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1 INDICATIONS AND USAGE ZEMBRACE SymTouch is indicated for the acute treatment of migraine with or without aura in adults. ZEMBRACE SymTouch 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 has been established. ( 1 ) Not indicated for the prophylactic therapy of migraine. ( 1 ) Limitations of Use : Use only if a clear diagnosis of migraine has been established. If a patient has no response to the first migraine attack treated with ZEMBRACE SymTouch, reconsider the diagnosis before ZEMBRACE SymTouch is administered to treat any subsequent attacks. ZEMBRACE SymTouch injection is not indicated for the prevention of migraine attacks.

2 DOSAGE AND ADMINISTRATION For subcutaneous use only. ( 2.1 ) Acute treatment of migraine: 3 mg Single dose. ( 2.1 ) Maximum dose in a 24-hour period: 12 mg. Separate doses by at least 1 hour. ( 2.1 ) 2.1 Dosing Information The recommended dose of ZEMBRACE SymTouch is 3 mg injected subcutaneously. The maximum cumulative injected dose that may be given in 24 hours is 12 mg, with doses of ZEMBRACE SymTouch separated by at least 1 hour. ZEMBRACE SymTouch may also be given at least 1 hour following a dose of another sumatriptan product. 2.2 Administration Using ZEMBRACE SymTouch ZEMBRACE SymTouch is available as a prefilled, ready-to-use, single dose, disposable auto-injector containing 3 mg sumatriptan. With ZEMBRACE SymTouch, the needle penetrates approximately ¼ inch (6 mm). The injection is intended to be given subcutaneously. Do not administer by any other route. Instruct patients on the proper use of ZEMBRACE SymTouch and direct them to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.

3 DOSAGE FORMS AND STRENGTHS Injection: 3 mg sumatriptan in 0.5 mL prefilled, ready-to-use, single dose, disposable auto-injector. Injection: 3 mg prefilled, ready-to-use, single-dose disposable auto-injector. ( 3 )

4 CONTRAINDICATIONS ZEMBRACE SymTouch 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 (i.e., within 24 hours) use of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 (5-HT 1 ) agonist [see Drug Interactions (7.1 , 7.3) ] . Concurrent administration of an MAO-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ] . Known hypersensitivity to sumatriptan (angioedema and anaphylaxis seen) [see Warnings and Precautions (5.9) ] . Severe hepatic impairment [see Clinical Pharmacology (12.3) ] . History of coronary artery disease or coronary 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 )

5 WARNINGS AND PRECAUTIONS Myocardial ischemia/infarction and Prinzmetal's angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors. ( 5.1 ) Arrhythmias: Discontinue ZEMBRACE SymTouch if occurs. ( 5.2 ) Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally, not associated with myocardial ischemia; evaluate for coronary artery disease in patients at high risk. ( 5.3 ) Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue ZEMBRACE SymTouch if occurs. ( 5.4 ) Gastrointestinal ischemia and reactions, peripheral vasospastic reactions: Discontinue ZEMBRACE SymTouch if occurs. ( 5.5 ) Medication overuse headache: Detoxification may be necessary. ( 5.6 ) Serotonin syndrome: Discontinue ZEMBRACE SymTouch if occurs. ( 5.7 ) Seizures: Use with caution in patients with epilepsy or a lowered seizure threshold. ( 5.10 ) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina The use of ZEMBRACE SymTouch injection is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of sumatriptan injection. Some of these reactions occurred in patients without known CAD. 5-HT 1 agonists, including ZEMBRACE SymTouch injection, may cause coronary artery vasospasm (Prinzmetal's angina), even in patients without a history of CAD. Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving ZEMBRACE SymTouch injection. If there is evidence of CAD or coronary artery vasospasm, ZEMBRACE SymTouch injection is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of ZEMBRACE SymTouch injection in a medically supervised setting and performing an electrocardiogram (ECG) immediately following ZEMBRACE SymTouch injection. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of ZEMBRACE SymTouch injection. 5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT 1 agonists. Discontinue ZEMBRACE SymTouch injection if these disturbances occur. ZEMBRACE SymTouch injection is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with sumatriptan injection and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of ZEMBRACE SymTouch injection is contraindicated in patients with CAD and those with Prinzmetal's variant angina. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities.

high cardiac risk. The use of ZEMBRACE SymTouch injection is contraindicated in patients with CAD and those with Prinzmetal's variant angina. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue ZEMBRACE SymTouch injection if a cerebrovascular event occurs. Before treating headaches in patients not previously diagnosed with migraine or in patients who present with atypical symptoms, exclude other potentially serious neurological conditions. ZEMBRACE SymTouch injection is contraindicated in patients with a history of stroke or TIA. 5.5 Other Vasospasm Reactions ZEMBRACE SymTouch injection may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT 1 agonist, rule out a vasospastic reaction before receiving additional ZEMBRACE SymTouch injections. Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists have not been clearly established. 5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. 5.7 Serotonin Syndrome Serotonin syndrome may occur with ZEMBRACE SymTouch injection, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.4) ] . Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue ZEMBRACE SymTouch injection if serotonin syndrome is suspected. 5.8 Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT 1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with ZEMBRACE SymTouch. ZEMBRACE SymTouch injection is contraindicated in patients with uncontrolled hypertension. 5.9 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients receiving sumatriptan.

of hypertension. Monitor blood pressure in patients treated with ZEMBRACE SymTouch. ZEMBRACE SymTouch injection is contraindicated in patients with uncontrolled hypertension. 5.9 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients receiving sumatriptan. 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. ZEMBRACE SymTouch injection is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan. 5.10 Seizures Seizures have been reported following administration of sumatriptan. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent. ZEMBRACE SymTouch injection should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Myocardial ischemia, myocardial infarction, and Prinzmetal's angina [see Warnings and Precautions (5.1) ] Arrhythmias [see Warnings and Precautions (5.2) ] Chest, throat, neck, and/or jaw pain/tightness/pressure [see Warnings and Precautions (5.3) ] Cerebrovascular events [see Warnings and Precautions (5.4) ] Other vasospasm reactions [see Warnings and Precautions (5.5) ] Medication overuse headache [see Warnings and Precautions (5.6) ] Serotonin syndrome [see Warnings and Precautions (5.7) ] Increase in blood pressure [see Warnings and Precautions (5.8) ] Hypersensitivity reactions [see Contraindications (4) , Warnings and Precautions (5.9) ] Seizures [see Warnings and Precautions (5.10) ] Most common adverse reactions (≥5% and > placebo) were injection site reactions, tingling, dizziness/vertigo, warm/hot sensation, burning sensation, feeling of heaviness, pressure sensation, flushing, feeling of tightness, and numbness/paresthesia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 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. Adverse Reactions in Placebo-Controlled Trials with Sumatriptan Injection Migraine Headache: Table 1 lists adverse reactions that occurred in 2 US placebo-controlled clinical trials in migraine subjects (Studies 2 and 3), following either a single 6-mg dose of sumatriptan injection or placebo. Only reactions that occurred at a frequency of 2% or more in groups treated with sumatriptan injection 6 mg and that occurred at a frequency greater than the placebo group are included in Table 1. Table 1: Adverse Reactions in Pooled Placebo-Controlled Trials in Patients with Migraine (Studies 2 and 3) Adverse Reaction 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 Includes injection site pain, stinging/burning, swelling, erythema, bruising, bleeding. 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.

