Sumatriptan Succinate

1 INDICATIONS AND USAGE Sumatriptan tablets are indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use: • Use only if a clear diagnosis of migraine headache has been established. If a patient has no response to the first migraine attack treated with sumatriptan tablets, reconsider the diagnosis of migraine before sumatriptan tablets are administered to treat any subsequent attacks. • Sumatriptan tablets are not indicated for the prevention of migraine attacks. • Safety and effectiveness of sumatriptan tablets have not been established for cluster headache. Sumatriptan is a serotonin (5-HT 1B/1D ) receptor agonist (triptan) indicated for acute treatment of migraine with or without aura in adults. ( 1) Limitations of Use: Use only if a clear diagnosis of migraine headache has been established. ( 1 ) Not indicated for the prophylactic therapy of migraine attacks. ( 1 ) Not indicated for the treatment of cluster headache. ( 1 )

DOSAGE AND ADMINISTRATION In controlled clinical trials, single doses of 25, 50, or 100 mg of sumatriptan tablets were effective for the acute treatment of migraine in adults. There is evidence that doses of 50 and 100 mg may provide a greater effect than 25 mg (see CLINICAL TRIALS ). There is also evidence that doses of 100 mg do not provide a greater effect than 50 mg. Individuals may vary in response to doses of sumatriptan tablets. The choice of dose should therefore be made on an individual basis, weighing the possible benefit of a higher dose with the potential for a greater risk of adverse events. If the headache returns or the patient has a partial response to the initial dose, the dose may be repeated after 2 hours, not to exceed a total daily dose of 200 mg. If a headache returns following an initial treatment with sumatriptan succinate injection, additional single sumatriptan tablets (up to 100 mg/day) may be given with an interval of at least 2 hours between tablet doses. The safety of treating an average of more than 4 headaches in a 30-day period has not been established. Because of the potential of MAO-A inhibitors to cause unpredictable elevations in the bioavailability of oral sumatriptan, their combined use is contraindicated (see CONTRAINDICATIONS ). Hepatic disease/functional impairment may also cause unpredictable elevations in the bioavailability of orally administered sumatriptan. Consequently, if treatment is deemed advisable in the presence of liver disease, the maximum single dose should in general not exceed 50 mg (see CLINICAL PHARMACOLOGY for the basis of this recommendation).

3 DOSAGE FORMS AND STRENGTHS 25 mg Tablets: White, round, biconvex film-coated tablets debossed with “RDY” on one side and “291” on the other side. Each tablet contains 35 mg of sumatriptan succinate, USP equivalent to 25 mg of sumatriptan. 50 mg Tablets: White, round, biconvex film-coated tablets debossed with “RDY” on one side and “292” on the other side. Each tablet contains 70 mg of sumatriptan succinate, USP equivalent to 50 mg of sumatriptan. 100 mg Tablets: White, capsule shaped, biconvex film-coated tablets debossed with “RDY” on one side and “293” on the other side. Each tablet contains 140 mg of sumatriptan succinate, USP equivalent to 100 mg of sumatriptan. Tablets: 25 mg, 50 mg, and 100 mg ( 3 )

4 CONTRAINDICATIONS Sumatriptan tablets are contraindicated in patients with: • Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal’s angina [see Warnings and Precautions ( 5.1 )] • Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Warnings and Precautions ( 5.2 )] • History of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke [see Warnings and Precautions ( 5.4 )] • Peripheral vascular disease [see Warnings and Precautions ( 5.5 )] • Ischemic bowel disease [see Warnings and Precautions ( 5.5 )] • Uncontrolled hypertension [see Warnings and Precautions ( 5.8 )] • Recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 (5-HT 1 ) agonist [see Drug Interactions ( 7.1 , 7.3 )] • Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor [see Drug Interactions ( 7.2 ), Clinical Pharmacology ( 12.3 )] • Hypersensitivity to sumatriptan (angioedema and anaphylaxis seen) [see Warnings and Precautions ( 5.9 )] • Severe hepatic impairment [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] History of coronary artery disease or coronary artery vasospasm ( 4 ) Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders ( 4 ) History of stroke, transient ischemic attack, or hemiplegic or basilar migraine ( 4 ) Peripheral vascular disease ( 4 ) Ischemic bowel disease ( 4 ) Uncontrolled hypertension ( 4 ) Recent (within 24 hours) use of another 5-HT 1 agonist (e.g., another triptan) or of an ergotamine-containing medication. ( 4 ) Concurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor. ( 4 ) Hypersensitivity to sumatriptan (angioedema and anaphylaxis seen). ( 4 ) Severe hepatic impairment. ( 4 )

