Sumatriptan

1 INDICATIONS AND USAGE Sumatriptan 25 mg, 50 mg and 100 mg 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 is 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 )

2 DOSAGE AND ADMINISTRATION Single dose of 25-mg, 50-mg, or 100-mg tablet. ( 2.1 ) A second dose should only be considered if some response to the first dose was observed. Separate doses by at least 2 hours. ( 2.1 ) Maximum dose in a 24-hour period: 200 mg. ( 2.1 ) Maximum single dose should not exceed 50 mg in patients with mild to moderate hepatic impairment. ( 2.2 ) 2.1 Dosing Information The recommended dose of sumatriptan tablets is 25 mg, 50 mg, or 100 mg. Doses of 50mg and 100mg may provide a greater effect than the 25-mg dose, but doses of 100mg may not provide a greater effect than the 50-mg dose. Higher doses may have a greater risk of adverse reactions [see Clinical Studies (14) ] . If the migraine has not resolved by 2 hours after taking sumatriptan tablets, or returns after a transient improvement, a second dose may be administered at least 2 hours after the first dose. The maximum daily dose is 200 mg in a 24-hour period. Use after sumatriptan Injection If the migraine returns following an initial treatment with sumatriptan 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. 2.2 Dosing in Patients with Hepatic Impairment If treatment is deemed advisable in the presence of mild to moderate hepatic impairment, the maximum single dose should not exceed 50 mg [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ].

3 DOSAGE FORMS AND STRENGTHS 25-mg Tablets : Round, White colored film-coated tablets debossed with “V” on one side and “22”on the other side. Each tablet contains 35 mg of sumatriptan succinate equivalent to 25 mg of sumatriptan. 50-mg Tablets: Round, White colored film-coated tablets debossed with “V” on one side and “23” on the other side. Each tablet contains 70 mg of sumatriptan succinate equivalent to 50 mg of sumatriptan. 100-mg Tablets: Round, Pink colored film-coated tablets debossed with “V”’ on one side and “24”’ on the other side. Each tablet contains 140 mg of sumatriptan succinate 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-hydroxytryptamine 1 (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 tablets (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 tablets (angioedema and anaphylaxis seen) ( 4 ) Severe hepatic impairment ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the prescribing information: • Myocardial ischemia, myocardial infarction, and Prinzmetal’s angina [see Warnings and Precautions (5.1)] • Arrhythmias [see Warnings and Precautions (5.2)] • Chest, throat, neck, and/or jaw pain/tightness/pressure [see Warnings and Precautions (5.3)] • Cerebrovascular events [see Warnings and Precautions (5.4)] • Other vasospasm reactions [see Warnings and Precautions (5.5)] • Medication overuse headache [see Warnings and Precautions (5.6)] • Serotonin syndrome [see Warnings and Precautions (5.7)] • Increase in blood pressure [see Warnings and Precautions (5.8)] • Hypersensitivity reactions [see Contraindications (4), Warnings and Precautions (5.9)] • Seizures [see Warnings and Precautions (5.10)] Most common adverse reactions (≥2% and >placebo) were paresthesia, warm/cold sensation, chest pain/tightness/pressure and/or heaviness, neck/throat/jaw pain/tightness/pressure, other sensations of pain/pressure/tightness/heaviness, vertigo, and malaise/fatigue. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bionpharma Inc. at 1-888-235-BION or 1-888-235-2466 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 1 lists adverse reactions that occurred in placebo-controlled clinical trials in patients who took at least 1 dose of study drug. Only treatment-emergent adverse reactions that occurred at a frequency of 2% or more in any group treated with sumatriptan tablets and that occurred at a frequency greater than the placebo group are included in Table 1. Table 1. Adverse Reactions Reported by at Least 2% of Patients Treated with Sumatriptan Tablets and at a Greater Frequency than Placebo Adverse Reaction Percent of Patients Reporting Sumatriptan Tablets 25 mg (n = 417) Sumatriptan Tablets 50 mg (n = 771) Sumatriptan Tablets 100 mg (n = 437) Placebo (n = 309) Atypical sensations 5 6 6 4 Paresthesia (all types) 3 5 3 2 Sensation warm/cold 3 2 3 2 Pain and other pressure sensations 6 6 8 4 Chest - pain/tightness/ pressure and/or heaviness 1 2 2 1 Neck/throat/jaw - pain/ tightness/pressure <1 2 3 <1 Pain - location specified 2 1 1 1 Other - pressure/tightness/ heaviness 1 1 3 2 Neurological Vertigo <1 <1 2 <1 Other Malaise/fatigue 2 2 3 <1 The incidence of adverse reactions 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 reactions. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of sumatriptan tablets, sumatriptan nasal spray, and sumatriptan injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to sumatriptan or a combination of these factors. Cardiovascular Hypotension, palpitations. Neurological Dystonia, tremor. Reproductive System and Breast Disorders Breast pain [see Use in Specific Populations (8.2)] .

