Sumatriptan Succinate

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 Wockhardt USA LLC. at 1-800-346-6854 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 migraine patients (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) a Includes injection site pain, stinging/burning, swelling, erythema, bruising, bleeding. Adverse Reaction Percent of Subjects Reporting 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 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 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. Cardiovascular Hypotension, palpitations. Neurological Dystonia, tremor.

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-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 (angioedema and anaphylaxis seen) sumatriptan [ 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 sumatriptan (angioedema and anaphylaxis seen) ( 4 ) • Severe hepatic impairment ( 4 )

11 DESCRIPTION Sumatriptan injection, USP 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 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 readily soluble in water and in saline. Sumatriptan injection, USP is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 0.5 mL of sumatriptan injection, 12 mg/mL contains 6 mg of sumatriptan (base) as the succinate salt and 3.5 mg of sodium chloride, USP in Water for Injection, USP. The pH range of solution is approximately 4.2 to 5.3. The osmolality of injection is in between 270 to 330 mOsmol. Structure

2 DOSAGE AND ADMINISTRATION • For subcutaneous use only ( 2.1 ) • Acute treatment of migraine: single dose of 1 mg to 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 ) • Patients receiving doses other than 4 mg or 6 mg: Use the 6-mg single-dose vial ( 2.3 ) 2.1 Dosing Information The maximum single recommended adult dose of sumatriptan injection, USP 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, lower doses (1 mg to 5 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. 2.3 Administration of Doses of Sumatriptan Injection Other than 4 mg or 6 mg In patients receiving doses other than 4 mg or 6 mg, use the 6 mg single-dose vial; do not use the sumatriptan injection prefilled syringe. Visually inspect the vial for particulate matter and discoloration before administration. Do not use if particulates and discolorations are noted.

1 INDICATIONS AND USAGE Sumatriptan injection, USP 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, USP, reconsider the diagnosis before sumatriptan injection, USP is administered to treat any subsequent attacks. • Sumatriptan injection, USP is not indicated for the prevention of migraine or cluster headache attacks. Sumatriptan injection, USP 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 )

10 OVERDOSAGE Coronary vasospasm was observed after intravenous administration of sumatriptan 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 sumatriptan 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.

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 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 sumatriptan injection in patients receiving MAO-A inhibitors is contraindicated [ see Clinical Pharmacology (12.3) ]. 7.3 Other 5-HT1 Agonists Because their vasospastic effects may be additive, co-administration of sumatriptan 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 co-administration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [ see Warnings and Precautions (5.7) ].

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension [ see Warnings and Precautions (5.8) ]. Peripheral (Small) Arteries In healthy volunteers (N = 18), a trial evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance. Heart Rate Transient increases in blood pressure observed in some patients in clinical trials carried out during sumatriptan's development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate. 12.3 Pharmacokinetics Absorption and Bioavailability The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects was 97% ± 16% of that obtained following intravenous injection. After a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males (age: 24 ± 6 years, weight: 70 kg), the maximum serum concentration (C max ) of sumatriptan was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (T max ) was 12 minutes after injection (range: 5 to 20 minutes). In this trial, the same dose injected subcutaneously in the thigh gave a C max of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by autoinjector techniques. The T max or amount absorbed was not significantly altered by either the site or technique of injection. Distribution Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. Following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age: 33 years, mean weight: 77 kg) the volume of distribution central compartment of sumatriptan was 50 ± 8 liters and the distribution half-life was 15 ± 2 minutes. Metabolism In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive. Elimination After a single 6-mg subcutaneous dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the IAA metabolite. Following a 6-mg subcutaneous injection into the deltoid area of the arm, the systemic clearance of sumatriptan was 1,194 ± 149 mL/min and the terminal half-life was 115 ± 19 minutes. Specific Populations Age The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). Hepatic Impairment The effect of mild to moderate hepatic disease on the pharmacokinetics of subcutaneously administered sumatriptan has been evaluated. There were no significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in moderately hepatically impaired subjects compared with healthy controls. The pharmacokinetics of subcutaneously administered sumatriptan in patients with severe hepatic impairment has not been studied. The use of sumatriptan injection in this population is contraindicated [ see Contraindications (4) ]. Race The systemic clearance and C max of subcutaneous sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects. Drug Interaction Studies Monoamine Oxidase-A Inhibitors In a trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan, resulting in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half-life.

