Imitrex (Sumatriptan Succinate)

IMITREX® Injection/Tablets IMITREX® Nasal Spray

Glaxo Wellcome

Sumatriptan Succinate

Sumatriptan

Migraine Therapy

Action And Clinical Pharmacology: Sumatriptan has been shown to be effective in relieving migraine headache. It is an agonist for a vascular 5-hydroxytryptamine1D (5-HT1D) receptor subtype (a member of the 5-HT1 family), and has only weak affinity for 5-HT1A receptors and no significant activity (as measured using standard radioligand binding assays) or pharmacological activity at 5-HT2, 5-HT3, 5-HT4, 5-HT5A, or 5-HT7 receptor subtypes, or at alpha1-, alpha2-, or beta-adrenergic; dopamine1 or dopamine2; muscarinic; or benzodiazepine receptors.

Sumatriptan activates the 5-HT1D receptor subtype which is present on cranial arteries, on the basilar artery and in the vasculature of dura matter. This action correlates with relief of headache. The antimigrainous effect of sumatriptan is believed to be due to vasoconstriction of cranial arteries, which are dilated and edematous during a migraine attack.

Experimental data from animal studies shows that sumatriptan also activates 5-HT1 receptors on peripheral terminals of the trigeminal nerve which innervates cranial blood vessels. This causes the inhibition of neuropeptide release. It is thought that such an action may contribute to the anti-migraine action of sumatriptan in humans.

Cardiovascular Effects: In vitro studies in human isolated epicardial coronary arteries suggest that the predominant contractile effect of 5-HT is mediated via 5-HT2 receptors. However, 5-HT1 receptors also contribute to some degree to the contractile effect seen. Transient increases in systolic and diastolic blood pressure (up to 20 mmHg) of rapid onset (within minutes), have occurred after i.v. administration of up to 64 µg/kg (3.2 mg for 50 kg subject) to healthy volunteers. These changes were not dose related and returned to normal within 10 to 15 minutes. Following oral administration of 200 mg or intranasal administration of 40 mg, however, mean peak increases in blood pressure were smaller and of slower onset than after i.v. or s.c. administration.

Pharmacokinetics: Sumatriptan is rapidly absorbed after oral, s.c. and intranasal administration. The mean bioavailability is 96% after s.c. dosing, 14% after oral dosing, and 16% after intranasal administration. The low oral and intranasal bioavailability is primarily due to metabolism (hepatic and pre-systemic) and partly due to incomplete absorption. The oral absorption of sumatriptan is not significantly affected either during migraine attacks or by food.

Following an oral dose of 100 mg, a mean Cmax of 54 ng/mL was attained. The time to peak plasma level was variable (0.5 to 5 hours); however, 70 to 80% of Cmax values were attained within 30 to 45 minutes of oral dosing. The mean plasma half-life was approximately 2 hours (range 1.9 to 2.2 hours).

Following a 6 mg s.c. dose (standard injection) in the deltoid region of the arm or thigh or autoinjection into the thigh, a mean Cmax value of 60 ng/mL was attained at approximately 15 minutes. Mean plasma half-life was approximately 2 hours (range 1.7 to 2.3 hours).

Following a 5 mg, 10 mg and 20 mg intranasal dose, Cmax values were 4.7 ng/mL, 8.5 ng/mL and 14.4 ng/mL, respectively. The time to peak plasma level was 1 to 1.5 hours. The elimination half-life is approximately 2 hours (range 1.3 to 5.4 hours). Inter-patient and intra-patient variability was noted in most pharmacokinetic parameters assessed.

Sumatriptan is extensively metabolized by the liver and cleared to a lesser extent by renal excretion. The major metabolite, the indole acetic acid analogue of sumatriptan is mainly excreted in the urine where it is present as a free acid (35%) and the glucuronide conjugate (11%). It has no known 5-HT1 or 5-HT2 activity. Minor metabolites have not been identified.

Plasma protein binding of sumatriptan in humans is low (14 to 21%).

