IMITREX

1 INDICATIONS AND USAGE IMITREX injection is indicated in adults for (1) the acute treatment of migraine, with or without aura, and (2) the acute treatment of cluster headache. Limitations of Use • Use only if a clear diagnosis of migraine or cluster headache has been established. If a patient has no response to the first migraine or cluster headache attack treated with IMITREX injection, reconsider the diagnosis before IMITREX injection is administered to treat any subsequent attacks. • IMITREX injection is not indicated for the prevention of migraine or cluster headache attacks. IMITREX injection is a serotonin (5-HT 1B/1D ) receptor agonist (triptan) indicated for: • Acute treatment of migraine with or without aura in adults. ( 1 ) • Acute treatment of cluster headache in adults. ( 1 ) Limitations of Use • Use only if a clear diagnosis of migraine or cluster headache has been established. ( 1 ) • Not indicated for the prophylactic therapy of migraine or cluster headache attacks. ( 1 )

2 DOSAGE AND ADMINISTRATION • For subcutaneous use only. ( 2.1 ) • Acute treatment of migraine: single dose of 4 mg or 6 mg. ( 2.1 ) • Acute treatment of cluster headache: single dose of 6 mg. ( 2.1 ) • Maximum dose in a 24-hour period: 12 mg, separate doses by at least 1 hour. ( 2.1 ) • The needle shield of the prefilled syringe contains dry natural rubber (a latex derivative) which may cause allergic reactions in latex-sensitive patients. ( 2.2 ) 2.1 Dosing Information The maximum single recommended adult dose of IMITREX injection for the acute treatment of migraine or cluster headache is 6 mg injected subcutaneously. For the treatment of migraine, if side effects are dose limiting, the lower dose of 4 mg may be used [see Clinical Studies ( 14.1 )] . For the treatment of cluster headache, the efficacy of lower doses has not been established. The maximum cumulative dose that may be given in 24 hours is 12 mg, two 6-mg injections separated by at least 1 hour. A second 6-mg dose should only be considered if some response to a first injection was observed. 2.2 Administration Using the IMITREX STATdose Pen An autoinjector device (IMITREX STATdose Pen) is available for use with 4-mg and 6-mg prefilled syringe cartridges. With this device, the needle penetrates approximately 1/4 inch (5 to 6 mm). The injection is intended to be given subcutaneously, and intramuscular or intravascular delivery must be avoided. Instruct patients on the proper use of IMITREX STATdose Pen and direct them to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle. The needle shield of the prefilled syringe contains dry natural rubber (a latex derivative) [see Warnings and Precautions ( 5.9 )] .

3 DOSAGE FORMS AND STRENGTHS Injection: 4-mg and 6-mg single-dose prefilled syringe cartridges for use with the IMITREX STATdose Pen. Each 0.5 mL injection contains 5.6 mg or 8.4 mg of sumatriptan succinate equivalent to 4 mg or 6 mg of sumatriptan, respectively. Injection: 4- and 6-mg single-dose prefilled syringe cartridges for use with IMITREX STATdose Pen. ( 3 )