ADVERSE REACTIONS Serious cardiac events, including some that have been fatal, have occurred following the use of sumatriptan succinate injection or tablets. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS , WARNINGS , and PRECAUTIONS ) . Significant hypertensive episodes, including hypertensive crises, have been reported on rare occasions in patients with or without a history of hypertension (see WARNINGS ). Incidence in Controlled Clinical Trials Table 2 lists adverse events that occurred in placebo-controlled clinical trials in patients who took at least 1 dose of study drug. Only events that occurred at a frequency of 2% or more in any group treated with sumatriptan tablets and were more frequent in that group than in the placebo group are included in Table 2. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 2. Treatment Emergent Adverse Events Reported by at Least 2% of Patients in Controlled Migraine Trials a Adverse Event Type Percent of Patients Reporting Placebo (N = 309) Sumatriptan 25 mg (N = 417) Sumatriptan 50 mg (N = 771) Sumatriptan 100 mg (N = 437) Atypical sensations 4% 5% 6% 6% Paresthesia (all types) 2% 3% 5% 3% Sensation warm/cold 2% 3% 2% 3% Pain and other pressure sensations 4% 6% 6% 8% Chest - pain/tightness/pressure and/or heaviness 1% 1% 2% 2% Neck/throat/jaw - pain/ tightness/pressure <1% <1% 2% 3% Pain - location specified 1% 2% 1% 1% Other - pressure/tightness/ heaviness 2% 1% 1% 3% Neurological Vertigo <1% <1% <1% 2% Other Malaise/fatigue <1% 2% 2% 3% a Events that occurred at a frequency of 2% or more in the group treated with sumatriptan tablets and that occurred more frequently in that group than the placebo group. Other events that occurred in more than 1% of patients receiving sumatriptan tablets and at least as often on placebo included nausea and/or vomiting, migraine, headache, hyposalivation, dizziness, and drowsiness/sleepiness. Sumatriptan tablets are generally well tolerated. Across all doses, most adverse reactions were mild and transient and did not lead to long-lasting effects. The incidence of adverse events in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse events. Other Events Observed in Association With the Administration of Sumatriptan 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 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 sumatriptane tablets (25, 50, or 100 mg) and reported an event divided by the total number of patients (N = 6,348) exposed to sumatriptan 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 occur …

Drug Interactions Monoamine Oxidase Inhibitors (MAO) Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels (see CONTRAINDICATIONS and PRECAUTIONS ). 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. Alcohol Alcohol consumed 30 minutes prior to sumatriptan ingestion had no effect on the pharmacokinetics of sumatriptan.

Drug Interactions Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome: Cases of life‐threatening serotonin syndrome have been reported during combined use of SSRIs or SNRIs and triptans (see WARNINGS ). Ergot-Containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided (see CONTRAINDICATIONS ). Monoamine Oxidase-A Inhibitors MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan tablets in patients receiving MAO-A inhibitors is contraindicated (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS ).

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1) 8.1 Pregnancy Risk Summary Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population ( see Data ). In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal ( see Data ). In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy. Data Human Data : The Sumatriptan/Naratriptan/Treximet (sumatriptan and naproxen sodium) Pregnancy Registry, a population-based international prospective study, collected data for sumatriptan from January 1996 to September 2012. The Registry documented outcomes of 626 infants and fetuses exposed to sumatriptan during pregnancy (528 with earliest exposure during the first trimester, 78 during the second trimester, 16 during the third trimester, and 4 unknown). The occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to sumatriptan was 4.2% (20/478 [95% CI: 2.6% to 6.5%]) and during any trimester of exposure was 4.2% (24/576 [95% CI: 2.7% to 6.2%]). The sample size in this study had 80% power to detect at least a 1.73-to 1.91-fold increase in the rate of major malformations. The number of exposed pregnancy outcomes accumulated during the registry was insufficient to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Of the 20 infants with reported birth defects after exposure to sumatriptan in the first trimester, 4 infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and 3 infants had pyloric stenosis. No other birth defect was reported for more than 2 infants in this group. In a study using data from the Swedish Medical Birth Register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not. Of the 2,257 births with first-trimester exposure to sumatriptan, 107 infants were born with malformations (relative risk 0.99 [95% CI: 0.91 to 1.21]). A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group. Of the 415 women who redeemed prescriptions for sumatriptan during the first trimester, 15 had infants with major congenital malformations (OR 1.16 [95% CI: 0.69 to 1.94]) while for the 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy, 20 had infants with major congenital malformations (OR 1.83 [95% CI: 1.17 to 2.88]), each compared with the population comparison group. Additional smaller observational studies evaluating use of sumatriptan during pregnancy have not suggested an increased risk of teratogenicity. Ani …