No differences have been observed between the pharmacokinetic parameters in healthy elderly volunteers compared with younger volunteers (less than 65 years old).

Significant relief begins about 10 to 15 minutes following s.c. injection, 15 minutes following intranasal administration and 30 minutes following oral administration.

Indications And Clinical Uses: For the relief of migraine attacks with or without aura.

Sumatriptan is not indicated for prophylactic therapy of migraine, or for the management of hemiplegic or basilar migraine.

Contra-Indications: Patients with known hypersensitivity to any of the components of the formulations.

Sumatriptan is contraindicated in patients with ischemic heart disease, angina pectoris including Prinzmetal angina (coronary vasospasm), previous myocardial infarction and uncontrolled hypertension. Sumatriptan is also contraindicated in patients taking ergotamine containing preparations or ergot derivatives (such as dihydroergotamine), and in patients receiving treatment with monoamine oxidase (MAO) inhibitors or use within 2 weeks of discontinuation of MAO inhibitor therapy.

Until further data are available, the use of sumatriptan is contraindicated in patients with hemiplegic migraine, basilar migraine and in patients receiving treatment with selective 5-HT (serotonin) reuptake inhibitors and lithium.

Manufacturers’ Warnings In Clinical States:

There is no experience in patients with recent cerebrovascular accidents or cardiac arrhythmias (especially tachycardias). Therefore, the use of sumatriptan in these patients is not recommended.

Sumatriptan should only be used where there is a clear diagnosis of migraine headache.

As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. There have been rare reports where patients received sumatriptan for severe headaches which subsequently were shown to have been secondary to an evolving neurological lesion (cerebrovascular accident, subarachnoid hemorrhage). In this regard, it should be noted that migraineurs may be at risk of certain cerebrovascular events (e.g., cerebrovascular accident, transient ischemic attack). However, if a patient does not respond to the first dose, the opportunity should be taken to review the diagnosis before a second dose is given.

Sumatriptan has been associated with transient chest pain and tightness which may mimic angina pectoris and may be intense. Only in rare cases have the symptoms been identified as the result of coronary vasospasm. The vasospasm may result in arrhythmia, ischemia or myocardial infarction. Serious coronary events following sumatriptan have occurred but are extremely rare. Although it is not clear how many of these can be attributed to sumatriptan, because of its potential to cause coronary vasospasm, sumatriptan should not be given to patients in whom unrecognized coronary artery disease (CAD) is likely without a prior evaluation for underlying cardiovascular disease. Such patients include postmenopausal women, males over 40, patients with risk factors for CAD (hypertension, hypercholesterolemia, obesity, diabetes, smoking, or strong family history of CAD).

Consideration should be given to administering the first dose of sumatriptan injection in the physician’s office to patients in whom unrecognized coronary artery disease is comparatively likely. If the patient experiences symptoms which are severe or persistent and are consistent with angina, appropriate investigations should be carried out to check for the possibility of ischemic changes. A careful medical history should be taken before sumatriptan is prescribed to exclude pre-existing cardiovascular disease.

Sumatriptan should be used with caution in patients in whom there is a concern of ischemic heart disease, as well as in patients with arteriosclerotic diseases such as peripheral and/or cerebral vascular disease.

There have been rare reports of serious and/or life-threatening arrhythmias, including atrial fibrillation, ventricular fibrillation, ventricular tachycardia and myocardial infarction, as well as transient ischemic ST wave elevations associated with sumatriptan injection.

Sumatriptan injection should never be given i.v.

The recommended dose of sumatriptan should not be exceeded.

Precautions: Cluster Headache: There is insufficient information on the efficacy and safety of sumatriptan in the treatment of cluster headache, which is present in an older, predominantly male population. The need for prolonged use and the demand for repeated medication in this condition renders the dosing information inapplicable for cluster headache.

General: Prolonged vasospastic reactions have been reported with ergotamine. As these effects may be additive, 24 hours should elapse before sumatriptan can be taken following any ergotamine-containing preparation. Conversely, ergotamine-containing preparations should not be taken until 6 hours have elapsed following sumatriptan administration.