<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. Adverse Reactions in a Study with ZEMBRACE SymTouch The most common adverse reactions in a placebo-controlled trial with ZEMBRACE SymTouch were injection site reactions (including injection site bruising, erythema, hemorrhage, induration, irritation, pain, paresthesia, pruritis, swelling, and urticaria), occurring in 30% of ZEMBRACE SymTouch-treated patients compared to 13% of placebo-treated patients. Adverse reactions with ZEMRACE SymTouch are expected to be similar to those observed with sumatriptan injection. 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval 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

<table width="100%"><caption>Table 1: Adverse Reactions in Pooled Placebo-Controlled Trials in Patients with Migraine (Studies 2 and 3)</caption><col width="34%" align="left" valign="top"/><col width="33%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th rowspan="2" styleCode="Lrule Rrule">Adverse Reaction</th><th colspan="2" styleCode="Rrule">Percent of Subjects Reporting</th></tr><tr><th align="center" styleCode="Rrule">Sumatriptan Injection 6 mg Subcutaneous (n = 547) </th><th styleCode="Rrule">Placebo (n = 370) </th></tr></thead><tbody><tr><td styleCode="Lrule Rrule">Atypical sensations</td><td styleCode="Rrule">42</td><td styleCode="Rrule">9</td></tr><tr><td styleCode="Lrule Rrule"> Tingling</td><td styleCode="Rrule">14</td><td styleCode="Rrule">3</td></tr><tr><td styleCode="Lrule Rrule"> Warm/hot sensation</td><td styleCode="Rrule">11</td><td styleCode="Rrule">4</td></tr><tr><td styleCode="Lrule Rrule"> Burning sensation</td><td styleCode="Rrule">7</td><td styleCode="Rrule">&lt;1</td></tr><tr><td styleCode="Lrule Rrule"> Feeling of heaviness</td><td styleCode="Rrule">7</td><td styleCode="Rrule">1</td></tr><tr><td styleCode="Lrule Rrule"> Pressure sensation</td><td styleCode="Rrule">7</td><td styleCode="Rrule">2</td></tr><tr><td styleCode="Lrule Rrule"> Feeling of tightness</td><td styleCode="Rrule">5</td><td styleCode="Rrule">&lt;1</td></tr><tr><td styleCode="Lrule Rrule"> Numbness</td><td styleCode="Rrule">5</td><td styleCode="Rrule">2</td></tr><tr><td styleCode="Lrule Rrule"> Feeling strange</td><td styleCode="Rrule">2</td><td styleCode="Rrule">&lt;1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Tight feeling in head</td><td styleCode="Rrule">2</td><td styleCode="Rrule">&lt;1</td></tr><tr><td styleCode="Lrule Rrule">Cardiovascular</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Flushing</td><td styleCode="Rrule">7</td><td styleCode="Rrule">2</td></tr><tr><td styleCode="Lrule Rrule"> Chest discomfort</td><td styleCode="Rrule">5</td><td styleCode="Rrule">1</td></tr><tr><td styleCode="Lrule Rrule"> Tightness in chest</td><td styleCode="Rrule">3</td><td styleCode="Rrule">&lt;1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pressure in chest</td><td styleCode="Rrule">2</td><td styleCode="Rrule">&lt;1</td></tr><tr><td styleCode="Lrule Rrule">Ear, nose, and throat</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Throat discomfort</td><td styleCode="Rrule">3</td><td styleCode="Rrule">&lt;1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Discomfort: nasal cavity/sinuses</td><td styleCode="Rrule">2</td><td styleCode="Rrule">&lt;1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Injection site reaction <footnote ID="K1298">Includes injection site pain, stinging/burning, swelling, erythema, bruising, bleeding.</footnote></td><td styleCode="Rrule">59</td><td styleCode="Rrule">24</td></tr><tr><td styleCode="Lrule Rrule">Miscellaneous</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Jaw discomfort</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Musculoskeletal</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Weakness</td><td styleCode="Rrule">5</td><td styleCode="Rrule">&lt;1</td></tr><tr><td styleCode="Lr

le"> Jaw discomfort</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Musculoskeletal</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Weakness</td><td styleCode="Rrule">5</td><td styleCode="Rrule">&lt;1</td></tr><tr><td styleCode="Lr ule Rrule"> Neck pain/stiffness</td><td styleCode="Rrule">5</td><td styleCode="Rrule">&lt;1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Myalgia</td><td styleCode="Rrule">2</td><td styleCode="Rrule">&lt;1</td></tr><tr><td styleCode="Lrule Rrule">Neurological</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Dizziness/vertigo</td><td styleCode="Rrule">12</td><td styleCode="Rrule">4</td></tr><tr><td styleCode="Lrule Rrule"> Drowsiness/sedation</td><td styleCode="Rrule">3</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">2</td><td styleCode="Rrule">&lt;1</td></tr><tr><td styleCode="Lrule Rrule">Skin</td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"> Sweating</td><td styleCode="Rrule">2</td><td styleCode="Rrule">1</td></tr></tbody></table>

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 ZEMBRACE SymTouch 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 ZEMBRACE SymTouch injection in patients receiving MAO-A inhibitors is contraindicated [see Clinical Pharmacology (12.3) ] . 7.3 Other 5-HT 1 Agonists Because their vasospastic effects may be additive, coadministration of ZEMBRACE SymTouch injection and other 5-HT 1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of serotonin syndrome have been reported during coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7) ] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see Data ) . In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryo lethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryo lethal (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.

edical 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 embryo lethality 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 embryo lethality. 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 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 ZEMBRACE SymTouch 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 ZEMBRACE SymTouch. 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. ZEMBRACE SymTouch 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.

urs 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 subjects 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. Post-marketing 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 subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. 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 ZEMBRACE SymTouch injection [see Warnings and Precautions (5.1) ] .

8.1 Pregnancy Risk Summary Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see Data ) . In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryo lethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryo lethal (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.

edical 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 embryo lethality 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 embryo lethality. 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.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. ZEMBRACE SymTouch 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 subjects 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. Post-marketing 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 subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. 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 ZEMBRACE SymTouch injection [see Warnings and Precautions (5.1) ] .

