Sumatriptan: Wikis

  

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Sumatriptan
Systematic (IUPAC) name
1-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]- N-methyl-methanesulfonamide
Identifiers
CAS number 103628-46-2
ATC code N02CC01
PubChem 5358
DrugBank APRD00379
ChemSpider 5165
Chemical data
Formula C14H21N3O2S 
Mol. mass 295.402 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 15% (oral)/ 96% (s.c)
Protein binding 14%-21%
Metabolism MAO
Half life 2.5 hours
Excretion 60% urine; 40% feces
Therapeutic considerations
Licence data

US FDA:link

Pregnancy cat. C
Legal status
Routes tablet, subcutaneous injection, nasal spray
 Yes check.svgY(what is this?)  (verify)

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

Contents

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 name Imigran Recovery. 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).[citation needed]

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.[1]. This combination has shown a benefit over either medicine used separately.[2]

In July 2009, the United States FDA approved Sumavel DosePro(R) (Zogenix Inc., Emeryville and San Diego, California, USA). This is a unique pre-filled, single-use delivery system for 6 mg subcutaneous sumatriptan. It has no needle, and uses gas pressure as a power source. The drug is delivered in less than 100 msec. Sumavel DosePro is about the size of a white board marker or fat felt-tipped pen, and became available for prescription in the USA in early 2010; a corresponding product application has been filed in Europe. [3]

Mode of action

Sumatriptan is structurally similar to serotonin (5HT), and is a 5-HT (types 5-HT1D and 5-HT1B[4]) agonist. The specific receptor subtypes it activates are present in the cerebral arteries. Dilation of these arteries is thought to be a major cause of headache pain, and activating these receptors causes vasoconstriction.

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.[5][6]

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.[7] 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[8].

Type Common Less Common Rare
Atypical Sensations Burning sensations and numbness

Chest symptoms (not due to ischemia)

"tight feeling around the head" Dysesthesia
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

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. [9]

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).[3]

References

  1. ^ GSK press release - Treximet (sumatriptan and naproxen sodium) tablets approved by FDA for acute treatment of migraine
  2. ^ Brandes JL, Kudrow D, Stark SR, et al. (April 2007). "Sumatriptan-naproxen for acute treatment of migraine: a randomized trial". JAMA 297 (13): 1443–54. doi:10.1001/jama.297.13.1443. PMID 17405970. http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=17405970. 
  3. ^ a b Brandes, J.; Cady, R.; Freitag, F.; Smith, T.; Chandler, P.; Fox, A.; Linn, L.; Farr, S. (2009). "Needle-free subcutaneous sumatriptan (Sumavel DosePro): bioequivalence and ease of use.". Headache 49 (10): 1435–1444. doi:10.1111/j.1526-4610.2009.01530.x. PMID 19849720.  edit
  4. ^ Razzaque Z, Heald MA, Pickard JD, et al. (1999). "Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1B- and 5-HT1F-receptor activation". Br J Clin Pharmacol 47 (1): 75–82. doi:10.1046/j.1365-2125.1999.00851.x. PMID 10073743. 
  5. ^ Fox, AW (2004). "Onset of effect of 5-HT1B/1D agonists: a model with pharmacokinetic validation". Headache 44 (2): 142–7. PMID 14756852.  edit
  6. ^ Freidank-Mueschenborn, E.; Fox, A. (2005). "Resolution of concentration-response differences in onset of effect between subcutaneous and oral sumatriptan". Headache 45 (6): 632–637. doi:10.1111/j.1526-4610.2005.05129a.x. PMID 15953294.  edit
  7. ^ "Patient bleeds dark green blood". BBC News. 8 June 2007. http://news.bbc.co.uk/2/hi/health/6733203.stm. Retrieved 6 March 2010. 
  8. ^ Imitrex Tablets
  9. ^ "PAR PHARMACEUTICAL BEGINS SHIPMENT OF SUMATRIPTAN INJECTION". Par Pharmaceutical. 2008-11-06. http://www.parpharm.com/media/NR_20081106.jsp. Retrieved 2008-11-25. 







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