobility may be much lower in some soils. Volatilization of sumatriptan from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.5X10-14 atm-cu m/mole(SRC), using a fragment constant estimation method(6). Sumatriptan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.1X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(7). Biodegradation data were not available(SRC, 2009).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 80(SRC), determined from a log Kow of 0.93(2) and a regression-derived equation(3), indicates that sumatriptan is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 4.5X10-14 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2009).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), sumatriptan, which has an estimated vapor pressure of 7.1X10-8 mm Hg at 25 °C is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase sumatriptan may be removed from the air by wet or dry deposition(SRC). Sumatriptan does not contain chromophores that absorb at wavelengths >290 nm(4) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

The safety of treating more than 4 headaches in a month with sumatriptan has not been investigated yet. Notably, adverse reactions to sumatriptan are influenced by the dosage and can be dose-dependent. Individuals experiencing nausea and vomiting can opt for subcutaneous injection instead of the oral form of sumatriptan. However, it is noteworthy that subcutaneous administration of the drug is associated with a higher occurrence of adverse events.

Sumatriptan is distributed into milk in humans and animals; in animals, sumatriptan concentrations are eight-fold higher than concurrent maternal plasma concentrations. In a limited number of healthy lactating women, the total recovery of sumatriptan in breast milk averaged 0.24% of a single 6-mg subcutaneous dose, corresponding to an average infant exposure of 3.5% of the maternal dose on a weight-adjusted basis.

The excretion of a 6 mg subcutaneous dose of sumatriptan in breast milk was studied in five lactating volunteer subjects with a mean age of 27.6 years and a mean body weight of 75 kg. Drug concentrations in milk and plasma over the ensuing 8 hr were measured by high-performance liquid chromatography. The mean milk:plasma ratio estimated from the areas under the milk and plasma concentration-time curves (AUC) was 4.9 (95% CI 4.1-5.7), indicating a significant transfer of sumatriptan into the milk compartment. The mean total recovery of drug in milk was estimated to be only 14.4 ug (95% CI 6.1-22.7 ug), or 0.24% of the 6 mg administered dose. On a weight-adjusted basis this corresponded to a mean infant exposure of 3.5% of the maternal dose (95% CI 0.3-6.7%). If oral bioavailability in the infant is similar to that in adults (14%), the weight-adjusted infant dose is reduced to 0.49%. Furthermore, allowance for reduced clearance in the infant predicts an infant exposure varying from 4.9% in a very premature neonate to 0.7% in a 30 week old infant. Since sumatriptan is usually administered as a single dose at infrequent intervals, the low level of excretion in breast milk suggests that continued breast feeding following its use will not pose a significant risk to the suckling infant. Even this minor exposure could be largely avoided by expressing and discarding all milk for 8 hr after the dose.

The available data concerning sumatriptan overdose and toxicity are limited. A case report highlights a male patient aged 36 who self-reported excessive use of sumatriptan, administering 66 subcutaneous injections of 6 mg within 4 weeks. No adverse reactions were clinically observed, and laboratory parameters remained unaffected.

The 5-HT_1B and 5-HT_1D receptors function as autoreceptors, which inhibit the firing of serotonin neurons and a reduction in the synthesis and release of serotonin upon activation. After sumatriptan binds to these receptors, adenylate cyclase activity is inhibited via regulatory G proteins, incrases intracellular calcium, and affects other intracellular events. This results in vasoconstriction and inhibtion of sensory nociceptive (trigeminal) nerve firing and vasoactive neuropeptide release. Sumatriptan stimulates 5-HT receptors of the 1D subtype, most likely presynaptic receptors, resulting in selective vasoconstriction of inflamed and dilated cranial blood vessels in the carotid circulation. Sumatriptan also blocks the release of vasoactive neuropeptides from perivascular trigeminal axons in the dura mater during migraine and may inhibit the release of inflammatory mediators from the trigeminal nerve.

The Koc of sumatriptan is estimated as 80(SRC), using a log Kow of 0.93(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that sumatriptan is expected to have high mobility in soil. However, aromatic amines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group(4,5), suggesting that mobility may be much lower in some soils(SRC).