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.

12.2 Pharmacodynamics Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension [ see Warnings and Precautions (5.8) ]. Peripheral (Small) Arteries In healthy volunteers (N = 18), a trial evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance. Heart Rate Transient increases in blood pressure observed in some patients in clinical trials carried out during sumatriptan's development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate.

12.3 Pharmacokinetics Absorption and Bioavailability The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects was 97% ± 16% of that obtained following intravenous injection. After a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males (age: 24 ± 6 years, weight: 70 kg), the maximum serum concentration (C max ) of sumatriptan was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (T max ) was 12 minutes after injection (range: 5 to 20 minutes). In this trial, the same dose injected subcutaneously in the thigh gave a C max of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by autoinjector techniques. The T max or amount absorbed was not significantly altered by either the site or technique of injection. Distribution Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. Following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age: 33 years, mean weight: 77 kg) the volume of distribution central compartment of sumatriptan was 50 ± 8 liters and the distribution half-life was 15 ± 2 minutes. Metabolism In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive. Elimination After a single 6-mg subcutaneous dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the IAA metabolite. Following a 6-mg subcutaneous injection into the deltoid area of the arm, the systemic clearance of sumatriptan was 1,194 ± 149 mL/min and the terminal half-life was 115 ± 19 minutes. Specific Populations Age The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). Hepatic Impairment The effect of mild to moderate hepatic disease on the pharmacokinetics of subcutaneously administered sumatriptan has been evaluated. There were no significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in moderately hepatically impaired subjects compared with healthy controls. The pharmacokinetics of subcutaneously administered sumatriptan in patients with severe hepatic impairment has not been studied. The use of sumatriptan injection in this population is contraindicated [ see Contraindications (4) ]. Race The systemic clearance and C max of subcutaneous sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects. Drug Interaction Studies Monoamine Oxidase-A Inhibitors In a trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan, resulting in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half-life.

20191001

3

3 DOSAGE FORMS AND STRENGTHS • Injection: 6-mg single-dose vial • Injection: 6-mg single-dose vial ( 3 )

Sumatriptan Succinate Sumatriptan Succinate SUMATRIPTAN SUCCINATE SUMATRIPTAN SODIUM CHLORIDE WATER clear, colorless to pale yellow

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In carcinogenicity studies in mouse and rat in which sumatriptan was administered orally for 78 weeks and 104 weeks, respectively, at doses up to 160 mg/kg/day (the highest dose in rat was reduced from 360 mg/kg/day during Week 21). The highest dose to mice and rats was approximately 130 and 260 times the single MRHD of 6 mg administered subcutaneously on a mg/m 2 basis. There was no evidence in either species of an increase in tumors related to sumatriptan administration. Mutagenesis Sumatriptan was negative in in vitro (bacterial reverse mutation [Ames], gene cell mutation in Chinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays. Impairment of Fertility When sumatriptan was administered by subcutaneous injection to male and female rats prior to and throughout the mating period, there was no evidence of impaired fertility at doses up to 60 mg/kg/day or approximately 100 times the single human dose of 6 mg on a mg/m 2 basis. When sumatriptan (5, 50, 500 mg/kg/day) was administered orally to male and female rats prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day. It is not clear whether this finding was due to an effect on males or females or both. 13.2 Animal Toxicology and/or Pharmacology Corneal Opacities Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dose 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 plasma exposure at the lowest dose tested was approximately 3 times the human exposure after a 6-mg subcutaneous dose.