Sumatriptan should be used with caution in patients with a history of epilepsy or structural brain lesions which lower their convulsion threshold.

Chest, jaw or neck tightness is relatively common (3 to 5% in controlled clinical trials) after sumatriptan injection, but has only been rarely associated with ischemic ECG changes.

Sumatriptan may cause a short-lived elevation of blood pressure (see Pharmacology and Contraindications).

Occupational Hazards: Patients should be cautioned that drowsiness may occur as a result of treatment with sumatriptan. They should be advised not to perform skilled tasks e.g., driving or operating machinery if drowsiness occurs.

Concomitant Disease: Since there have been rare reports of seizures occurring, sumatriptan should be used with caution in patients with a history of epilepsy or structural brain lesions which lower their convulsive threshold.

Concomitant Medications: There have been reports of patients with known hypersensitivity to sulphonamides exhibiting an allergic reaction following administration of sumatriptan. Reactions ranged from cutaneous hypersensitivity to anaphylaxis.

Renal Impairment: The effects of renal impairment on the efficacy and safety of sumatriptan have not been evaluated. Therefore sumatriptan is not recommended in this patient population.

Hepatic Impairment: The effect of hepatic impairment on the efficacy and safety of sumatriptan has not been evaluated; however, the pharmacokinetic profile of sumatriptan in patients with moderate* hepatic impairment shows that these patients, following an oral dose of 50 mg, have much higher plasma sumatriptan concentrations than healthy subjects. Therefore, an oral dose of 50 mg may be considered in patients with hepatic impairment.

*Assessed by aminopyrine breath test (>0.2 to 0.4 scaling units).

The pharmacokinetic parameters of 6 mg s.c. sumatriptan do not differ statistically between normal volunteers and moderately hepatically impaired subjects.

Geriatrics (>65 years): Experience of the use of sumatriptan in patients aged over 65 years is limited. Therefore the use of sumatriptan in patients over 65 years is not recommended.

Pregnancy: Reproduction studies, performed in rats, have not revealed any evidence of impaired fertility, teratogenicity, or post-natal development due to sumatriptan. Reproduction studies, performed in rabbits by the oral route, have shown increased incidence of variations in cervico-thoracic blood vessel configuration in the fetuses. These effects were only seen at the highest dose tested, which affected weight gain in the dams, and at which blood levels were in excess of 50 times those seen in humans after therapeutic doses. A direct association with sumatriptan treatment is considered unlikely but cannot be excluded. Therefore, the use of sumatriptan is not recommended in pregnancy.

In a rat fertility study, oral doses of sumatriptan resulting in plasma levels approximately 150 times those seen in humans after a 6 mg s.c. dose and approximately 200 times those seen in humans after a 100 mg oral dose were associated with a reduction in the success of insemination. This effect did not occur during a s.c. study where maximum plasma levels achieved approximately 100 times those in humans by the s.c. route and approximately 150 times those in humans by the oral route.

Lactation: Sumatriptan is excreted in breast milk in animals. No data exists in humans, therefore, caution is advised when administering sumatriptan to nursing women.

Drug Interactions: Single dose pharmacokinetic drug interaction studies have not shown evidence of interactions with propranolol, flunarizine, pizotifen or alcohol. Multiple dose interaction studies have not been performed.

Adverse Reactions: The most common adverse reaction associated with sumatriptan administered s.c. is transient pain (local erythema and burning sensation) at the site of injection.

Other side effects which have been reported for all routes of administration, but were more common for s.c. route, include sensations of tingling, heat, heaviness, pressure or tightness in any part of the body, chest symptoms, flushing, dizziness and feelings of weakness. Transient increases in blood pressure arising soon after treatment have been recorded. Hypotension, bradycardia, tachycardia and palpitations have been reported rarely.