/HUMAN EXPOSURE STUDIES/ The excretion of a 6 mg subcutaneous dose of sumatriptan in breast milk was studied in five lactating volunteer subjects with a mean age of 27.6 years and a mean body weight of 75 kg. Drug concentrations in milk and plasma over the ensuing 8 hr were measured by high-performance liquid chromatography. The mean milk:plasma ratio estimated from the areas under the milk and plasma concentration-time curves (AUC) was 4.9 (95% CI 4.1-5.7), indicating a significant transfer of sumatriptan into the milk compartment. The mean total recovery of drug in milk was estimated to be only 14.4 ug (95% CI 6.1-22.7 ug), or 0.24% of the 6 mg administered dose. On a weight-adjusted basis this corresponded to a mean infant exposure of 3.5% of the maternal dose (95% CI 0.3-6.7%). If oral bioavailability in the infant is similar to that in adults (14%), the weight-adjusted infant dose is reduced to 0.49%. Furthermore, allowance for reduced clearance in the infant predicts an infant exposure varying from 4.9% in a very premature neonate to 0.7% in a 30 week old infant. Since sumatriptan is usually administered as a single dose at infrequent intervals, the low level of excretion in breast milk suggests that continued breast feeding following its use will not pose a significant risk to the suckling infant. Even this minor exposure could be largely avoided by expressing and discarding all milk for 8 hr after the dose.

/HUMAN EXPOSURE STUDIES/ Patients (N = 670) have received single oral doses of 140 to 300 mg without significant adverse effects. Volunteers (N = 174) have received single oral doses of 140 to 400 mg without serious adverse events.

/SIGNS AND SYMPTOMS/ Cerebral angiopathy of the postpartum period is a rare entity, sometimes promoted by vasoconstrictives drug prescription. Its clinical presentation includes headaches, seizures and focal neurological deficits, which develop shortly after a normal pregnancy. The diagnosis is based on clinical findings and angiography, showing multiple narrowing of the intracranial cerebral arteries. This neurological feature is reversible and the clinical outcome is good. We report a case of benign cerebral angiopathy in a 20-year-old woman in the postpartum period, occurring after administration of sumatriptan and ergot derivates.

/SIGNS AND SYMPTOMS/ Other arrhythmias or ECG abnormalities reported infrequently in patients receiving sumatriptan therapy include bradycardia, tachycardia, nonspecific ST or T wave changes, prolongation of PR or QTC intervals, sinus arrhythmias, abnormal P waves with nodal rhythm, QRS/T-axis deviations, nonsustained ventricular premature complexes, isolated junctional ectopic beats, atrial ectopic beats, and delayed activation of the right ventricle.

For more Human Toxicity Excerpts (Complete) data for Sumatriptan (21 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

sumatriptan

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl sumatriptan, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl sumatriptan succinate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sumatriptan succinate/

N02CC01

N - Nervous system

QN - Nervous system

N02CC01

Sumatriptan constricts cranial blood vessels and prevents the release of vasoactive peptides. The dose of sumatriptan varies widely by route of administration and in most cases, no more than 2 doses should be given daily. Medication overuse headaches may occur in patients who use sumatriptan frequently.

Sumatriptan is an agonist of 5-HT_1B and 5-HT_1D. This agonism leads to constriction of cranial blood vessels and inhibits the release of pro-inflammatory neuropeptides. Sumatriptan decreases carotid arterial blood flow, but increases blood flow velocity in the internal carotid artery and middle cerebral artery.[A179734 Agonism of the 5-HT_1B and 5-HT_1D receptors also inhibits sensory neurons, preventing the release of vasoactive peptides.[A179734 Sumatriptan does not cross the blood brain barrier.

Sumatriptan and other currently available drugs that are effective for acute migraine, including dihydroergotamine and ergotamine, have binding affinity for serotonin type 1 (5-HT1) receptors, particularly the 5-HT1D (also called 5-HT1Dalpha) and 5-HT1B (also called 5-HT1Dbeta) subtypes located on trigeminal sensory neurons innervating dural blood vessels. The 5-HT1B and 5-HT1D receptors function as autoreceptors, activation of which leads to inhibition of firing of serotonin neurons and a reduction in the synthesis and release of serotonin. Upon binding to these 5-HT1 receptor subtypes, sumatriptan inhibits adenylate cyclase activity via regulatory G proteins, increases intracellular calcium, and affects other intracellular events that lead to vasoconstriction and inhibition of sensory nociceptive (trigeminal) nerve firing and vasoactive neuropeptide release. Sumatriptan has the highest affinity for the 5-HT1D receptor, the most common serotonin receptor subtype in the brain, and a 2- to 17-fold lower affinity for 5-HT1A receptors; agonist activity at 5-HT1A and other serotonin receptors may be responsible for some of the adverse effects noted with administration of serotonin or serotonergic antimigraine drugs (eg, ergotamine, dihydroergotamine). Sumatriptan has essentially no affinity for (based on standard radioligand binding assays) nor pharmacologic activity at other serotonin receptors (eg, 5-HT2, 5-HT3) or at receptors of the dopamine1, dopamine2, muscarinic, histamine, benzodiazepine, or alpha1-, alpha2-, or beta-adrenergic type.

