Sumatriptan

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) ] Local irritation [see Warnings and Precautions (5.9) ] Hypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.10) ] Seizures [see Warnings and Precautions (5.11) ] Most common adverse reactions (≥1% and >placebo) were burning sensation, disorder/discomfort of nasal cavity/sinuses, throat discomfort, nausea and/or vomiting, bad/unusual taste, and dizziness/vertigo. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Florida Pharmaceutical Products, LLC at 1-800-315-0985 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 worldwide placebo-controlled clinical trials in 3,419 patients with migraine. Only treatment-emergent adverse reactions that occurred at a frequency of 1% or more in the group treated with sumatriptan nasal spray 20 mg and that occurred at a frequency greater than the placebo group are included in Table 1. Table 1. Adverse Reactions Reported by at Least 1% of Patients and at a Greater Frequency than Placebo in Controlled Migraine Clinical Trials Adverse Reaction Percent of Patients Reporting Sumatriptan Nasal Spray 5 mg (n = 496) Sumatriptan Nasal Spray 10 mg (n = 1,007) Sumatriptan Nasal Spray 20 mg (n = 1,212) Placebo (n = 704) Atypical sensations Burning sensation 0.4 0.6 1.4 0.1 Ear, nose, and throat Disorder/discomfort of nasal cavity/sinuses 2.8 2.5 3.8 2.4 Throat discomfort 0.8 1.8 2.4 0.9 Gastrointestinal Nausea and/or vomiting 12.2 11.0 13.5 11.3 Neurological Bad/unusual taste 13.5 19.3 24.5 1.7 Dizziness/vertigo 1.0 1.7 1.4 0.9 The incidence of adverse reactions in controlled clinical trials was not affected by gender, weight, or age of the patients; use of prophylactic medications; or presence of aura. 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.

4 CONTRAINDICATIONS Sumatriptan nasal spray 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, 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) and Clinical Pharmacology (12.3) ] Hypersensitivity to sumatriptan (angioedema and anaphylaxis seen) [see Warnings and Precautions (5.10) ] 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 nasal spray (angioedema and anaphylaxis seen). ( 4 ) Severe hepatic impairment. ( 4 )

11 DESCRIPTION Sumatriptan nasal spray contains sumatriptan, a selective 5-HT 1B/1D receptor agonist. Sumatriptan is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide, and it has the following structure: The empirical formula is C 14 H 21 N 3 O 2 S, representing a molecular weight of 295.4. Sumatriptan is a white to off-white powder that is very slightly soluble in water and in saline. Each sumatriptan nasal spray contains 20 mg of sumatriptan in a 100-MicroL unit dose aqueous buffered solution containing monobasic potassium phosphate NF, anhydrous dibasic sodium phosphate USP, sulfuric acid NF, sodium hydroxide NF, and water for injection USP. The pH of the solution is approximately 5.5. The osmolality of the solution is 372 or 742 mOsmol for the 5 and 20 mg sumatriptan nasal spray, respectively. sumatriptan chemical structure

2 DOSAGE AND ADMINISTRATION The recommended adult dose of sumatriptan nasal spray for the acute treatment of migraine is 5 mg, 10 mg, or 20 mg. The 20 mg dose may provide a greater effect than the 5 mg and 10 mg doses, but may have a greater risk of adverse reactions [see Clinical Studies (14) ] . The 5 mg and 20 mg doses are given as a single spray in 1 nostril. The 10 mg dose may be achieved by the administration of a single 5 mg dose in each nostril. If the migraine has not resolved by 2 hours after taking sumatriptan nasal spray or returns after a transient improvement, 1 additional dose may be administered at least 2 hours after the first dose. The maximum daily dose is 40 mg in a 24 hour period. The safety of treating an average of more than 4 headaches in a 30 day period has not been established. Single dose of 5 mg, 10 mg, or 20 mg of nasal spray. ( 2 ) A second dose should only be considered if some response to the first dose was observed. Separate doses by at least 2 hours. ( 2 ) Maximum dose in a 24-hour period: 40 mg. ( 2 )

1 INDICATIONS AND USAGE Sumatriptan nasal spray is 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 nasal spray, reconsider the diagnosis of migraine before Sumatriptan nasal spray is administered to treat any subsequent attacks. Sumatriptan is not indicated for the prevention of migraine attacks. Safety and effectiveness of sumatriptan nasal spray 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 )