Mechanism of Action Sumatriptan is an agonist for a vascular 5-hydroxytryptamine 1 receptor subtype (probably a member of the 5-HT 1D family) having only a weak affinity for 5-HT 1A , 5-HT 5A , and 5-HT 7 receptors and no significant affinity (as measured using standard radioligand binding assays) or pharmacological activity at 5-HT 2 , 5-HT 3 , or 5-HT 4 receptor subtypes or at alpha 1- , alpha 2- , or beta-adrenergic; dopamine 1 ; dopamine 2 ; muscarinic; or benzodiazepine receptors. The vascular 5-HT 1 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-HT 1 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.

11 DESCRIPTION Sumatriptan tablets USP contain sumatriptan succinate, a selective 5-HT 1B/1D receptor agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure: The molecular formula is C 14 H 21 N 3 O 2 S•C 4 H 6 O 4 , representing a molecular weight of 413.5. Sumatriptan succinate USP is a white or almost white powder that is freely soluble in water, sparingly soluble in methanol, practically inso luble in methylene chloride. Each sumatriptan tablet USP for oral administration contains 35, 70, or 140 mg of sumatriptan succinate USP equivalent to 25, 50, or 100 mg of sumatriptan, respectively. Each tablet also contains the inactive ingredients croscarmellose sodium, lactose anhydrous, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, talc, titanium dioxide and triacetin. strucure

10 OVERDOSAGE Patients in clinical trials (N = 670) received single oral doses of 140 to 300 mg without significant adverse reactions. Volunteers (N = 174) received single oral doses of 140 to 400 mgwithout serious adverse reactions. Overdose in animals has been fatal and has been heralded by convulsions, tremor, paralysis, inactivity, ptosis, erythema of the extremities, abnormal respiration, cyanosis, ataxia, mydriasis, salivation, and lacrimation. The elimination half-life of sumatriptan is approximately 2.5 hours [see Clinical Pharmacology ( 12.3 )], and therefore monitoring of patients after overdose with sumatriptan tablets should continue for at least 12 hours or while symptoms or signs persist. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

16 HOW SUPPLIED/STORAGE AND HANDLING Sumatriptan tablets USP, 25, 50, and 100 mg of sumatriptan (base) as the succinate. Sumatriptan tablets USP, 25 mg are white, round, biconvex film-coated tablets debossed with “RDY” on one side and “291” on the other side. The tablets are supplied in bottles of 30, 36, 90, 100, 500 and unit of use blister pack of 9’s and 27's. Bottles of 30 NDC 55111-291-30 Bottles of 36 NDC 55111-291-36 Bottles of 90 NDC 55111-291-90 Bottles of 100 NDC 55111-291-01 Bottles of 500 NDC 55111-291-05 Unit of use blister pack of 9 (1 x 9) NDC 55111-291-09 Unit of use blister pack of 27(3 x 9) NDC 55111-291-98 Sumatriptan tablets USP, 50 mg are white, round, biconvex film-coated tablets debossed with “RDY” on one side and “292” on the other side. The tablets are supplied in bottles of 30, 36, 90, 100, 500 and unit of use blister pack of 9’s and 27's. Bottles of 30 NDC 55111-292-30 Bottles of 36 NDC 55111-292-36 Bottles of 90 NDC 55111-292-90 Bottles of 100 NDC 55111-292-01 Bottles of 500 NDC 55111-292-05 Unit of use blister pack of 9 (1 x 9) NDC 55111-292-09 Unit of use blister pack of 27(3 x 9) NDC 55111-292-98 Sumatriptan tablets USP, 100 mg are white, capsule shaped, biconvex film-coated tablets debossed with “RDY” on one side and “293” on the other side. The tablets are supplied in bottles of 30, 36, 90, 100, 500 and unit of use blister pack of 9’s and 27's. Bottles of 30 NDC 55111-293-30 Bottles of 36 NDC 55111-293-36 Bottles of 90 NDC 55111-293-90 Bottles of 100 NDC 55111-293-01 Bottles of 500 NDC 55111-293-05 Unit of use blister pack of 9 (1 x 9) NDC 55111-293-09 Unit of use blister pack of 27(1 x 9) NDC 55111-293-98 Store at 20° to 25°C (68°to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).