Mechanism of Action

Sumatriptan is an agonist for a vascular 5-hydroxytryptamine1 receptor subtype (probably a member of the 5-HT1D family) having only a weak affinity for  5-HT1A, 5-HT5A, and 5-HT7 receptors and no significant affinity (as measured using standard radioligand binding assays) or pharmacological activity at 5-HT2, 5-HT3, or 5-HT4 receptor subtypes or at alpha1-, alpha2-, or beta-adrenergic; dopamine1; dopamine2; muscarinic; or benzodiazepine receptors.

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.

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 Cmax of 5 and 16 ng/mL following dosing with a 5 and 20 mg intranasal dose, respectively. The mean Cmax 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 Cmax is similar during a migraine attack and during a migraine-free period, but the tmax 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 Cmax after 100 mg is approximately 25% less than expected (based on the 25 mg dose).

A food effect study involving administration of sumatriptan succinate tablets 100 mg to healthy volunteers under fasting conditions and with a high-fat meal indicated that the Cmax 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 14C-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

Drug Interactions

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events

Sumatriptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (see CONTRAINDICATIONS). It is strongly recommended that sumatriptan not be given to patients in whom unrecognized CAD is predicted by the presence of  risk  factors  (e.g.,  hypertension,  hypercholesterolemia,  smoker,  obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history or electrocardiographic investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, sumatriptan should not be administered (see CONTRAINDICATIONS).

For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of sumatriptan tablets take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received sumatriptan. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following sumatriptan succinate tablets, in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of sumatriptan and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use sumatriptan.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to sumatriptan.

Drug-Associated Cardiac Events and Fatalities

Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of sumatriptan succinate injection or sumatriptan succinate tablets. Considering the extent of use of sumatriptan in patients with migraine, the incidence of these events is extremely low.

The fact that sumatriptan can cause coronary vasospasm, that some of these events have occurred in patients with no prior cardiac disease history and with documented absence of CAD, and the close proximity of the events to sumatriptan use support the conclusion that some of these cases were caused by the drug. In many cases, however, where there has been known underlying coronary artery disease, the relationship is uncertain.

Drug-Associated Cerebrovascular Events and Fatalities

Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with oral or subcutaneous sumatriptan, and some have resulted in fatalities. The relationship of sumatriptan to these events is uncertain. In a number of cases, it appears possible that the cerebrovascular events were primary, sumatriptan having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. 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. It should also be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., cerebrovascular accident, transient ischemic attack).

Other Vasospasm-Related Events

Sumatriptan may cause vasospastic reactions other than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported. Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of sumatriptan. Visual disorders may also be part of a migraine attack.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome may occur with triptans, including treatment with Sumatriptan Succinate, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Increase in Blood Pressure

Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients with and without a history of hypertension. Sumatriptan is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS). Sumatriptan should be administered with caution to patients with controlled hypertension as transient increases in blood pressure and peripheral vascular resistance have been observed in a small proportion of patients.

Concomitant Drug Use

In patients taking MAO-A inhibitors, sumatriptan plasma levels attained after treatment with recommended doses are 7-fold higher following oral administration than those obtained under other conditions. Accordingly, the coadministration of sumatriptan succinate tablets and an MAO-A inhibitor is contraindicated (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).

Hypersensitivity

Hypersensitivity (anaphylaxis/anaphylactoid) reactions have occurred on rare occasions in patients receiving sumatriptan. Such reactions can be life threatening or fatal. In general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens (see CONTRAINDICATIONS).

General

Chest discomfort and jaw or neck tightness have been reported following use of sumatriptan succinate tablets and have also been reported infrequently following administration of sumatriptan succinate Nasal Spray. Chest, jaw, or neck tightness is relatively common after administration of sumatriptan succinate injection. Only rarely have these symptoms been associated with ischemic ECG changes. However, because sumatriptan may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following sumatriptan should be evaluated for the presence of CAD or a predisposition to Prinzmetal variant angina before receiving additional doses of sumatriptan, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud syndrome following sumatriptan should be evaluated for atherosclerosis or predisposition to vasospasm  (see WARNINGS).

Sumatriptan should also be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as impaired hepatic or renal function.

There have been rare reports of seizure following administration of sumatriptan. Sumatriptan should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

Care should be taken to exclude other potentially serious neurologic conditions before treating headache in patients not previously diagnosed with migraine headache or who experience a headache that is atypical for them. There have been rare reports where patients received sumatriptan for severe headaches that were subsequently shown to have been secondary to an evolving neurologic lesion (see WARNINGS).

For a given attack, if a patient does not respond to the first dose of sumatriptan, the diagnosis of migraine should be reconsidered before administration of a second dose.

Overuse of acute migraine treatments has been associated with the exacerbation of headache (medication overuse headache) in susceptible patients. Withdrawal of the treatment may be necessary.