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) ] , and therefore monitoring of patients after overdose with ZEMBRACE SymTouch 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.

11 DESCRIPTION ZEMBRACE SymTouch injection contains sumatriptan succinate, a selective 5-HT 1B/1D receptor agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino) ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure: The empirical formula is C 14 H 21 N 3 O 2 S∙C 4 H 6 O 4 , representing a molecular weight of 413.5. Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in saline. ZEMBRACE SymTouch is a clear, colorless to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 0.5 mL of ZEMBRACE SymTouch contains 4.2 mg of sumatriptan succinate equivalent to 3 mg of sumatriptan (base) and 4.15 mg of sodium chloride, USP in Water for Injection, USP. The pH range of solution is approximately 4.2 to 5.3 and the osmolality of injection is approximately 291 mOsmol (275 to 315 mOsmol). Chemical Structure

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 subjects 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 After a single 3 mg dose, ZEMBRACE SymTouch was bioequivalent to IMITREX subcutaneous injection. 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 auto-injector 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).

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). Patients with 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 ZEMBRACE SymTouch 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 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 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 subjects 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 After a single 3 mg dose, ZEMBRACE SymTouch was bioequivalent to IMITREX subcutaneous injection. 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 auto-injector 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). Patients with 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 ZEMBRACE SymTouch 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 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In carcinogenicity studies in mouse and rat, sumatriptan was administered orally for 78 weeks and 104 weeks, respectively, at doses up to 160 mg/kg/day (the high dose in rat was reduced from 360 mg/kg/day during Week 21). The highest dose tested in mice and rats was approximately 130 and 260 times, respectively, 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 (0, 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. 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In carcinogenicity studies in mouse and rat, sumatriptan was administered orally for 78 weeks and 104 weeks, respectively, at doses up to 160 mg/kg/day (the high dose in rat was reduced from 360 mg/kg/day during Week 21). The highest dose tested in mice and rats was approximately 130 and 260 times, respectively, 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 (0, 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.

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.

14 CLINICAL STUDIES Clinical Studies with Sumatriptan Injection 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 Dose in Study 1 Dose of Sumatriptan Injection Percent Patients With Relief Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication Adverse Reactions Incidence (%) at 10 Minutes at 30 Minutes at 1 Hour at 2 Hours 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 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 1-Hour Data Study 2 Study 3 Placebo (n = 190) Sumatriptan 6 mg (n = 384) Placebo (n = 180) Sumatriptan 6 mg (n = 350) Subjects with pain relief (grade 0/1) 18% 70% P<0.05 versus placebo. 26% 70% Subjects with no pain 5% 48% 13% 49% Subjects without nausea 48% 73% 50% 73% Subjects without photophobia 23% 56% 25% 58% Subjects with little or no clinical disability A successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally. 34% 76% 34% 76% 2-Hour Data Study 2 Study 3 Placebo Includes patients that may have received an additional placebo injection 1 hour after the initial injection. Sumatriptan 6 mg Includes patients that may have received an additional 6 mg of sumatriptan injection 1 hour after the initial injection. Placebo Sumatriptan 6 mg Subjects with pain relief (grade 0/1) 31% 81% 39% 82% Subjects with no pain 11% 63% 19% 65% Subjects without nausea 56% 82% 63% 81% Subjects without photophobia 31% 72% 35% 71% Subjects with little or no clinical disability 42% 85% 49% 84% Sumatriptan injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks.

bjects with no pain 11% 63% 19% 65% Subjects without nausea 56% 82% 63% 81% Subjects without photophobia 31% 72% 35% 71% Subjects with little or no clinical disability 42% 85% 49% 84% Sumatriptan injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks. The efficacy of sumatriptan injections was unaffected by whether or not the migraine was associated with aura, duration of attack, gender or age of the subject, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers). Clinical Study with ZEMBRACE SymTouch In a double-blind, randomized, placebo-controlled clinical trial of ZEMBRACE SymTouch, 230 patients with migraine with or without aura received either ZEMBRACE SymTouch (N=111) or placebo (N=119) for a single migraine attack. The patients had a mean age of 41 years (range 18 to 65 years); approximately 76% were White and 85% were female. The study excluded patients with medication overuse headache, treatment with onabotulinumtoxin A within 180 days, and patients with a history of cluster headache. The primary efficacy endpoint was the proportion of patients who were pain-free (defined as a reduction from pre-dose moderate [Grade 2] or severe [Grade 3] pain to none [Grade 0]) 2 hours after the first dose. Of the ZEMBRACE SymTouch-treated patients, 46% were pain free at 2 hours after treatment compared to 27% of the placebo-treated patients.

<table width="100%"><caption>Table 2: Proportion of Patients with Migraine Relief and Incidence of Adverse Reactions by Time and by Sumatriptan Dose in Study 1</caption><col width="17%" valign="top" align="left"/><col width="16%" valign="top" align="center"/><col width="17%" valign="top" align="center"/><col width="17%" valign="top" align="center"/><col width="16%" valign="top" align="center"/><col width="17%" valign="top" align="center"/><thead><tr styleCode="Botrule"><th rowspan="2" styleCode="Lrule Rrule">Dose of Sumatriptan Injection</th><th colspan="4" styleCode="Rrule">Percent Patients With Relief <footnote ID="K2474">Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication</footnote></th><th rowspan="2" styleCode="Rrule">Adverse Reactions Incidence (%) </th></tr><tr><th align="center" styleCode="Rrule">at 10 Minutes</th><th styleCode="Rrule">at 30 Minutes</th><th styleCode="Rrule">at 1 Hour</th><th styleCode="Rrule">at 2 Hours</th></tr></thead><tbody><tr><td styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">5</td><td styleCode="Rrule">15</td><td styleCode="Rrule">24</td><td styleCode="Rrule">21</td><td styleCode="Rrule">55</td></tr><tr><td styleCode="Lrule Rrule">1 mg</td><td styleCode="Rrule">10</td><td styleCode="Rrule">40</td><td styleCode="Rrule">43</td><td styleCode="Rrule">40</td><td styleCode="Rrule">63</td></tr><tr><td styleCode="Lrule Rrule">2 mg</td><td styleCode="Rrule">7</td><td styleCode="Rrule">23</td><td styleCode="Rrule">57</td><td styleCode="Rrule">43</td><td styleCode="Rrule">63</td></tr><tr><td styleCode="Lrule Rrule">3 mg</td><td styleCode="Rrule">17</td><td styleCode="Rrule">47</td><td styleCode="Rrule">57</td><td styleCode="Rrule">60</td><td styleCode="Rrule">77</td></tr><tr><td styleCode="Lrule Rrule">4 mg</td><td styleCode="Rrule">13</td><td styleCode="Rrule">37</td><td styleCode="Rrule">50</td><td styleCode="Rrule">57</td><td styleCode="Rrule">80</td></tr><tr><td styleCode="Lrule Rrule">6 mg</td><td styleCode="Rrule">10</td><td styleCode="Rrule">63</td><td styleCode="Rrule">73</td><td styleCode="Rrule">70</td><td styleCode="Rrule">83</td></tr><tr><td styleCode="Lrule Rrule">8 mg</td><td styleCode="Rrule">23</td><td styleCode="Rrule">57</td><td styleCode="Rrule">80</td><td styleCode="Rrule">83</td><td styleCode="Rrule">93</td></tr></tbody></table>

