Sumatriptan Succinate

1 INDICATIONS AND USAGE Sumatriptan 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 sumatriptan injection, reconsider the diagnosis before sumatriptan injection is administered to treat any subsequent attacks. Sumatriptan injection is not indicated for the prevention of migraine or cluster headache attacks. Sumatriptan injection is a serotonin (5-HT1B/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 ) 2.1 Dosing Information The maximum single recommended adult dose of sumatriptan 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 Sumatriptan injection Autoinjector An autoinjector device is available for use with 4-mg and 6-mg prefilled syringes. With this prefilled syringe autoinjector, 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 Sumatriptan injection autoinjector and direct them to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.

3 DOSAGE FORMS AND STRENGTHS Injection: 4-mg and 6-mg single-dose prefilled syringe with the Sumatriptan injection, USP autoinjector. 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 syringes for use with sumatriptan injection autoinjector pen. ( 3 )

4 CONTRAINDICATIONS Sumatriptan 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 [ 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-HT1) 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 injection (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-HT1 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 injection (angioedema and anaphylaxis seen). ( 4 ) Severe hepatic impairment. ( 4 )

5 WARNINGS AND PRECAUTIONS Myocardial ischemia/infarction and Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors. ( 5.1 ) Arrhythmias: Discontinue sumatriptan injection if occurs. ( 5.2 ) Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not associated with myocardial ischemia; evaluate for coronary artery disease in patients at high risk. ( 5.3 ) Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue sumatriptan injection if occurs. ( 5.4 ) Gastrointestinal ischemic reactions and peripheral vasospastic reactions: Discontinue sumatriptan injection if occurs. ( 5.5 ) Medication overuse headache: Detoxification may be necessary. ( 5.6 ) Serotonin syndrome: Discontinue sumatriptan injection if occurs. ( 5.7 ) Seizures: Use with caution in patients with epilepsy or a lowered seizure threshold. ( 5.10 ) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina The use of sumatriptan injection is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of sumatriptan injection. Some of these reactions occurred in patients without known CAD. Sumatriptan injection may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD. Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving sumatriptan injection. If there is evidence of CAD or coronary artery vasospasm, sumatriptan injection is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of sumatriptan injection in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of sumatriptan injection. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of sumatriptan injection. 5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT 1 agonists. Discontinue sumatriptan injection if these disturbances occur. Sumatriptan injection is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with sumatriptan injection and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of sumatriptan injection is contraindicated in patients with CAD and those with Prinzmetal’s variant angina. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue sumatriptan injection if a cerebrovascular event occurs. Before treating headaches in patients not previously diagnosed with migraine or cluster headache or in patients who present with atypical symptoms, exclude other potentially serious neurological conditions. Sumatriptan injection is contraindicated in patients with a history of stroke or TIA. 5.5 Other Vasospasm Reactions Sumatriptan injection may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT 1 agonist, rule out a vasospastic reaction before receiving additional sumatriptan injection. Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists has not been clearly established. 5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. 5.7 Serotonin Syndrome Serotonin syndrome may occur with sumatriptan injection, particularly during coadministration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [ see Drug Interactions ( 7.4 ) ]. 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). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue sumatriptan injection if serotonin syndrome is suspected. 5.8 Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT 1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with sumatriptan injection. Sumatriptan injection is contraindicated in patients with uncontrolled hypertension. 5.9 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients receiving sumatriptan injection. Such reactions can be life-threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. Sumatriptan injection is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan injection. 5.10 Seizures Seizures have been reported following administration of sumatriptan. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent. Sumatriptan injection should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

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 Alembic Pharmaceuticals, Inc. at 1-866-210- 9797 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 sumatriptan injection or placebo. Only reactions that occurred at a frequency of 2% or more in groups treated with sumatriptan 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 Sumatriptan 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 sumatriptan 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 sumatriptan injection 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% sumatriptan injection, 0% placebo), nausea and vomiting (4% sumatriptan injection, 0% placebo), and bronchospasm (1% sumatriptan injection, 0% placebo). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of IMITREX tablets, IMITREX 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. Cardiovascular Hypotension, palpitations. Neurological Dystonia, tremor. Reproductive System and Breast Disorders Breast pain [see Use in Specific Populations (8.2)].

16 HOW SUPPLIED/STORAGE AND HANDLING Sumatriptan injection, USP, 4 mg/0.5mL and 6 mg/0.5mL 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: Each pack contains a Patient Information and Instructions for Use leaflet. (NDC 62332-656-05) Sumatriptan Injection, USP, 4 mg/0.5 mL autoinjector system includes, 1 prefilled single-dose syringe, one such autoinjector is packaged in carton. (NDC 62332-656-01) Sumatriptan Injection, USP, 4 mg/0.5 mL autoinjector system includes, 1 prefilled single-dose syringe, two such autoinjectors are packaged in carton. (NDC 62332-657-05) Sumatriptan Injection, USP, 6 mg/0.5 mL autoinjector system includes, 1 prefilled single-dose syringe, one such autoinjector is packaged in carton. (NDC 62332-657-01) Sumatriptan Injection, USP, 6 mg/0.5 mL autoinjector system includes, 1 prefilled single-dose syringe, two such autoinjectors are packaged in carton. Store between 2° and 30°C (36° and 86°F). Protect from light.