Sumatriptan

Sumatriptan

Clinical data
License data	US FDA: Sumatriptan
Pregnancy category	C
Routes of administration	tablet, subcutaneous injection, nasal spray
ATC code	N02CC01 (WHO)
Pharmacokinetic data
Bioavailability	15% (oral)/ 96% (s.c)
Protein binding	14%-21%
Metabolism	MAO
Elimination half-life	2.5 hours
Excretion	60% urine; 40% feces
Identifiers
IUPAC name 1-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]- N-methyl-methanesulfonamide
CAS Number	103628-46-2
PubChem CID	5358
IUPHAR/BPS	54
DrugBank	APRD00379
ChemSpider	5165 Y
UNII	8R78F6L9VO
KEGG	D00451 N
ChEMBL	ChEMBL128
CompTox Dashboard (EPA)	DTXSID4023628
ECHA InfoCard	100.130.518
Chemical and physical data
Formula	C14H21N3O2S
Molar mass	295.402 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES O=S(=O)(NC)Cc1cc2c(cc1)ncc2CCN(C)C
InChI InChI=1S/C14H21N3O2S/c1-15-20(18,19)10-11-4-5-14-13(8-11)12(9-16-14)6-7-17(2)3/h4-5,8-9,15-16H,6-7,10H2,1-3H3 Y Key:KQKPFRSPSRPDEB-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Sumatriptan (trade names Imitrex, Imigran, Imigran recovery) is a triptan sulfa drug containing a sulfonamide group for the treatment of migraine headaches. Imitrex is marketed and manufactured by GlaxoSmithKline as well as various generic drug manufacturers.

Approval and availability

Sumatriptan was the first triptan available (in 1991), and, in the United States and most developed countries, is available only by medical prescription. Several dosage forms for sumatriptan have been approved, including tablets, solution for injection, and nasal inhalers.

In the United Kingdom, sumatriptan is available over the counter, under the names Imigran Recovery and Migraleve Ultra. It is sold in packs of two 50 mg tablets for approximately £7.99 (equivalent to about $12 US). In the U.S. the cost in 2009 is about $15. Larger pack sizes, a nasal spray preparation, and a liquid preparation for injection are also available by prescription. Patent Protection in the UK and Europe expired on 16 May 2006, under UK Patent GB2162522 (extended by supplementary protection certificate SPC/GB93/07). In the United States, Glaxo Smith Kline was able to extend their US patent considerably beyond this date through patent litigation. However, a generic injectable version of sumatriptan came to market in August 2008 (Dr Reddy's Labs Ltd).

On April 15, 2008, the US FDA approved a combination of sumatriptan and naproxen, an NSAID, which is marketed in the USA under the trade name Treximet.. This combination has shown a benefit over either medicine used separately.

In July 2009, the US FDA approved a single-use jet injector formulation of sumatriptan. The device delivers a subcutaneous injection of 6 mg sumatriptan. A similar application has been filed in Europe.

Phase III studies with a iontophoretic transdermal patch (Zelrix) started in July 2008. This patch uses low voltage controlled by a pre-programmed microchip to deliver a single dose of sumatriptan through the skin within 30 minutes.

Mode of action

Sumatriptan is structurally similar to serotonin (5HT), and is a 5-HT (types 5-HT_1D and 5-HT_1B) agonist. The specific receptor subtypes it activates are present on the cranial arteries and veins. Acting as an agonist at these receptors, Sumatriptan reduces the vascular inflammation associated with migraine.

The specific receptor subtype it activates is present in the cranial and basilar arteries. Activation of these receptors causes vasoconstriction of those dilated arteries. Sumatriptan is also shown to decrease the activity of the trigeminal nerve, which probably accounts for sumatriptan's efficacy in treating cluster headaches. The injectable form of the drug has been shown to abort a cluster headache within fifteen minutes in 96% of cases.

Pharmacokinetics

Sumatriptan is administered in several forms; tablets, subcutaneous injection, and nasal spray. Oral administration (as succinate) suffers from poor bioavailability, partly due to presystemic metabolism—some of it gets broken down in the stomach and bloodstream before it reaches the target arteries. A new rapid-release tablet formulation has the same bioavailability, but the maximum concentration is achieved on average 10–15 minutes earlier. When injected, sumatriptan is faster acting (usually within 10 minutes), but the effect lasts for a shorter time. Sumatriptan is metabolised primarily by monoamine oxidase A into an indole acetic acid analogue, part of which is further conjugated with glucuronic acid. These metabolites are excreted in the urine and bile. Only about 3% of the active drug may be recovered unchanged.

There is no simple, direct relationship between sumatriptan concentration (pharmacokinetics) per se in the blood and its anti-migraine effect (pharmacodynamics). This paradox has, to some extent been resolved by comparing the rates of absorption of the various sumatriptan formulations, rather than the absolute amounts of drug that they deliver.

Side effects

Large doses of sumatriptan (200 mg/day) can cause sulfhemoglobinemia, a rare condition in which the blood changes from red to greenish-black, due to the integration of sulfur into the hemoglobin molecule. If sumatriptan is discontinued, the condition reverses within a few weeks.