eCode="Rrule">63</td><td styleCode="Rrule">73</td><td styleCode="Rrule">70</td><td styleCode="Rrule">83</td></tr><tr><td styleCode="Lrule Rrule">8 mg</td><td styleCode="Rrule">23</td><td styleCode="Rrule">57</td><td styleCode="Rrule">80</td><td styleCode="Rrule">83</td><td styleCode="Rrule">93</td></tr></tbody></table> <table width="100%"><caption>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</caption><col width="40%" align="left" valign="top"/><col width="10%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="10%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><tbody><tr styleCode="Botrule"><td align="center" rowspan="2" styleCode="Lrule Rrule">1-Hour Data</td><td colspan="2" styleCode="Rrule">Study 2</td><td colspan="2" styleCode="Rrule">Study 3</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Rrule">Placebo (n = 190) </td><td styleCode="Rrule">Sumatriptan 6 mg (n = 384) </td><td styleCode="Rrule">Placebo (n = 180) </td><td styleCode="Rrule">Sumatriptan 6 mg (n = 350) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Subjects with pain relief (grade 0/1)</td><td styleCode="Rrule">18%</td><td styleCode="Rrule">70% <footnote ID="foot1">P&lt;0.05 versus placebo.

6 mg (n = 384) </td><td styleCode="Rrule">Placebo (n = 180) </td><td styleCode="Rrule">Sumatriptan 6 mg (n = 350) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Subjects with pain relief (grade 0/1)</td><td styleCode="Rrule">18%</td><td styleCode="Rrule">70% <footnote ID="foot1">P&lt;0.05 versus placebo. </footnote></td><td styleCode="Rrule">26%</td><td styleCode="Rrule">70% <footnoteRef IDREF="foot1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Subjects with no pain</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">48% <footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">13%</td><td styleCode="Rrule">49% <footnoteRef IDREF="foot1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Subjects without nausea</td><td styleCode="Rrule">48%</td><td styleCode="Rrule">73% <footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">50%</td><td styleCode="Rrule">73% <footnoteRef IDREF="foot1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Subjects without photophobia</td><td styleCode="Rrule">23%</td><td styleCode="Rrule">56% <footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">25%</td><td styleCode="Rrule">58% <footnoteRef IDREF="foot1"/></td></tr><tr styleCode="Botrule" valign="bottom"><td styleCode="Lrule Rrule">Subjects with little or no clinical disability <footnote ID="foot4">A successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally.</footnote></td><td styleCode="Rrule">34%</td><td styleCode="Rrule">76% <footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">34%</td><td styleCode="Rrule">76% <footnoteRef IDREF="foot1"/></td></tr><tr styleCode="Botrule"><td align="center" rowspan="2" styleCode="Lrule Rrule">2-Hour Data</td><td colspan="2" styleCode="Rrule">Study 2</td><td colspan="2" styleCode="Rrule">Study 3</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Rrule">Placebo <footnote ID="foot2">Includes patients that may have received an additional placebo injection 1 hour after the initial injection.</footnote></td><td styleCode="Rrule">Sumatriptan 6 mg <footnote ID="foot3">Includes patients that may have received an additional 6 mg of sumatriptan injection 1 hour after the initial injection.</footnote></td><td styleCode="Rrule">Placebo <footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">Sumatriptan 6 mg <footnoteRef IDREF="foot3"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Subjects with pain relief (grade 0/1)</td><td styleCode="Rrule">31%</td><td styleCode="Rrule">81% <footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">39%</td><td styleCode="Rrule">82% <footnoteRef IDREF="foot1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Subjects with no pain</td><td styleCode="Rrule">11%</td><td styleCode="Rrule">63% <footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">19%</td><td styleCode="Rrule">65% <footnoteRef IDREF="foot1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Subjects without nausea</td><td styleCode="Rrule">56%</td><td styleCode="Rrule">82% <footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">63%</td><td styleCode="Rrule">81% <footnoteRef IDREF="foot1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Subjects without photophobia</td><td styleCode="Rrule">31%</td><td styleCode="Rrule">72% <footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">35%</td><td styleCode="Rrule">71% <footnoteRef IDREF="foot1"/></td></tr><tr styleCode="Botrule" valign="bottom"><td styleCode="Lrule Rrule">Subjects with little or no clinical disability <footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">42%</td><td styleCode="Rrule">85% <footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">49%</td><td styleCode="Rrule">84% <foot

EF="foot1"/></td></tr><tr styleCode="Botrule" valign="bottom"><td styleCode="Lrule Rrule">Subjects with little or no clinical disability <footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">42%</td><td styleCode="Rrule">85% <footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">49%</td><td styleCode="Rrule">84% <foot noteRef IDREF="foot1"/></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ZEMBRACE ® SymTouch ® 3 mg/0.5 mL Injection contains sumatriptan as the succinate salt and is supplied as a clear, colorless to pale yellow, sterile, nonpyrogenic solution in a prefilled, ready-to-use, single dose, disposable auto-injector unit (NDC # 0245-0809-89). Each carton contains 4 units (NDC # 0245-0809-38) and a Patient Information and Instructions for Use leaflet. 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). Protect from light.