ANDA078593

Sumatriptan Succinate

Sumatriptan Succinate

71205-111

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL DRUG: Sumatriptan succinate GENERIC: Sumatriptan succinate DOSAGE: Injection ADMINSTRATION: subcutaneous NDC: 71205-111-01 STRENGTH: 6 mg (base)/0.5 mL QTY: 0.5 mL Single-Dose Vial Label 71205-111-01

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Risk of Myocardial Ischemia and/or Infarction, Prinzmetal's Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events Inform patients that sumatriptan injection may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring of speech, and should ask for medical advice if any indicative sign or symptoms are observed. Apprise patients of the importance of this follow-up [ see Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.5 , 5.8 ) ]. Anaphylactic/Anaphylactoid Reactions Inform patients that anaphylactic/anaphylactoid reactions 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 [ see Contraindications (4) , Warnings and Precautions (5.9) ]. Concomitant Use with Other Triptans or Ergot Medications Inform patients that use of sumatriptan injection within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) is contraindicated [ see Contraindications (4) , Drug Interactions ( 7.1 , 7.3 ) ]. Serotonin Syndrome Caution patients about the risk of serotonin syndrome with the use of sumatriptan injection or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors [ see Warnings and Precautions (5.7) , Drug Interactions (7.4) ]. Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [ see Warnings and Precautions (5.6) ]. Pregnancy Inform patients that sumatriptan injection should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [ see Use in Specific Populations (8.1) ]. Nursing Mothers Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [ see Use in Specific Populations (8.3) ]. Ability to Perform Complex Tasks Treatment with sumatriptan injection may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of sumatriptan injection. How to Use Sumatriptan Injection Instruct patients to read the Instructions for Use before starting therapy. Provide patients instruction on the proper use of sumatriptan injection if they are able to self-administer sumatriptan injection in medically unsupervised situations. Inform patients that the injection is intended to be given subcutaneously and intramuscular or intravascular delivery should be avoided. Instruct patients to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle. Manufactured by: Wockhardt Limited At: Plot no. 42 to 52, Sy. No. 166, 171, 172, 177, Phase - III, TSIIC, Pashamylaram (V), Patancheru (M), Sangareddy Dist. - 502307, Telangana State, India. Distributed by: Wockhardt USA LLC. 20 Waterview Blvd. Parsippany, NJ 07054 USA. Iss.100417