10 OVERDOSAGE In clinical trials, the highest single doses of sumatriptan nasal spray administered without significant reactions were 40 mg to 12 volunteers and 40 mg to 85 subjects with migraine, which is twice the highest single recommended dose. In addition, 12 volunteers were administered a total daily dose of 60 mg (20 mg 3 times daily) for 3.5 days without significant 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 hours [see Clinical Pharmacology (12.3) ] , and therefore monitoring of patients after overdose with sumatriptan nasal spray 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 nasal spray within 24 hours of each other is contraindicated. 7.2 Monoamine Oxidase-A Inhibitors MAO-A inhibitors increase systemic exposure by up to 7-fold. Therefore, the use of sumatriptan nasal spray 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, co-administration of sumatriptan nasal spray 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 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. 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 : In a trial of 20 female volunteers, the mean maximum concentration following a 5 and 20 mg intranasal dose was 5 and 16 ng/mL, respectively. The mean C max following a 6 mg subcutaneous injection is 71 ng/mL (range: 49 to 110 ng/mL). The mean C max is 18 ng/mL (range: 7 to 47 ng/mL) following oral dosing with 25 mg and 51 ng/mL (range: 28 to 100 ng/mL) following oral dosing with 100 mg of sumatriptan. In a trial of 24 male volunteers, the bioavailability relative to subcutaneous injection was low, approximately 17%, primarily due to presystemic metabolism and partly due to incomplete absorption. Clinical and pharmacokinetic data indicate that administration of two 5 mg doses, 1 dose in each nostril, is equivalent to administration of a single 10 mg dose in 1 nostril. 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. The apparent volume of distribution is 2.7 L/kg. 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 : The elimination half-life of sumatriptan administered as a nasal spray is approximately 2 hours, similar to the half-life seen after subcutaneous injection. Only 3% of the dose is excreted in the urine as unchanged sumatriptan; 42% of the dose is excreted as the major metabolite, the indole acetic acid analogue of sumatriptan. The total plasma clearance is approximately 1,200 mL/min. 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). Intranasal sumatriptan has not been evaluated for age differences. Patients with Renal Impairment: The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined. Patients with Hepatic Impairment: The effect of mild to moderate hepatic disease on the pharmacokinetics of the intranasal formulation of sumatriptan has not been evaluated. Sumatriptan bioavailability following intranasal administration is 17%, similar to that after oral administration (15%). Following oral administration, an approximately 70% increase in C max and AUC was observed in one small trial of patients with moderate liver impairment (n = 8) matched for sex, age and weight with healthy subjects (n = 8). Similar changes can be expected following intranasal administration. The pharmacokinetics of sumatriptan in patients with severe hepatic impairment has not been studied. The use of sumatriptan nasal spray in patients with severe hepatic impairment is contraindicated [see Contraindications (4) ] . Racial Groups: The systemic clearance and C max of subcutaneous sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects. Intranasal sumatriptan has not been evaluated for race differences. Drug Interaction Studies : Monoamine Oxidase-A Inhibitors: Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels [see Contraindications (4) and Drug Interactions (7.2) ] . MAO inhibitors interaction studies have not been performed with intranasal sumatriptan. Due to gut and hepatic metabolic first-pass effects, the increase of systemic exposure after co-administration of an MAO-A inhibitor with oral sumatriptan is greater than after co-administration of the MAO inhibitors with subcutaneous sumatriptan. The effects of an MAO inhibitor on systemic exposure after intranasal sumatriptan would be expected to be greater than the effect after subcutaneous sumatriptan but smaller than the effect after oral sumatriptan because only swallowed drug would be subject to first-pass effects. 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. A small trial evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from a 25 mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure. Xylometazoline: An in vivo drug interaction trial indicated that 3 drops of xylometazoline (0.1% w/v), a decongestant, administered 15 minutes prior to a 20 mg nasal dose of sumatriptan did not alter the pharmacokinetics of sumatriptan.

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.