Binding to Melanin-Containing Tissues

In rats treated with a single subcutaneous dose (0.5 mg/kg) or oral dose (2 mg/kg) of radiolabeled sumatriptan, the elimination half-life of radioactivity from the eye was 15 and 23 days, respectively, suggesting that sumatriptan and/or its metabolites bind to the melanin of the eye. Because there could be an accumulation in melanin-rich tissues over time, this raises the possibility that sumatriptan could cause toxicity in these tissues after extended use. However, no effects on the retina related to treatment with sumatriptan  were  noted  in  any  of  the  oral  or  subcutaneous  toxicity  studies.  Although  no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects.

Corneal Opacities

Sumatriptan causes corneal opacities and defects in the corneal epithelium in dogs; this raises the possibility that these changes may occur in humans. While patients were   not systematically evaluated for these changes in clinical trials, and no specific recommendations for monitoring are being offered, prescribers should be aware of the possibility of these changes (see ANIMALTOXICOLOGY).

Information for Patients

See PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided for patients.

Patients should be cautioned about the risk of serotonin syndrome with the use of sumatriptan or other triptans, especially during combined use with SSRIs or SNRIs.

Laboratory Tests

No specific laboratory tests are recommended for monitoring patients prior to and/or after treatment with sumatriptan.

Drug Interactions

Drug/Laboratory Test Interactions

Sumatriptan succinate tablets are not known to interfere with commonly employed clinical laboratory tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy

Teratogenic Effects: Pregnancy Category C.  In reproductive toxicity studies in rats and rabbits, oral treatment with sumatriptan was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to rabbits, sumatriptan has been shown to be embryolethal. There are no adequate and well-controlled studies in pregnant women. Therefore, sumatriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In assessing this information, the following findings should be considered.

Nursing Mothers

Sumatriptan is excreted in human breast milk following subcutaneous administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with sumatriptan succinate tablets.

Pediatric Use

Safety and effectiveness of sumatriptan succinate tablets in pediatric patients have not been established.

Completed placebo-controlled clinical trials evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These studies did not establish the efficacy of oral sumatriptan compared to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse events in theses patients appeared to be both dose- and age-dependent, with younger patients reporting events more commonly than older adolescents. Post-marketing experience includes a limited number of reports that describe pediatric patients who have experienced adverse events, some clinically serious, after use of subcutaneous sumatriptan and/or oral sumatriptan. These reports include events similar in nature to those reported rarely in adults. A myocardial infarct has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration. Since clinical data to determine the frequency of serious adverse events in pediatric patients who might receive injectable, oral, or intranasal sumatriptan are not presently available, the use of sumatriptan in patients aged younger than 18 years is not recommended.

Geriatric Use

The use of sumatriptan in elderly patients is not recommended because elderly patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and blood pressure increases may be more pronounced in the elderly (see WARNINGS).

Other Events Observed in Association With the Administration of Sumatriptan Succinate Tablets

In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. Because the reports include events observed in open and uncontrolled studies, the role of sumatriptan succinate tablets in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used sumatriptan succinate tablets (25, 50, or 100 mg) and reported an event divided by the total number of patients (N = 6,348) exposed to sumatriptan succinate tablets. All reported events are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients, infrequent adverse events are those occurring in 1/100 to 1/1,000 patients, and rare adverse events are those occurring in fewer than 1/1,000 patients.

Other Events Observed in the Clinical Development of Sumatriptan

The following adverse events occurred in clinical trials with sumatriptan succinate injection and sumatriptan succinate nasal spray. Because the reports include events observed in open and uncontrolled studies, the role of sumatriptan in their causation cannot be reliably determined. All reported events are included except those already listed, those too general to be informative, and those not reasonably associated with the use of the drug.

Postmarketing Experience (Reports for Subcutaneous or Oral Sumatriptan)

The following section enumerates potentially important adverse events that have occurred in clinical practice and that have been reported spontaneously to various surveillance systems. The events enumerated represent reports arising from both domestic and nondomestic use of oral or subcutaneous dosage forms of sumatriptan. The events enumerated include all except those already listed in the ADVERSE REACTIONS section above or those too general to be informative. Because the reports cite events reported spontaneously from worldwide postmarketing experience, frequency of events and the role of sumatriptan in their causation cannot be reliably determined. It is assumed, however, that systemic reactions following sumatriptan use are likely to be similar regardless of route of administration.

Corneal Opacities

Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dosage tested, 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established; however, the relative exposure at the lowest dose tested was approximately 5 times the human exposure after a 100 mg oral dose. There is evidence of alterations in corneal appearance on the first day of intranasal dosing to dogs. Changes were noted at the lowest dose tested, which was approximately one half the maximum single human oral dose of 100 mg on a mg/m2 basis.

RX Only

Manufactured by:

Dr. Reddy’s Laboratories Limited

Bachepalli – 502 325 INDIA

Issued: 0809