4 CONTRAINDICATIONS IMITREX injection is 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 [s ee 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 IMITREX (angioedema and anaphylaxis seen) [see Warnings and Precautions ( 5.9 )] . • Severe hepatic impairment [see 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 IMITREX (angioedema and anaphylaxis seen). ( 4 ) • Severe hepatic impairment. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • 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 (≥5% and >placebo) were injection site reactions, tingling, dizziness/vertigo, warm/hot sensation, burning sensation, feeling of heaviness, pressure sensation, flushing, feeling of tightness, and numbness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 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. Migraine Headache Table 1 lists adverse reactions that occurred in 2 U.S. placebo‐controlled clinical trials in patients with migraines (Studies 2 and 3) following either a single 6‐mg dose of IMITREX injection or placebo. Only reactions that occurred at a frequency of 2% or more in groups treated with IMITREX injection 6 mg and that occurred at a frequency greater than the placebo group are included in Table 1 . Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials in Patients with Migraine (Studies 2 and 3) Adverse Reaction IMITREX Injection 6 mg Subcutaneous (n = 547) % Placebo (n = 370) % Atypical sensations 42 9 Tingling 14 3 Warm/hot sensation 11 4 Burning sensation 7 <1 Feeling of heaviness 7 1 Pressure sensation 7 2 Feeling of tightness 5 <1 Numbness 5 2 Feeling strange 2 <1 Tight feeling in head 2 <1 Cardiovascular Flushing 7 2 Chest discomfort 5 1 Tightness in chest 3 <1 Pressure in chest 2 <1 Ear, nose, and throat Throat discomfort 3 <1 Discomfort: nasal cavity/sinuses 2 <1 Injection site reaction a 59 24 Miscellaneous Jaw discomfort 2 0 Musculoskeletal Weakness 5 <1 Neck pain/stiffness 5 <1 Myalgia 2 <1 Neurological Dizziness/vertigo 12 4 Drowsiness/sedation 3 2 Headache 2 <1 Skin Sweating 2 1 a Includes injection site pain, stinging/burning, swelling, erythema, bruising, bleeding. 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. Cluster Headache In the controlled clinical trials assessing the efficacy of IMITREX injection as a treatment for cluster headache (Studies 4 and 5), no new significant adverse reactions were detected that had not already been identified in trials of IMITREX in patients with migraine. Overall, the frequency of adverse reactions reported in the trials of cluster headache was generally lower than in the migraine trials. Exceptions include reports of paresthesia (5% IMITREX injection, 0% placebo), nausea and vomiting (4% IMITREX injection, 0% placebo), and bronchospasm (1% IMITREX injection, 0% placebo). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of IMITREX tablets, IMITREX nasal spray, and IMITREX 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 causa …

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 IMITREX injection within 24 hours of each other is contraindicated. 7.2 Monoamine Oxidase-A Inhibitors MAO-A inhibitors increase systemic exposure by 2-fold. Therefore, the use of IMITREX injection 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 IMITREX injection 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. Ani …

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 and cluster headaches 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 IMITREX injection contains 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 empirical 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 is a white to off-white powder that is readily soluble in water and in saline. IMITREX injection is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 0.5 mL of IMITREX injection 8-mg/mL solution contains 5.6 mg of sumatriptan succinate equivalent to 4 mg of sumatriptan and 3.8 mg of sodium chloride, USP in Water for Injection, USP. Each 0.5 mL of IMITREX injection 12-mg/mL solution contains 8.4 mg of sumatriptan succinate equivalent to 6 mg of sumatriptan and 3.5 mg of sodium chloride, USP in Water for Injection, USP. The pH range of both solutions is approximately 4.2 to 5.3. The osmolality of both injections is 291 mOsmol. Sumatriptan Chemical Structure

10 OVERDOSAGE Coronary vasospasm was observed after intravenous administration of IMITREX injection [see Contraindications ( 4 )] . Overdoses would be expected from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly cause convulsions, tremor, inactivity, erythema of the extremities, reduced respiratory rate, cyanosis, ataxia, mydriasis, injection site reactions (desquamation, hair loss, and scab formation), and paralysis. The elimination half-life of sumatriptan is about 2 hours [see Clinical Pharmacology ( 12.3 )] ; therefore, monitoring of patients after overdose with IMITREX injection should continue for at least 10 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 IMITREX injection contains sumatriptan (base) as the succinate salt and is supplied as a clear, colorless to pale yellow, sterile, nonpyrogenic solution as follows: Prefilled Syringe and/or Autoinjector Pen: The needle shield of the prefilled syringe contains dry natural rubber (a latex derivative) that has the potential to cause allergic reactions in latex-sensitive individuals. Each pack contains a Patient Information and Instructions for Use leaflet. • IMITREX STATdose System, 4 mg, containing 1 IMITREX STATdose Pen, 2 prefilled single-dose syringe cartridges, and 1 carrying case (NDC 0173-0739-00). • IMITREX STATdose System, 6 mg, containing 1 IMITREX STATdose Pen, 2 prefilled single-dose syringe cartridges, and 1 carrying case (NDC 0173-0479-00). • Two 4-mg single-dose prefilled syringe cartridges for use with IMITREX STATdose System (NDC 0173-0739-02). • Two 6-mg single-dose prefilled syringe cartridges for use with IMITREX STATdose System (NDC 0173-0478-00). Store between 2° and 30°C (36° and 86°F). Protect from light.