Sumatriptan may cause coronary vasospasm in patients with a history of coronary artery disease, known to be susceptible to coronary artery vasospasm, and, very rarely, without prior history suggestive of coronary artery disease.

There have been rare reports of serious and/or life-threatening arrhythmias, including atrial fibrillation, ventricular fibrillation, ventricular tachycardia, myocardial infarction, and transient ischemic ST elevation associated with sumatriptan injection (see Warnings).

Fatigue and drowsiness have been reported at slightly higher rates for the oral route, as were nausea and vomiting; the relationship of the latter adverse reactions to sumatriptan is not clear. Hypersensitivity reactions to sumatriptan have been reported including anaphylactic shock, anaphylactoid reactions, rash, urticaria, pruritus and erythema.

There have been rare reports of seizures, the majority of these patients have a previous history of epilepsy or structural lesions predisposing to epilepsy (see Precautions).

Of the 3 630 patients treated with Sumatriptan nasal spray in clinical trials, there was one report of a coronary vasospasm related to Sumatriptan administration.

Minor disturbances of liver function tests have occasionally been observed with sumatriptan treatment. There is no evidence that clinically significant abnormalities occurred more frequently with sumatriptan than with placebo.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There have been no reports of overdosage with sumatriptan. Experience with doses outside of the recommended labeling are as follows: One patient received two 6 mg s.c. doses within 30 minutes and 1 patient received four 100 mg tablets within 24 hours, with no adverse events. The highest dose of sumatriptan nasal spray administered without significant adverse effects was 20 mg given 3 times daily for 4 days.

If overdosage with sumatriptan occurs, the patient should be monitored and standard supportive treatment applied as required. Toxicokinetics are not available.

The effect of hemodialysis or peritoneal dialysis on the serum concentration of sumatriptan is unknown.

Dosage And Administration: General: Sumatriptan is indicated for the acute treatment of migraine headache with or without aura. Sumatriptan should not be used prophylactically. Sumatriptan may be given orally, s.c. or as a nasal spray.

In selecting the appropriate formulation for individual patients, consideration should be given to the patient’s preference for formulation and the patient’s requirement for rapid onset of relief. Significant relief begins about 10 to 15 minutes following s.c. injection, 15 minutes following intranasal administration and 30 minutes following oral administration.

In addition to relieving the pain of migraine, sumatriptan (all formulations) has also been shown to be effective in relieving associated symptoms of migraine (nausea, vomiting, phonophobia, photophobia). Sumatriptan is equally effective when administered at any stage of a migraine attack. Long-term (12 to 24 months) clinical studies with maximum recommended doses of sumatriptan indicate that there is no evidence of the development of tachyphylaxis, or medication-induced (rebound) headache.

Twenty-four hours should elapse before sumatriptan is taken following any ergotamine-containing preparation or ergot derivative (such as dihydroergotamine). Conversely, ergotamine-containing preparations or ergot derivatives should not be taken until 6 hours have elapsed following sumatriptan administration.

Injection: Sumatriptan injection should be injected s.c. (on the outside of the thigh) using an autoinjector.

Adults: The recommended dose is a single 6 mg s.c. injection.

Clinical trials have shown that approximately 70 to 72% of patients have headache relief within 1 hour after a single s.c. injection. This number increases to 82% by 2 hours.

If adequate relief has not been attained within 2 hours, additional doses should not be used as they are unlikely to be of clinical benefit. Sumatriptan may be taken for subsequent attacks provided a minimum of 1 hour has elapsed since the last dose. Not more than 12 mg (two 6 mg injections) should be taken in any 24-hour period.

Administration during migraine aura prior to other symptoms occurring may not prevent the development of a headache.

Patients should be advised to read the patient instruction leaflet regarding the safe disposal of syringes and needles.

Nasal Spray: The minimal effective single adult dose of sumatriptan nasal spray is 5 mg. The maximum recommended single dose is 20 mg.

If adequate relief has not been attained within 2 hours of initial treatment, additional doses should not be administered for the same attack as they are unlikely to be of clinical benefit. Sumatriptan may be taken for subsequent attacks provided a minimum of 2 hours has elapsed since the last dose. No more than a total of 40 mg should be taken in any 24-hour period.