Serious cardiac events, including some that have been fatal, have occurred following the use of Imitrex Injection or Tablets. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation.

In the below table, "Common" is reported in at least 1/100 patients, "Less common" in 1/100 to 1/1000 patients and "Rare" in less than 1/1000 patients. Some of the symptoms listed below are classic symptoms associated with migraine itself, such as photo/phonophobia, visual disturbances, and nausea.

Type	Common	Less Common	Rare
Atypical Sensations	Burning sensations and numbness Chest symptoms (not due to ischemia)	"tight feeling around the head"	Dysesthesia, Bleeding Rectum
Cardiovascular	Palpitations, syncope, as well as changes in blood pressure.	Arrhythmia, changes in ECG, hypertension, hypotension, pallor, pulsating sensations, and tachycardia.	Angina, atherosclerosis, bradycardia, cerebral ischemia, cerebrovascular lesion, heart block, peripheral cyanosis, thrombosis, transient myocardial ischemia, and vasodilation.
Ear, Nose, and Throat	Sinusitis, tinnitus; allergic rhinitis; upper respiratory inflammation; ear, nose, and throat hemorrhage; external otitis; hearing loss; nasal inflammation; and sensitivity to noise.	Hearing disturbances and otalgia.	Feeling of fullness in the ear(s).
Endocrine and Metabolic	Thirst.	Elevated thyrotropin stimulating hormone (TSH) levels; galactorrhea; hyperglycemia; hypoglycemia; hypothyroidism; polydipsia; weight gain; weight loss; endocrine cysts, lumps, and masses; and fluid disturbances.
Eye	Sclera, mydriasis, blindness and low vision, visual disturbances, eye edema and swelling, eye irritation and itching, accommodation disorders, external ocular muscle disorders, eye hemorrhage, eye pain, and keratitis and conjunctivitis.
Gastrointestinal	Diarrhea and gastric symptoms.	Constipation, dysphagia, and gastroesophageal reflux.	Gastrointestinal bleeding, hematemesis, melena, peptic ulcer, gastrointestinal pain, dyspeptic symptoms, dental pain, feelings of gastrointestinal pressure, gastritis, gastroenteritis, hypersalivation, abdominal distention, oral itching and irritation, salivary gland swelling, and swallowing disorders.
Hematological Disorders	Anemia
Musculoskeletal	Myalgia	Muscle cramps.	Tetany; muscle atrophy, weakness, and tiredness; arthralgia and articular rheumatitis; acquired musculoskeletal deformity; muscle stiffness, tightness, and rigidity; and musculoskeletal inflammation.
Neurological	Phonophobia and photophobia.	Confusion, depression, difficulty concentrating, disturbance of smell, dysarthria, euphoria, facial pain, heat sensitivity, incoordination, lacrimation, monoplegia, sleep disturbance, shivering, syncope, and tremor.	Aggressiveness, apathy, bradylogia, cluster headache, convulsions, decreased appetite, drug abuse, dystonic reaction, facial paralysis, hallucinations, hunger, hyperesthesia, hysteria, increased alertness, memory disturbance, neuralgia, paralysis, personality change, phobia, radiculopathy, rigidity, suicide, twitching, agitation, anxiety, depressive disorders, detachment, motor dysfunction, neurotic disorders, psychomotor disorders, taste disturbances, and raised intracranial pressure.
Respiratory	Dyspnea.	Asthma.	Hiccups, breathing disorders, cough, and bronchitis.
Skin	Sweating.	Erythema, pruritus, rash, and skin tenderness.	Dry/scaly skin, tightness of skin, wrinkling of skin, eczema, seborrheic dermatitis, and skin nodules.
Breasts	Tenderness.	Nipple discharge, swelling, cysts, lumps, masses and primary malignant breast neoplasm.
Urogenital	Dysmenorrhea, increased urination, and intermenstrual bleeding.	Abortion and hematuria, urinary frequency, bladder inflammation, micturition disorders, urethritis, urinary infections, menstruation symptoms, abnormal menstrual cycle, inflammation of fallopian tubes, and menstrual cycle symptoms.
Miscellaneous	Hypersensitivity.	Fever, fluid retention, and overdose.	Edema, hematoma, lymphadenopathy, speech disturbance, voice disturbances, contusions.

Generics

Sumatriptan vails 100 5509

On November 6, 2008, Par Pharmaceutical announced that it would begin shipping generic versions of Imitrex Injection (sumatriptan succinate injection) 4 mg and 6 mg starter kits and 4 mg and 6 mg pre-filled syringe cartridges to the trade immediately. In addition, Par anticipates launching the 6 mg vials early in 2009.

Mylan Laboratories Inc. has received FDA approval for its generic version of Imitrex tablets in 25, 50, and 100 milligram doses. The drug will soon be available, or is already available, in European markets since Glaxo's patent protections have expired in those jurisdictions. However, sales of the generic drug are still restricted in the U.S. since Glaxo won an extension on their patent until 2009. A generic version of the drug in tablet form became available December 2008 in the United States and is distributed by Ranbaxy.

See also Sumavel DosePro (above).

Chemistry

File:Sumatriptan synth.png

U.S. patent 4,785,016