14 CLINICAL STUDIES 14.1 Migraine In controlled clinical trials enrolling more than 1,000 patients during migraine attacks who were experiencing moderate or severe pain and 1 or more of the symptoms enumerated in Table 3, onset of relief began as early as 10 minutes following a 6-mg sumatriptan injection. Lower doses of sumatriptan injection may also prove effective, although the proportion of patients obtaining adequate relief was decreased and the latency to that relief is greater with lower doses. In Study 1, 6 different doses of sumatriptan injection (n = 30 each group) were compared with placebo (n = 62), in a single-attack, parallel-group design, the dose-response relationship was found to be as shown in Table 2. Table 2. Proportion of Patients with Migraine Relief and Incidence of Adverse Reactions by Time and by Sumatriptan Injection Dose in Study 1 a Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication. Dose of Percent Patients with Relief a Adverse Sumatriptan Injection at 10 Minutes at 30 Minutes at 1 Hour at 2 Hours Reactions Incidence (%) Placebo 5 15 24 21 55 1 mg 10 40 43 40 63 2 mg 7 23 57 43 63 3 mg 17 47 57 60 77 4 mg 13 37 50 57 80 6 mg 10 63 73 70 83 8 mg 23 57 80 83 93 In 2 randomized, placebo-controlled clinical trials of sumatriptan injection 6 mg in 1,104 patients with moderate or severe migraine pain (Studies 2 and 3), the onset of relief was less than 10 minutes. Headache relief, as defined by a reduction in pain from severe or moderately severe to mild or no headache, was achieved in 70% of the patients within 1 hour of a single 6-mg subcutaneous dose of sumatriptan injection. Approximately 82% and 65% of patients treated with sumatriptan injection 6 mg had headache relief and were pain free within 2 hours, respectively. Table 3 shows the 1- and 2-hour efficacy results for sumatriptan injection 6 mg in Studies 2 and 3. Table 3. Proportion of Patients with Pain Relief and Relief of Migraine Symptoms after 1 and 2 Hours of Treatment in Studies 2 and 3 a P <0.05 versus placebo. b A successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally. c Includes patients that may have received an additional placebo injection 1 hour after the initial injection. d Includes patients that may have received an additional 6 mg of sumatriptan injection 1 hour after the initial injection. 1-Hour Data Study 2 Study 3 Placebo (n = 190) Sumatriptan Injection 6 mg (n = 384) Placebo (n = 180) Sumatriptan Injection 6 mg (n = 350) Patients with pain relief (grade 0/1) 18% 70% a 26% 70% a Patients with no pain 5% 48% a 13% 49% a Patients without nausea 48% 73% a 50% 73% a Patients without photophobia 23% 56% a 25% 58% a Patients with little or no clinical disability b 34% 76% a 34% 76% a 2-Hour Data Study 2 Study 3 Placebo c Sumatriptan Injection 6 mg d Placebo c Sumatriptan Injection 6 mg d Patients with pain relief (grade 0/1) 31% 81% a 39% 82% a Patients with no pain 11% 63% a 19% 65% a Patients without nausea 56% 82% a 63% 81% a Patients without photophobia 31% 72% a 35% 71% a Patients with little or no clinical disability b 42% 85% a 49% 84% a Sumatriptan injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks. The efficacy of sumatriptan injection was unaffected by whether or not the migraine was associated with aura, duration of attack, gender or age of the patient, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers). 14.2 Cluster Headache The efficacy of sumatriptan injection in the acute treatment of cluster headache was demonstrated in 2 randomized, double-blind, placebo-controlled, 2-period crossover trials (Studies 4 and 5). Patients 21 to 65 years of age were enrolled and were instructed to treat a moderate to very severe headache within 10 minutes of onset. Headache relief was defined as a reduction in headache severity to mild or no pain. In both trials, the proportion of individuals gaining relief at 10 or 15 minutes was significantly greater among patients receiving 6 mg of sumatriptan injection compared with those who received placebo (see Table 4). Table 4. Proportion of Patients with Cluster Headache Relief by Time in Studies 4 and 5 a P<0.05. (n = Number of headaches treated.) Study 4 Study 5 Placebo Sumatriptan Injection 6 mg Placebo Sumatriptan Injection 6 mg (n = 39) (n = 39) (n = 88) (n = 92) Patients with pain relief (no/mild) 5 Minutes post-injection 8% 21% 7% 23% a 10 Minutes post-injection 10% 49% a 25% 49% a 15 Minutes post-injection 26% 74% a 35% 75% a An estimate of the cumulative probability of a patient with a cluster headache obtaining relief after being treated with either sumatriptan injection or placebo is presented in Figure 1. Figure 1. Time to Relief of Cluster Headache from Time of Injection a a The figure uses Kaplan-Meier (product limit) Survivorship Plot. Patients taking rescue medication were censored at 15 minutes. The plot was constructed with data from patients who either experienced relief or did not require (request) rescue medication within a period of 2 hours following treatment. As a consequence, the data in the plot are derived from only a subset of the 258 headaches treated (rescue medication was required in 52 of the 127 placebo-treated headaches and 18 of the 131 headaches treated with sumatriptan injection). Other data suggest that treatment with sumatriptan injection is not associated with an increase in early recurrence of headache and has little effect on the incidence of later-occurring headaches (i.e., those occurring after 2, but before 18 or 24 hours). Figure 01

8.5 Geriatric Use Clinical trials of sumatriptan injection did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving sumatriptan injection [ see Warnings and Precautions (5.1) ].