Within the range of 5 to 20 mg, an increase in dose was not associated with any significant increase in the incidence or severity of adverse events other than taste disturbance (see Adverse Effects).

The nasal spray should be administered into one nostril only. The device is a ready to use single dose unit and must not be primed before administration. Patients should be advised to read the patient instruction leaflet regarding the use of the nasal spray device before administration.

Tablets: Adults: The recommended adult dose is a single 100 mg tablet.

However, based on the physician’s clinical judgment, a 50 mg dose may be considered adequate. The appropriateness should be based on the patient’s needs and response to treatment.

Clinical trials have shown that approximately 50 to 75% of patients have headache relief within 2 hours after oral dosing with 100 mg, and that a further 15 to 25% have headache relief by 4 hours.

If adequate relief has not been attained within 4 hours, additional doses should not be used as they are unlikely to be of clinical benefit. Sumatriptan may be taken to treat subsequent migraine attacks. Not more than 300 mg should be taken in any 24-hour period.

The tablet should be swallowed whole with water, not crushed, chewed or split.

Hepatic Impairment: In patients with mild or moderate hepatic impairment, plasma sumatriptan concentrations up to two times those seen in healthy subjects have been observed. Therefore, a 50 mg dose (single tablet) may be considered in these patients (see Precautions).

Availability And Storage: Injection: Each prefilled syringe contains: sumatriptan (base) 6 mg as the succinate salt, in an isotonic sodium chloride solution (total volume=0.5 mL). Also contains water for injection. Syringes are placed in a tamper-evident carrying/disposal case. Two prefilled syringes plus an autoinjector are packed in a patient starter kit. Refill pack of 2´2 prefilled syringes in a carton. Also available to physicians or hospitals in a single dose vial (total volume=0.5 mL) containing 6 mg of sumatriptan base, as the succinate salt. Store between 2 and 30°C and protect from light.

Nasal Spray: 5 mg: Each unit dose spray contains: sumatriptan (base) as the hemisulfate salt 5 mg in an aqueous buffered solution. Nonmedicinal ingredients: anhydrous dibasic sodium phosphate, monobasic potassium phosphate, purified water, sodium hydroxide and sulfuric acid. Boxes of 6 nasal spray devices (3´2 devices). Store between 2 and 30°C and protect from light.

20 mg: Each unit dose spray contains: sumatriptan (base) as the hemisulfate salt 20 mg in an aqueous buffered solution. Nonmedicinal ingredients: anhydrous dibasic sodium phosphate, monobasic potassium phosphate, purified water, sodium hydroxide and sulfuric acid. Boxes of 6 nasal spray devices (3´2 devices). Store between 2 and 30°C and protect from light.

Tablets: 50 mg: Each white, film-coated tablet contains: sumatriptan (base) 50 mg as the succinate salt. Nonmedicinal ingredients: croscarmellose sodium, lactose, magnesium stearate and microcrystalline cellulose. The tablets are coated with Opadry White containing methylhydroxypropyl cellulose, titanium dioxide and triacetin. Gluten- and tartrazine-free. Blister packs containing 6 tablets, packed in cartons of 4. Store between 2 and 30°C.

100 mg: Each pink, film-coated tablet contains: sumatriptan (base) 100 mg as the succinate salt. Nonmedicinal ingredients: croscarmellose sodium, lactose, magnesium stearate and microcrystalline cellulose. The tablets are coated with Opadry Pink containing methylhydroxypropyl cellulose, titanium dioxide triacetin and iron oxide red. Gluten- and tartrazine-free. Blister packs containing 6 tablets, packed in cartons of 4. Store between 2 and 30°C. (Shown in Product Recognition Section)

IMITREX® Injection/Tablets IMITREX® Nasal Spray Glaxo Wellcome Sumatriptan SuccinateSumatriptan Migraine Therapy

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