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 : In a trial of 20 female volunteers, the mean maximum concentration following a 5 and 20 mg intranasal dose was 5 and 16 ng/mL, respectively. The mean C max following a 6 mg subcutaneous injection is 71 ng/mL (range: 49 to 110 ng/mL). The mean C max is 18 ng/mL (range: 7 to 47 ng/mL) following oral dosing with 25 mg and 51 ng/mL (range: 28 to 100 ng/mL) following oral dosing with 100 mg of sumatriptan. In a trial of 24 male volunteers, the bioavailability relative to subcutaneous injection was low, approximately 17%, primarily due to presystemic metabolism and partly due to incomplete absorption. Clinical and pharmacokinetic data indicate that administration of two 5 mg doses, 1 dose in each nostril, is equivalent to administration of a single 10 mg dose in 1 nostril. 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. The apparent volume of distribution is 2.7 L/kg. 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 : The elimination half-life of sumatriptan administered as a nasal spray is approximately 2 hours, similar to the half-life seen after subcutaneous injection. Only 3% of the dose is excreted in the urine as unchanged sumatriptan; 42% of the dose is excreted as the major metabolite, the indole acetic acid analogue of sumatriptan. The total plasma clearance is approximately 1,200 mL/min. 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). Intranasal sumatriptan has not been evaluated for age differences. Patients with Renal Impairment: The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined. Patients with Hepatic Impairment: The effect of mild to moderate hepatic disease on the pharmacokinetics of the intranasal formulation of sumatriptan has not been evaluated. Sumatriptan bioavailability following intranasal administration is 17%, similar to that after oral administration (15%). Following oral administration, an approximately 70% increase in C max and AUC was observed in one small trial of patients with moderate liver impairment (n = 8) matched for sex, age and weight with healthy subjects (n = 8). Similar changes can be expected following intranasal administration. The pharmacokinetics of sumatriptan in patients with severe hepatic impairment has not been studied. The use of sumatriptan nasal spray in patients with severe hepatic impairment is contraindicated [see Contraindications (4) ] . Racial Groups: The systemic clearance and C max of subcutaneous sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects. Intranasal sumatriptan has not been evaluated for race differences. Drug Interaction Studies : Monoamine Oxidase-A Inhibitors: Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels [see Contraindications (4) and Drug Interactions (7.2) ] . MAO inhibitors interaction studies have not been performed with intranasal sumatriptan. Due to gut and hepatic metabolic first-pass effects, the increase of systemic exposure after co-administration of an MAO-A inhibitor with oral sumatriptan is greater than after co-administration of the MAO inhibitors with subcutaneous sumatriptan. The effects of an MAO inhibitor on systemic exposure after intranasal sumatriptan would be expected to be greater than the effect after subcutaneous sumatriptan but smaller than the effect after oral sumatriptan because only swallowed drug would be subject to first-pass effects. 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. A small trial evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from a 25 mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure. Xylometazoline: An in vivo drug interaction trial indicated that 3 drops of xylometazoline (0.1% w/v), a decongestant, administered 15 minutes prior to a 20 mg nasal dose of sumatriptan did not alter the pharmacokinetics of sumatriptan.

20211113

2

3 DOSAGE FORMS AND STRENGTHS Unit dose nasal spray devices containing 20 mg sumatriptan. Nasal spray: 20 mg ( 3 , 16 )

Sumatriptan sumatriptan POTASSIUM PHOSPHATE, MONOBASIC SODIUM PHOSPHATE, DIBASIC, ANHYDROUS SULFURIC ACID SODIUM HYDROXIDE WATER SUMATRIPTAN SUMATRIPTAN

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis : In carcinogenicity studies in mouse and rat in which sumatriptan was administered orally for 78 and 104 weeks, respectively, there was no evidence in either species of an increase in tumors related to sumatriptan administration. Carcinogenicity studies of sumatriptan using the nasal route have not been conducted. 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 (5, 50, or 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. 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. Fertility studies of sumatriptan using the intranasal route have not been conducted.

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 and 104 weeks, respectively, there was no evidence in either species of an increase in tumors related to sumatriptan administration. Carcinogenicity studies of sumatriptan using the nasal route have not been conducted. 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 (5, 50, or 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. 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. Fertility studies of sumatriptan using the intranasal route have not been conducted. 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.