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 ZEMBRACE SymTouch 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 when observing 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) ] . Hypersensitivity Reactions Inform patients that anaphylactic 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) and Warnings and Precautions (5.9) ] . Concomitant Use with Other Triptans or Ergot Medications Inform patients that use of ZEMBRACE SymTouch injection within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methylsergide) 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 ZEMBRACE SymTouch 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 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 ZEMBRACE SymTouch injection may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of ZEMBRACE SymTouch injection. How to Use ZEMBRACE SymTouch Provide patients instruction on the proper use of ZEMBRACE SymTouch injection if they are able to self-administer ZEMBRACE SymTouch injection in medically unsupervised conditions. Inform patients that the needle in the ZEMBRACE SymTouch penetrates approximately ¼ of an inch (6 mm). 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 for UPSHER-SMITH LABORATORIES, LLC Maple Grove, MN 55369 ZEMBRACE and SymTouch are registered trademarks of Upsher-Smith Laboratories, LLC. This product may be covered by one or more U.S. patent(s). See www.uslpatents.com. Revised: 2/2021

Patient Information ZEMBRACE ® SymTouch ® (Zem-brace Sim-Touch) (sumatriptan succinate) Injection This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 2/2021 What is the most important information I should know about ZEMBRACE SymTouch? ZEMBRACE SymTouch can cause serious side effects, including: Heart attack and other heart problems. Heart problems may lead to death. Stop taking ZEMBRACE SymTouch and get emergency medical help right away if you have any of the following symptoms of a heart attack: discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw pain or discomfort in your arms, back, neck, jaw, or stomach shortness of breath with or without chest discomfort breaking out in a cold sweat nausea or vomiting feeling lightheaded ZEMBRACE SymTouch is not for people with risk factors for heart disease unless a heart exam is done and shows no problem. You have a higher risk for heart disease if you: have high blood pressure have high cholesterol levels smoke are overweight have diabetes have a family history of heart disease What is ZEMBRACE SymTouch? ZEMBRACE SymTouch is a prescription medicine used to treat acute migraine headaches with or without aura in adults who have been diagnosed with migraine. ZEMBRACE SymTouch is not used to treat other types of headaches such as hemiplegic (that make you unable to move on one side of your body) or basilar (rare form of migraine with aura) migraines. ZEMBRACE SymTouch is not used to prevent or decrease the number of migraines you have. It is not known if ZEMBRACE SymTouch is safe and effective in children under 18 years of age. Who should not take ZEMBRACE SymTouch? Do not take ZEMBRACE SymTouch if you have: heart problems or a history of heart problems narrowing of blood vessels to your legs, arms, stomach, or kidney (peripheral vascular disease) uncontrolled high blood pressure hemiplegic migraines or basilar migraines. If you are not sure if you have these types of migraines, ask your healthcare provider. had a stroke, transient ischemic attacks (TIAs), or problems with your blood circulation severe liver problems an allergy to sumatriptan or any of the ingredients in ZEMBRACE SymTouch. See the end of this leaflet for a complete list of ingredients in ZEMBRACE SymTouch. taken any of the following medicines in the last 24 hours: almotriptan eletriptan frovatriptan naratriptan rizatriptan ergotamines dihydroergotamine Ask your healthcare provider if you are not sure if your medicine is listed above. What should I tell my healthcare provider before taking ZEMBRACE SymTouch? Before taking ZEMBRACE SymTouch, tell your healthcare provider about all of your medical conditions, including if you: have high blood pressure have high cholesterol have diabetes smoke are overweight have heart problems or family history of heart problems or stroke have kidney problems have liver problems have had epilepsy or seizures are not using effective birth control are pregnant or plan to become pregnant. It is not known if ZEMBRACE SymTouch can harm your unborn baby. are breastfeeding or plan to breastfeed. ZEMBRACE SymTouch passes into your breast milk. It is not known if this can harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take ZEMBRACE SymTouch.

to become pregnant. It is not known if ZEMBRACE SymTouch can harm your unborn baby. are breastfeeding or plan to breastfeed. ZEMBRACE SymTouch passes into your breast milk. It is not known if this can harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take ZEMBRACE SymTouch. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using ZEMBRACE SymTouch with certain other medicines can affect each other, causing serious side effects. Especially tell your healthcare provider if you take anti-depressant medicines called: selective serotonin reuptake inhibitors (SSRIs) serotonin norepinephrine reuptake inhibitors (SNRIs) tricyclic antidepressants (TCAs) monoamine oxidase inhibitors (MAOIs) Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine. How should I take ZEMBRACE SymTouch? Certain people should take their first dose of ZEMBRACE SymTouch in their healthcare provider's office or in another medical setting. Ask your healthcare provider if you should take your first dose in a medical setting. Use ZEMBRACE SymTouch exactly as your healthcare provider tells you to use it. Your healthcare provider may change your dose. Do not change your dose without first talking with your healthcare provider. For adults, the usual dose is a single injection given just below the skin. You should give an injection as soon as the symptoms of your headache start, but it may be given at any time during a migraine headache attack. If you did not get any relief after the first injection, do not give a second injection without first talking with your healthcare provider. You may use a second dose of ZEMBRACE SymTouch after the first dose of ZEMBRACE SymTouch OR after one dose of another sumatriptan medication separated by at least 1 hour, but not sooner, if your headache comes back or you only get some relief after your first injection. Do not take more than a total of 12 mg of ZEMBRACE SymTouch in a 24-hour period. Talk to your doctor about how many ZEMBRACE SymTouch you can take in a 24-hour period if you take another form of sumatriptan medication in between ZEMBRACE SymTouch. If you use too much ZEMBRACE SymTouch, call your healthcare provider or go to the nearest hospital emergency room right away. You should write down when you have headaches and when you take ZEMBRACE SymTouch so you can talk with your healthcare provider about how ZEMBRACE SymTouch is working for you. What should I avoid while taking ZEMBRACE SymTouch? ZEMBRACE SymTouch can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not drive a car, use machinery, or do anything where you need to be alert. What are the possible side effects of ZEMBRACE SymTouch? See " What is the most important information I should know about ZEMBRACE SymTouch? " ZEMBRACE SymTouch may cause serious side effects, including: changes in color or sensation in your fingers and toes (Raynaud's syndrome) stomach and intestinal problems (gastrointestinal and colonic ischemic events). Symptoms of gastrointestinal and colonic ischemic events include: sudden or severe stomach pain stomach pain after meals weight loss nausea or vomiting constipation or diarrhea bloody diarrhea fever problems with blood circulation to your legs and feet (peripheral vascular ischemia).