8.3 Nursing Mothers Sumatriptan is excreted in human milk following subcutaneous administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with sumatriptan injection.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Sumatriptan injection is not recommended for use in patients younger than 18 years of age. Two controlled clinical trials evaluated sumatriptan nasal spray (5 to 20 mg) in 1,248 pediatric migraineurs 12 to 17 years of age who treated a single attack. The trials did not establish the efficacy of sumatriptan nasal spray compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients 12 to 17 years of age enrolled a total of 701 pediatric migraineurs. These trials did not establish the efficacy of oral sumatriptan compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, with younger patients reporting reactions more commonly than older pediatric patients. Postmarketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal sumatriptan are not presently available.

8.1 Pregnancy Pregnancy Category C. There are no adequate and well-controlled trials of sumatriptan injection in pregnant women. 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. Sumatriptan injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of sumatriptan to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. The highest no-effect dose for embryofetal developmental toxicity in rats was 60 mg/kg/day, or approximately 100 times the single maximum recommended human dose (MRHD) of 6 mg administered subcutaneously on a mg/m 2 basis. Oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. Intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 and 0.75 mg/kg/day, or approximately 50 and 2 times, respectively, the single MRHD of 6 mg administered subcutaneously on a mg/m 2 basis. Oral administration of sumatriptan to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). The highest no-effect dose was 50 mg/kg/day, or approximately 80 times the single MRHD of 6 mg administered subcutaneously on a mg/m 2 basis. In offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. The highest no-effect dose for this effect was 60 mg/kg/day, or approximately 100 times the single MRHD of 6 mg administered subcutaneously on a mg/m 2 basis. Oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day, or approximately 160 times the single MRHD of 6 mg administered subcutaneously on a mg/m 2 basis.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) 8.1 Pregnancy Pregnancy Category C. There are no adequate and well-controlled trials of sumatriptan injection in pregnant women. 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. Sumatriptan injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of sumatriptan to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. The highest no-effect dose for embryofetal developmental toxicity in rats was 60 mg/kg/day, or approximately 100 times the single maximum recommended human dose (MRHD) of 6 mg administered subcutaneously on a mg/m 2 basis. Oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. Intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 and 0.75 mg/kg/day, or approximately 50 and 2 times, respectively, the single MRHD of 6 mg administered subcutaneously on a mg/m 2 basis. Oral administration of sumatriptan to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). The highest no-effect dose was 50 mg/kg/day, or approximately 80 times the single MRHD of 6 mg administered subcutaneously on a mg/m 2 basis. In offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. The highest no-effect dose for this effect was 60 mg/kg/day, or approximately 100 times the single MRHD of 6 mg administered subcutaneously on a mg/m 2 basis. Oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day, or approximately 160 times the single MRHD of 6 mg administered subcutaneously on a mg/m 2 basis. 8.3 Nursing Mothers Sumatriptan is excreted in human milk following subcutaneous administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with sumatriptan injection. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Sumatriptan injection is not recommended for use in patients younger than 18 years of age. Two controlled clinical trials evaluated sumatriptan nasal spray (5 to 20 mg) in 1,248 pediatric migraineurs 12 to 17 years of age who treated a single attack. The trials did not establish the efficacy of sumatriptan nasal spray compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients 12 to 17 years of age enrolled a total of 701 pediatric migraineurs. These trials did not establish the efficacy of oral sumatriptan compared with placebo in the treatment of migraine in pediatric patients. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, with younger patients reporting reactions more commonly than older pediatric patients. Postmarketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal sumatriptan are not presently available. 8.5 Geriatric Use Clinical trials of sumatriptan injection did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving sumatriptan injection [ see Warnings and Precautions (5.1) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Sumatriptan injection, USP contains sumatriptan (base) as the succinate salt and is supplied as a clear, colorless to pale yellow, sterile, nonpyrogenic solution as follows: Single-Dose Vial : NDC 71205-111-01 sumatriptan injection, USP single-dose vial (6 mg/0.5 mL) in cartons containing 1 vial. Store between 2° and 25°C (36° and 77°F). Protect from light.