Sumatriptan is a selective agonist of vascular serotonin (5-hydroxytryptamine; 5-HT) type 1-like receptors, probably the 5-HT1D and 5-HT1B subtypes. The mechanisms involved in the pathogenesis of migraine and cluster headache are not clearly understood; consequently, the precise mechanism of action of sumatriptan in the management of these disorders has not been established. However, current data suggest that sumatriptan may ameliorate migraine and cluster headache through selective constriction of certain large cranial blood vessels and/or inhibition of neurogenic inflammatory processes in the CNS. While some features of migraine clearly reflect effects on cerebral blood vessels, neurogenic mechanisms involving activation of the trigeminovascular system also have been implicated; current evidence suggests that both mechanisms may be involved.

The vascular 5-HT1 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-HT1 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.

Sumatriptan selectively reduces carotid arterial blood flow and/or constricts carotid arteriovenous anastomoses in anesthetized animals without appreciable effects on arterial blood pressure or total peripheral resistance. The drug produces contraction of vascular smooth muscle in vitro in saphenous veins in dogs and humans, but such contractions are weaker than those produced by serotonin or ergot alkaloids (eg, methysergide).

For more Mechanism of Action (Complete) data for Sumatriptan (9 total), please visit the HSDB record page.

Subcutaneous sumatriptan has a half life of 1.9h (95% CI of 1.7-2.0h). Oral sumatriptan has a half life of 1.7h (95% CI of 1.4-1.9h). Rectal sumatriptan has a half life of 1.8h (95% CI of 1.6-2.2h). Intranasal sumatriptan has a half life of 1.8h (95% CI of 1.7-2.0h).

Following single subcutaneous or oral doses of sumatriptan in healthy individuals, the terminal elimination half-life of the drug is 1.5-2.6 hours.

Following single-dose oral administration of large doses of sumatriptan or repeated administration of smaller doses, a second terminal elimination phase has been observed but not characterized. The prolonged elimination half-life with multiple dosing or administration of large single doses may indicate enterohepatic recycling or prolonged oral absorption and does not appear to affect substantially the disposition of the drug. Most of a dose of sumatriptan is excreted within 10-24 hours.

Following intranasal administration of sumatriptan, the elimination half-life reportedly is about 2 hours.

Sumatriptan is predominantly metabolized by monoamine oxidase A. The main metabolites are the inactive indole acetic acid and indole acetic acid glucuronide.

The principal metabolite of sumatriptan is its inactive indole acetic acid analog, which is formed by oxidative N-deamination of the N-dimethyl side chain. The indole acetic acid metabolite of sumatriptan achieves plasma concentrations 6-7 times higher than those of sumatriptan but has a half-life similar to that of the parent compound, suggesting that clearance of this metabolite is formation-rate limited. Other minor metabolites of sumatriptan, an ester glucuronide of the indole acetic acid derivative and an indole ethyl alcohol derivative, also have been identified.

Metabolism is the principal clearance process for sumatriptan. Sumatriptan is metabolized in the liver and possibly in the GI tract and is eliminated in urine and feces. In vitro studies suggest that sumatriptan is metabolized by monoamine oxidase (MAO), principally the A isoenzyme (MAO-A); inhibitors of this enzyme may increase systemic exposure to sumatriptan.

Hepatic. In vitro studies with human microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme. Route of Elimination: Only 3% of the dose is excreted in the urine as unchanged sumatriptan; 42% of the dose is excreted as the major metabolite, the indole acetic acid analogue of sumatriptan. Half Life: 2.5 hours

8R78F6L9VO

SUMATRIPTAN

Mechanisms of Action [MoA] - Serotonin 1b Receptor Agonists

Mechanisms of Action [MoA] - Serotonin 1d Receptor Agonists

Established Pharmacologic Class [EPC] - Serotonin-1b and Serotonin-1d Receptor Agonist

Sumatriptan is a Serotonin-1b and Serotonin-1d Receptor Agonist. The mechanism of action of sumatriptan is as a Serotonin 1b Receptor Agonist and Serotonin 1d Receptor Agonist.

Drugs used to cause constriction of the blood vessels.