tinal and colonic ischemic events). Symptoms of gastrointestinal and colonic ischemic events include: sudden or severe stomach pain stomach pain after meals weight loss nausea or vomiting constipation or diarrhea bloody diarrhea fever problems with blood circulation to your legs and feet (peripheral vascular ischemia). Symptoms of peripheral vascular ischemia include: cramping and pain in your legs or hips feeling of heaviness or tightness in your leg muscles burning or aching pain in your feet or toes while resting numbness, tingling, or weakness in your legs cold feeling or color changes in 1 or both legs or feet hives (itchy bumps); swelling of your tongue, mouth, or throat. medication overuse headaches. Some people who use too many ZEMBRACE SymTouch injections may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with ZEMBRACE SymTouch. serotonin syndrome . Serotonin syndrome is a rare but serious problem that can happen in people using ZEMBRACE SymTouch, especially if ZEMBRACE SymTouch is used with anti-depressant medicines called SSRIs or SNRIs. Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome: mental changes such as seeing things that are not there (hallucinations), agitation, or coma fast heartbeat changes in blood pressure high body temperature tight muscles trouble walking seizures . Seizures have happened in people taking ZEMBRACE SymTouch who have never had seizures before. Talk with your healthcare provider about your chance of having seizures while you take ZEMBRACE SymTouch. The most common side effects of ZEMBRACE SymTouch include: pain or redness at your injection site tingling or numbness in your fingers or toes dizziness warm, hot, burning feeling to your face (flushing) discomfort or stiffness in your neck feeling weak, drowsy, or tired Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of ZEMBRACE SymTouch. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ZEMBRACE SymTouch? Store between 68° to 77°F (20° to 25°C) Store your medicine away from light. Keep your medicine in the packaging or carrying case provided with it. Keep ZEMBRACE SymTouch and all medicines out of the reach of children. General information about the safe and effective use of ZEMBRACE SymTouch. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use ZEMBRACE SymTouch for a condition for which it was not prescribed. Do not give ZEMBRACE SymTouch to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about ZEMBRACE SymTouch. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ZEMBRACE SymTouch that is written for healthcare professionals. For more information, go to www.upsher-smith.com or call 1-888-650-3789. What are the ingredients in ZEMBRACE SymTouch Injection? Active ingredient: sumatriptan succinate Inactive ingredients: sodium chloride, water for injection Manufactured for UPSHER-SMITH LABORATORIES, LLC Maple Grove, MN 55369 ZEMBRACE and SymTouch are registered trademarks of Upsher-Smith Laboratories, LLC. This product may be covered by one or more U.S. patent(s). See www.uslpatents.com.

<table width="100%"><col width="70%" align="left" valign="top"/><col width="30%" align="right" valign="top"/><thead><tr><th align="center" colspan="2" styleCode="Lrule Rrule">Patient Information ZEMBRACE ^&#xAE;SymTouch ^&#xAE; (Zem-brace Sim-Touch) (sumatriptan succinate) Injection </th></tr></thead><tfoot><tr><td align="left">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align="right">Revised: 2/2021</td></tr></tfoot><tbody><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">What is the most important information I should know about ZEMBRACE SymTouch?</content></td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">ZEMBRACE SymTouch can cause serious side effects, including: Heart attack and other heart problems. Heart problems may lead to death. </content></td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Stop taking ZEMBRACE SymTouch and get emergency medical help right away if you have any of the following symptoms of a heart attack:</content></td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><list listType="unordered" styleCode="Disc"><item>discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back</item><item>severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw</item><item>pain or discomfort in your arms, back, neck, jaw, or stomach</item><item>shortness of breath with or without chest discomfort</item><item>breaking out in a cold sweat</item><item>nausea or vomiting</item><item>feeling lightheaded</item></list></td></tr><tr><td colspan="2" styleCode="Lrule Rrule">ZEMBRACE SymTouch is not for people with risk factors for heart disease unless a heart exam is done and shows no problem.

or without chest discomfort</item><item>breaking out in a cold sweat</item><item>nausea or vomiting</item><item>feeling lightheaded</item></list></td></tr><tr><td colspan="2" styleCode="Lrule Rrule">ZEMBRACE SymTouch is not for people with risk factors for heart disease unless a heart exam is done and shows no problem. You have a higher risk for heart disease if you:</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><list listType="unordered" styleCode="Disc"><item>have high blood pressure</item><item>have high cholesterol levels</item><item>smoke</item><item>are overweight</item><item>have diabetes</item><item>have a family history of heart disease</item></list></td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">What is ZEMBRACE SymTouch?</content></td></tr><tr><td colspan="2" styleCode="Lrule Rrule">ZEMBRACE SymTouch is a prescription medicine used to treat acute migraine headaches with or without aura in adults who have been diagnosed with migraine.</td></tr><tr><td colspan="2" styleCode="Lrule Rrule">ZEMBRACE SymTouch is not used to treat other types of headaches such as hemiplegic (that make you unable to move on one side of your body) or basilar (rare form of migraine with aura) migraines.</td></tr><tr><td colspan="2" styleCode="Lrule Rrule">ZEMBRACE SymTouch is not used to prevent or decrease the number of migraines you have.</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule">It is not known if ZEMBRACE SymTouch is safe and effective in children under 18 years of age.</td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Who should not take ZEMBRACE SymTouch?</content></td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Do not take ZEMBRACE SymTouch if you have:</content></td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><list listType="unordered" styleCode="Disc"><item>heart problems or a history of heart problems</item><item>narrowing of blood vessels to your legs, arms, stomach, or kidney (peripheral vascular disease)</item><item>uncontrolled high blood pressure</item><item>hemiplegic migraines or basilar migraines. If you are not sure if you have these types of migraines, ask your healthcare provider.</item><item>had a stroke, transient ischemic attacks (TIAs), or problems with your blood circulation</item><item>severe liver problems</item><item>an allergy to sumatriptan or any of the ingredients in ZEMBRACE SymTouch.

migraines. If you are not sure if you have these types of migraines, ask your healthcare provider.</item><item>had a stroke, transient ischemic attacks (TIAs), or problems with your blood circulation</item><item>severe liver problems</item><item>an allergy to sumatriptan or any of the ingredients in ZEMBRACE SymTouch. See the end of this leaflet for a complete list of ingredients in ZEMBRACE SymTouch.</item><item>taken any of the following medicines in the last 24 hours: <list listType="unordered" styleCode="Disc"><item>almotriptan</item><item>eletriptan</item><item>frovatriptan</item><item>naratriptan</item><item>rizatriptan</item><item>ergotamines</item><item>dihydroergotamine</item></list></item></list></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule">Ask your healthcare provider if you are not sure if your medicine is listed above.</td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">What should I tell my healthcare provider before taking ZEMBRACE SymTouch?</content></td></tr><tr><td colspan="2" styleCode="Lrule Rrule">Before taking ZEMBRACE SymTouch, tell your healthcare provider about all of your medical conditions, including if you:</td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><list listType="unordered" styleCode="Disc"><item>have high blood pressure</item><item>have high cholesterol</item><item>have diabetes</item><item>smoke</item><item>are overweight</item><item>have heart problems or family history of heart problems or stroke</item><item>have kidney problems</item><item>have liver problems</item><item>have had epilepsy or seizures</item><item>are not using effective birth control</item><item>are pregnant or plan to become pregnant. It is not known if ZEMBRACE SymTouch can harm your unborn baby.</item><item>are breastfeeding or plan to breastfeed. ZEMBRACE SymTouch passes into your breast milk. It is not known if this can harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take ZEMBRACE SymTouch.</item></list></td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Tell your healthcare provider about all the medicines you take,</content>including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using ZEMBRACE SymTouch with certain other medicines can affect each other, causing serious side effects. </td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Especially tell your healthcare provider if</content>you take anti-depressant medicines called: </td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><list listType="unordered" styleCode="Disc"><item>selective serotonin reuptake inhibitors (SSRIs)</item><item>serotonin norepinephrine reuptake inhibitors (SNRIs)</item><item>tricyclic antidepressants (TCAs)</item><item>monoamine oxidase inhibitors (MAOIs)</item></list></td></tr><tr><td colspan="2" styleCode="Lrule Rrule">Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule">Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.</td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">How should I take ZEMBRACE SymTouch?</content></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><list listType="unordered" styleCode="Disc"><item>Certain people should take their first dose of ZEMBRACE SymTouch in their healthcare provider&apos;s office or in another medical setting.