ANDA208967

Sumatriptan

sumatriptan

71921-170

HUMAN PRESCRIPTION DRUG

NASAL

PRINCIPAL DISPLAY PANEL NDC 71921-170-61 R x Only Sumatriptan Nasal Spray, USP 20 mg 0.1 mL per unit For Intranasal Use Only Each unit dose nasal spray contains 20 mg of sumatriptan. 1 Spray per unit. Do not test before use. 6 Nasal Spray Units FPP Rx Florida Pharmaceutical Products, LLC Imitrex Nasal 20 mg 6 count carton

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events : Inform patients that sumatriptan nasal spray 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 nasal spray. 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) and Warnings and Precautions (5.10) ] . Concomitant use with other Triptans or Ergot Medications : Inform patients that use of sumatriptan nasal spray within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) is contraindicated [see Contraindications (4) and Drug Interactions (7.1 , 7.3) ] . Serotonin Syndrome : Caution patients about the risk of serotonin syndrome with the use of sumatriptan nasal spray or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7) and 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 : Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant [see Use in Specific Populations (8.1) ] . Lactation : Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.2) ] . Ability to Perform Complex Tasks : Treatment with sumatriptan nasal spray may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of sumatriptan nasal spray. Local Irritation : Inform patients that they may experience local irritation of their nose and throat. The symptoms will generally resolve in less than 2 hours. How to Use sumatriptan nasal spray : Provide patients instruction on the proper use of sumatriptan nasal spray. Caution patients to avoid spraying the contents of the device in their eyes. Manufactured for Florida Pharmaceutical Products, LLC by Novocol Pharmaceutical of Canada, Inc. 25 Wolseley Court, Cambridge, Ontario. N1R 6X3 Canada Made in Canada. Rev. 02/2021 (2079-0)

Instructions for Use Sumatriptan nasal spray (soo” ma trip’ tan) For use in the nose only. Do not spray in your eyes. Step 1. Remove the sumatriptan nasal spray unit from the aluminum pouch (see Figure A) . Do not remove the unit until you are ready to use. The unit contains only 1 spray. Do not test before use. Figure A Step 2. While sitting down, gently blow your nose to clear your nasal passages (see Figure B) . Figure B Step 3. Keeping your head in an upright position, gently close 1 nostril with your index finger and breathe out gently through your mouth (see Figure C) . Figure C Figure D Step 4. With your other hand, hold the container with your thumb supporting the container at the bottom, and your index and middle fingers on either side of the nozzle (see Figure D). Insert the nozzle into your open nostril about ½ inch. Do not press the plunger yet. Figure E Step 5. Keep your head upright and close your mouth. While gently taking a breath in through your nose, press the plunger firmly to release the dose of sumatriptan nasal spray (see Figure E) . Figure F Step 6. Keep your head level and remove the nozzle from your nostril. While holding your head level, gently breathe in through your nose and out through your mouth for 10 to 20 seconds (see Figure F) . Do not breathe in deeply. This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. Manufactured for Florida Pharmaceutical Products, LLC by Novocol Pharmaceutical of Canada, Inc.. 25 Wolseley Court, Cambridge, Ontario. N1R 6X3 Canada Made in Canada. Rev. 02/2021 (2667-0) figure A figure B figure C figure D Figure E Figure F