Endogenous compounds and drugs that specifically stimulate SEROTONIN 5-HT1 RECEPTORS. Included under this heading are agonists for one or more of the specific 5-HT1 receptor subtypes.

A 6mg subcutaneous injection of sumatriptan reaches a Cmax of 69.5ng/mL (95% CI of 62.8-76.9ng/mL) with a Tmax of 0.17h (95% CI of 0.08-0.33h), an AUC of 9.0h\*ng/mL (95% CI of 7.5-10.9h\*ng/mL), and a bioavailability of 100%. A 25mg oral dose of sumatriptan reaches a Cmax of 16.5ng/mL (95% CI of 13.5-20.1ng/mL) with a Tmax of 1.50h (95% CI of 0.50-2.00h), an AUC of 8.7h\*ng/mL (95% CI of 6.1-12.5h\*ng/mL), and a bioavailability of 14.3% (95% CI of 11.4-17.9%). A 20mg intranasal dose of sumatriptan reaches a Cmax of 12.9ng/mL (95% CI of 10.5-15.9ng/mL) with a Tmax of 1.50h (95% CI of 0.25-3.00h), an AUC of 7.4h\*ng/mL (95% CI of 5.0-10.8h\*ng/mL), and a bioavailability of 15.8% (95% CI of 12.6-19.8%). A 25mg rectal dose of sumatriptan reaches a Cmax of 22.9ng/mL (95% CI of 18.4-28.6ng/mL) with a Tmax of 1.00h (95% CI of 0.75-3.00h), an AUC of 14.6h\*ng/mL (95% CI of 11.3-18.8h\*ng/mL), and a bioavailability of 19.2% (95% CI of 15.3-24.1%).

22±4% is excreted in the urine as unchanged sumatriptan and 38±7% in urine as indole acetic acid approximately 40% is excreted in the feces.

Sumatriptan has a volume of distribution of 50±8L for a 6mg subcutaneous dose, or 2.7L/kg.

Subcutaneous sumatriptan has a clearance of 0.22L/min (95% CI of 0.19-0.25L/min). Oral sumatriptan has a clearance of 0.17L/min (95% CI of 0.14-0.21L/min). Rectal sumatriptan has a clearance of 0.17L/min (95% CI of 0.14-0.21L/min). Intranasal sumatriptan has a clearance of 0.21L/min (95% CI of 0.18-0.25L/min). Total plasma clearance of sumatriptan is approximately 1200mL/min.

Sumatriptan is rapidly absorbed following subcutaneous or oral administration; oral absorption appears to occur in the small intestine. The drug also is absorbed rapidly following intranasal administration. The bioavailability of sumatriptan given subcutaneously is almost complete, averaging about 97% of that obtained with iv administration of the drug. The bioavailability of sumatriptan following oral or intranasal administration averages only about 15 or 17%, respectively, principally because of presystemic metabolism of the drug and in part because of incomplete absorption. The area under the plasma concentration-time curve (AUC) and peak serum concentration of sumatriptan increase linearly with single subcutaneous doses of 1-16 mg. The extent of sumatriptan absorption (AUC) also is dose-proportional following single oral doses of 25-200 mg; however, peak plasma concentrations after a 100-mg oral dose of sumatriptan are approximately 25% less than those predicted from a 25-mg oral dose.

Interindividual variability in the absorption of sumatriptan after oral administration results in multiple peaks in plasma concentration, possibly because of differences in the rates of gastric emptying, small-bowel transit, and/or presystemic metabolism; however, 75-80% of the final peak plasma concentration is reached within 45 minutes after dosing. Administration of higher than recommended single oral doses of sumatriptan (ie, 200-400 mg) is associated with a decrease in the rate of absorption.

THERAP CAT: Antimigraine

Use (kg; approx.) in Germany (2009): >750

For the treatment of migraine attacks with or without aura.

[3-[2-(dimethylamino)ethyl]]-2-[[3-[2-(dimethylamino)ethanyl]]-1H-indol-5-yl]]-N-methylmethane-sulphonamide

N-methyl[3-]-2-(methylamino)ethyl]-1H-indol-5-yl]methanesulphonamide

[3-[2-(dimethylamino)ethyl]-1-(hydroxymethyl)-1H-indol-5-yl]-N-methylmethanesulphonamide

N,N-dimethyl-2-[5-[(methylsulphamoyl)methyl]-1H-indol-3-yl]ethanamine N-oxide

For more Impurities (Complete) data for Sumatriptan (8 total), please visit the HSDB record page.