Code="bold">How should I take ZEMBRACE SymTouch?</content></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><list listType="unordered" styleCode="Disc"><item>Certain people should take their first dose of ZEMBRACE SymTouch in their healthcare provider&apos;s office or in another medical setting. Ask your healthcare provider if you should take your first dose in a medical setting.</item><item>Use ZEMBRACE SymTouch exactly as your healthcare provider tells you to use it.</item><item>Your healthcare provider may change your dose. Do not change your dose without first talking with your healthcare provider.</item><item>For adults, the usual dose is a single injection given just below the skin.</item><item>You should give an injection as soon as the symptoms of your headache start, but it may be given at any time during a migraine headache attack.</item><item>If you did not get any relief after the first injection, do not give a second injection without first talking with your healthcare provider.</item><item>You may use a second dose of ZEMBRACE SymTouch after the first dose of ZEMBRACE SymTouch OR after one dose of another sumatriptan medication separated by at least 1 hour, but not sooner, if your headache comes back or you only get some relief after your first injection.</item><item>Do not take more than a total of 12 mg of ZEMBRACE SymTouch in a 24-hour period. Talk to your doctor about how many ZEMBRACE SymTouch you can take in a 24-hour period if you take another form of sumatriptan medication in between ZEMBRACE SymTouch.</item><item>If you use too much ZEMBRACE SymTouch, call your healthcare provider or go to the nearest hospital emergency room right away.</item><item>You should write down when you have headaches and when you take ZEMBRACE SymTouch so you can talk with your healthcare provider about how ZEMBRACE SymTouch is working for you.</item></list></td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">What should I avoid while taking ZEMBRACE SymTouch?</content></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule">ZEMBRACE SymTouch can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not drive a car, use machinery, or do anything where you need to be alert.</td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">What are the possible side effects of ZEMBRACE SymTouch?</content></td></tr><tr><td colspan="2" styleCode="Lrule Rrule">See &quot; <linkHtml href="#important">What is the most important information I should know about ZEMBRACE SymTouch?</linkHtml>&quot; </td></tr><tr><td colspan="2" styleCode="Lrule Rrule">ZEMBRACE SymTouch may cause serious side effects, including:</td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">changes in color or sensation in your fingers and toes (Raynaud&apos;s syndrome)</content></item><item><content styleCode="bold">stomach and intestinal problems</content>(gastrointestinal and colonic ischemic events).

2" styleCode="Lrule Rrule"><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">changes in color or sensation in your fingers and toes (Raynaud&apos;s syndrome)</content></item><item><content styleCode="bold">stomach and intestinal problems</content>(gastrointestinal and colonic ischemic events). Symptoms of gastrointestinal and colonic ischemic events include: <list listType="unordered" styleCode="Disc"><item>sudden or severe stomach pain</item><item>stomach pain after meals</item><item>weight loss</item><item>nausea or vomiting</item><item>constipation or diarrhea</item><item>bloody diarrhea</item><item>fever</item></list></item><item><content styleCode="bold">problems with blood circulation to your legs and feet (peripheral vascular ischemia).</content>Symptoms of peripheral vascular ischemia include: <list listType="unordered" styleCode="Disc"><item>cramping and pain in your legs or hips</item><item>feeling of heaviness or tightness in your leg muscles</item><item>burning or aching pain in your feet or toes while resting</item><item>numbness, tingling, or weakness in your legs</item><item>cold feeling or color changes in 1 or both legs or feet</item></list></item><item><content styleCode="bold">hives (itchy bumps); swelling of your tongue, mouth, or throat.</content></item><item><content styleCode="bold">medication overuse headaches.</content>Some people who use too many ZEMBRACE SymTouch injections may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with ZEMBRACE SymTouch. </item><item><content styleCode="bold">serotonin syndrome</content>. Serotonin syndrome is a rare but serious problem that can happen in people using ZEMBRACE SymTouch, especially if ZEMBRACE SymTouch is used with anti-depressant medicines called SSRIs or SNRIs. Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome: <list listType="unordered" styleCode="Disc"><item>mental changes such as seeing things that are not there (hallucinations), agitation, or coma</item><item>fast heartbeat</item><item>changes in blood pressure</item><item>high body temperature</item><item>tight muscles</item><item>trouble walking</item></list></item><item><content styleCode="bold">seizures</content>. Seizures have happened in people taking ZEMBRACE SymTouch who have never had seizures before. Talk with your healthcare provider about your chance of having seizures while you take ZEMBRACE SymTouch. </item></list></td></tr><tr><td colspan="2" styleCode="Lrule Rrule">The most common side effects of ZEMBRACE SymTouch include:</td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><list listType="unordered" styleCode="Disc"><item>pain or redness at your injection site</item><item>tingling or numbness in your fingers or toes</item><item>dizziness</item><item>warm, hot, burning feeling to your face (flushing)</item><item>discomfort or stiffness in your neck</item><item>feeling weak, drowsy, or tired</item></list></td></tr><tr><td colspan="2" styleCode="Lrule Rrule">Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule">These are not all the possible side effects of ZEMBRACE SymTouch. Call your doctor for medical advice about side effects.