14 CLINICAL STUDIES The efficacy of sumatriptan nasal spray in the acute treatment of migraine headaches was demonstrated in 8, randomized, double-blind, placebo-controlled trials, of which 5 used the recommended dosing regimen and used the marketed formulation. Patients enrolled in these 5 trials were predominately female (86%) and Caucasian (95%), with a mean age of 41 years (range of 18 to 65 years). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 2 hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours postdose. A second dose of sumatriptan nasal spray or other medication was allowed 2 to 24 hours after the initial treatment for recurrent headache. The frequency and time to use of these additional treatments were also determined. In all trials, doses of 10 and 20 mg were compared with placebo in the treatment of 1 to 3 migraine attacks. Patients received doses as a single spray into 1 nostril. In 2 trials, a 5 mg dose was also evaluated. In all 5 trials utilizing the market formulation and recommended dosage regimen, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients receiving sumatriptan nasal spray at all doses (with one exception) compared with those who received placebo. In 4 of the 5 trials, there was a statistically significant greater percentage of patients with headache response at 2 hours in the 20 mg group when compared with the lower dose groups (5 and 10 mg). There were no statistically significant differences between the 5 and 10 mg dose groups in any trial. The results from the 5 controlled clinical trials are summarized in Table 2. Note that, in general, comparisons of results obtained in trials conducted under different conditions by different investigators with different samples of patients are ordinarily unreliable for purposes of quantitative comparison. Table 2. Percentage of Patients with Headache Response (No or Mild Pain) 2 Hours Following Treatment Sumatriptan Nasal Spray 5 mg Sumatriptan Nasal Spray 10 mg Sumatriptan Nasal Spray 20 mg Placebo Trial 1 49% a 46% a 64% a,b,c 25% (n = 121) (n = 112) (n = 118) (n = 63) Trial 2 Not applicable 44% a 55% a,b 25% (n = 273) (n = 277) (n = 138) Trial 3 Not applicable 54% a 63% a 35% (n = 106) (n = 202) (n = 100) Trial 4 Not applicable 43% 62% a,b 29% (n = 106) (n = 215) (n = 112) Trial 5 d 45% a 53% a 60% a,c 36% (n = 296) (n = 291) (n = 286) (n = 198) a P <0.05 in comparison with placebo. b P <0.05 in comparison with 10 mg. c P <0.05 in comparison with 5 mg. d Data are for attack 1 only of multi-attack trial for comparison. The estimated probability of achieving an initial headache response over the 2 hours following treatment is depicted in Figure 1. Figure 1. Estimated Probability of Achieving Initial Headache Response within 120 Minutes a a The figure shows the probability over time of obtaining headache response (no or mild pain) following treatment with intranasal sumatriptan. The averages displayed are based on pooled data from the 5 clinical controlled trials providing evidence of efficacy. Kaplan-Meier plot with patients not achieving response within 120 minutes censored to 120 minutes. For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was a lower incidence of these symptoms at 2 hours following administration of sumatriptan nasal spray compared with placebo. Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2. Figure 2. The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraine Over the 24 Hours Following the Initial Dose of Study Treatment a a Kaplan-Meier plot based on data obtained in the 3 clinical controlled trials providing evidence of efficacy with patients not using additional treatments censored to 24 hours. Plot also includes patients who had no response to the initial dose. No remedication was allowed within 2 hours postdose. There is evidence that doses above 20 mg do not provide a greater effect than 20 mg. There was no evidence to suggest that treatment with sumatriptan was associated with an increase in the severity of recurrent headaches. The efficacy of sumatriptan nasal spray was unaffected by presence of aura; duration of headache prior to treatment; gender, age, or weight of the subject; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants). There were insufficient data to assess the impact of race on efficacy. Figure 1. estimated probability of initial headache response within 120 minutes figure 2. probability of patients needing second dose or additional medication

8.5 Geriatric Use Clinical trials of sumatriptan nasal spray did not include sufficient numbers of patients aged 65 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 nasal spray [see Warnings and Precautions (5.1) ] .

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. sumatriptan nasal spray 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 adolescent migraineurs aged 12 to 17 years 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 adolescents. 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 aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These trials did not establish the efficacy of oral sumatriptan compared with placebo in the treatment of migraine in adolescents. 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 adolescents. 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 Risk Summary Data from a prospective 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. Animal Data : 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. 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, respectively. 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. 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. 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.

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 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. Animal Data : 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. 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, respectively. 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. 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. 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. 8.2 Lactation Risk Summary Sumatriptan is excreted in human milk following subcutaneous administration (see Data ) . There is no information regarding sumatriptan concentrations in milk from lactating women following administration of sumatriptan nasal spray. There are no data on the effects of sumatriptan on the breastfed infant or the effects of sumatriptan on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sumatriptan nasal spray and any potential adverse effects on the breastfed infant from sumatriptan or from the underlying maternal condition. Clinical Considerations Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with sumatriptan nasal spray. Data Following subcutaneous administration of a 6 mg dose of sumatriptan injection in 5 lactating volunteers, sumatriptan was present in milk. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. sumatriptan nasal spray 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 adolescent migraineurs aged 12 to 17 years 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 adolescents. 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 aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These trials did not establish the efficacy of oral sumatriptan compared with placebo in the treatment of migraine in adolescents. 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 adolescents. 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 nasal spray did not include sufficient numbers of patients aged 65 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 nasal spray [see Warnings and Precautions (5.1) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Sumatriptan nasal spray, 20 mg ( NDC 71921-170-61 ) is supplied in boxes of 6 nasal spray devices. Each unit dose spray supplies 20 mg of sumatriptan. Store between 2°C and 30°C (36°F and 86°F). Protect from light.