7 DRUG INTERACTIONS 7.1 Ergot-Containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan tablets within 24 hours of each other is contraindicated. 7.2 Monoamine Oxidase-A Inhibitors MAO‐A inhibitors increase systemic exposure by 7 fold. Therefore, the use of sumatriptan tablets in patients receiving MAO‐A inhibitors is contraindicated [see Clinical Pharmacology (12.3)] . 7.3 Other 5-HT 1 Agonists Because their vasospastic effects may be additive, coadministration of sumatriptan tablets and other 5‐HT 1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of serotonin syndrome have been reported during coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)] .

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. Anim …

12.1 Mechanism of Action Sumatriptan binds with high affinity to human cloned 5‐HT 1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5‐HT 1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro‐inflammatory neuropeptide release.

11 DESCRIPTION Sumatriptan tablets, USP contain sumatriptan succinate USP, a selective 5‐HT 1B/1D receptor agonist. Sumatriptan succinate, USP 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 to off‐white powder that is readily soluble in water and in saline. 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, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, sodium bicarbonate, and opadry. The components of opadry yellow used in the formulation of 25 mg tablets are hypromellose, titanium dioxide, polyethylene glycol 6000, iron oxide yellow, and polysorbate 80. The components of opadry pink used in the formulation of 50 mg tablets are hypromellose, titanium dioxide, polyethylene glycol 400, and iron oxide red. The components of opadry white used in the formulation of 100 mg tablets are hypromellose, titanium dioxide, and polyethylene glycol 400. chemical structure

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 mg without 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 25 mg, 50 mg and 100 mg tablets are supplied as film-coated, round shaped, tablets in the following strengths. Sumatriptan Tablets USP, 25 mg: Round, White colored film-coated tablets debossed with “V” on one side and “22”on the other side. They supplied as: Bottle pack of 36 tablets NDC 64980-660-36 Blister packs of 9 tablets (1 blister of 9 tablets) NDC 64980-660-91 Blister packs of 27 tablets (3 blisters of 9 tablets) NDC 64980-660-27 Sumatriptan Tablets USP, 50 mg: Round, White colored film-coated tablets debossed with “V” on one side and “23” on the other side. They supplied as: Bottle pack of 36 tablets NDC 64980-661-36 Blister packs of 9 tablets (1 blister of 9 tablets) NDC 64980-661-91 Blister packs of 27 tablets (3 blisters of 9 tablets) NDC 64980-661-27 Sumatriptan Tablets USP, 100 mg: Round, Pink colored film-coated tablets debossed with “V”on one side and “24”' on the other side. They supplied as: Bottle pack of 36 tablets NDC 64980-662-36 Blister packs of 9 tablets (1 blister of 9 tablets) NDC 64980-662-91 Blister packs of 27 tablets (3 blisters of 9 tablets) NDC 64980-662-27 Store between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].