styleCode="Lrule Rrule">Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule">These are not all the possible side effects of ZEMBRACE SymTouch. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">How should I store ZEMBRACE SymTouch?</content></td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><list listType="unordered" styleCode="Disc"><item>Store between 68&#xB0; to 77&#xB0;F (20&#xB0; to 25&#xB0;C)</item><item>Store your medicine away from light.</item><item>Keep your medicine in the packaging or carrying case provided with it.</item></list></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">Keep ZEMBRACE SymTouch and all medicines out of the reach of children.</content></td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">General information about the safe and effective use of ZEMBRACE SymTouch.</content></td></tr><tr><td colspan="2" styleCode="Lrule Rrule">Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use ZEMBRACE SymTouch for a condition for which it was not prescribed. Do not give ZEMBRACE SymTouch to other people, even if they have the same symptoms you have. It may harm them.</td></tr><tr><td colspan="2" styleCode="Lrule Rrule">This Patient Information leaflet summarizes the most important information about ZEMBRACE SymTouch. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ZEMBRACE SymTouch that is written for healthcare professionals.</td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule">For more information, go to www.upsher-smith.com or call 1-888-650-3789.</td></tr><tr><td colspan="2" styleCode="Lrule Rrule"><content styleCode="bold">What are the ingredients in ZEMBRACE SymTouch Injection?</content></td></tr><tr><td colspan="2" styleCode="Lrule Rrule">Active ingredient: sumatriptan succinate Inactive ingredients: sodium chloride, water for injection </td></tr><tr><td colspan="2" styleCode="Lrule Rrule">Manufactured for <content styleCode="bold">UPSHER-SMITH LABORATORIES, LLC</content> Maple Grove, MN 55369 </td></tr><tr><td colspan="2" styleCode="Lrule Rrule">ZEMBRACE and SymTouch are registered trademarks of Upsher-Smith Laboratories, LLC.</td></tr><tr><td colspan="2" styleCode="Lrule Rrule">This product may be covered by one or more U.S. patent(s). See www.uslpatents.com.</td></tr></tbody></table>

Instructions for Use ZEMBRACE ® SymTouch ® (Zem-brace Sim-Touch) (sumatriptan succinate) Injection This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 2/2021 Read this Instructions for Use before you start to use the ZEMBRACE ® SymTouch ® . There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about ZEMBRACE SymTouch when you start taking it and at regular checkups. The ZEMBRACE SymTouch Auto-injector is a single-use, pre-filled injection device with the exact dose you need. The device should be used only 1 time and then discarded. Important Precautions Keep out of reach of children. Do not use after the expiration date has passed. Do not store or expose to high temperatures. Do not freeze. Do not remove the Red Cap until you are ready to inject. Do not use if dropped after removing the Red Cap. Do not put or press thumb, fingers or hand over the Yellow Needle Guard. Step 1 – Inspect Auto-injector and Gather Supplies 1A – Remove Auto-injector from the carton 1B – Check the Expiration Date on the Auto-injector Do not use if the expiration date has passed. 1C – Inspect the medicine through the Medicine Viewing Window Inspect the appearance of ZEMBRACE SymTouch Auto-injector medicine through the medicine window. It must be a clear, colorless to pale yellow solution. Do not inject the medicine if the solution looks discolored or cloudy or contains lumps, flakes, or particles. 1D – Gather the following supplies Auto-injector Alcohol Swab Sterile Cotton Ball or Gauze Puncture-Resistant Sharps Container Step 2 – Choose and Prepare Your Injection Site 2A – Choose your injection site The recommended injection sites are the sides of the thighs and the arms. Caution : Do not inject where your skin is scarred, bruised, tender, red or near any open wound. 2B – Clean the injection site with an alcohol swab Do not touch injection site area after cleaning. 2C – Remove the Red Cap Hold the body of the Auto-injector in one hand and pull the Red Cap straight off. Warning: Do not put or press thumb, fingers or hand over the Yellow Needle Guard, doing so may result in a needle stick injury Step 3 – Inject the Medicine 3A – Place Auto-injector straight on your injection site Place the Auto-injector straight on your injection site (90 degrees) with the Yellow Needle Guard end gently pressed against your skin. 3B – Perform Injection Press and hold the Auto-injector down against your skin. You will hear the first "Click 1" as the injection starts. Continue to hold the device down until you hear the second "Click 2." Wait 5 seconds before you remove the Auto-injector! After "Click 2," continue to hold down and slowly count to 5 to make sure you receive your full dose. Important : To receive your full dose, always hold the Auto-injector down on your injection site for additional time after you hear the second click. This allows all of the medicine to be delivered. 3C – Remove Auto-injector from skin Remove the Auto-injector by lifting it straight away from your skin. The Yellow Needle Guard will drop down and lock over the needle. Step 4 – Confirm Injection and Dispose the Auto-injector 4A – Confirm Red Color in Medicine Viewing Window Look to confirm that the Red Plunger Rod has filled the Medicine Viewing Window. This means you received the full dose.

traight away from your skin. The Yellow Needle Guard will drop down and lock over the needle. Step 4 – Confirm Injection and Dispose the Auto-injector 4A – Confirm Red Color in Medicine Viewing Window Look to confirm that the Red Plunger Rod has filled the Medicine Viewing Window. This means you received the full dose. Caution : Call your healthcare provider if the Red Plunger Rod has not filled the Medicine Viewing Window. This may mean that only a partial dose was delivered. Do not try to reuse the Auto-injector. 4B – Disposal of the Auto-injector Put your used Auto-injector, caps, needles, and sharps in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. Do not recycle your used sharps disposal container. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic; can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out; upright and stable during use; leak-resistant; and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. If needed, make sure you get a refill of your Auto-injector. 4C – Treat Injection Site Treat the injection site with a cotton ball, gauze pad or bandage, as needed. Do not rub the injection site. Manufactured for UPSHER-SMITH LABORATORIES, LLC Maple Grove, MN 55369 ZEMBRACE and SymTouch are registered trademarks of Upsher-Smith Laboratories, LLC. This product may be covered by one or more U.S. patent(s). See www.uslpatents.com. Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

<table width="100%"><col width="25%" align="left" valign="top"/><col width="25%" align="left" valign="top"/><col width="35%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><thead><tr><th colspan="4" align="center" styleCode="Lrule Rrule">Instructions for Use ZEMBRACE ^&#xAE;SymTouch ^&#xAE; (Zem-brace Sim-Touch) (sumatriptan succinate) Injection </th></tr></thead><tfoot><tr><td colspan="3" align="left">This Instructions for Use has been approved by the U.S. Food and Drug Administration.</td><td align="right">Revised: 2/2021</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule">Read this Instructions for Use before you start to use the ZEMBRACE ^&#xAE;SymTouch ^&#xAE;. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about ZEMBRACE SymTouch when you start taking it and at regular checkups. The ZEMBRACE SymTouch Auto-injector is a single-use, pre-filled injection device with the exact dose you need. The device should be used only 1 time and then discarded. </td><td><paragraph><renderMultiMedia referencedObject="MM2"/><content styleCode="bold"><content styleCode="underline">Important Precautions</content></content> Keep out of reach of children. <content styleCode="bold">Do not</content>use after the expiration date has passed. <content styleCode="bold">Do not</content>store or expose to high temperatures. <content styleCode="bold">Do not</content>freeze. <content styleCode="bold">Do not</content>remove the Red Cap until you are ready to inject. <content styleCode="bold">Do not</content>use if dropped after removing the Red Cap. <content styleCode="bold">Do not</content>put or press thumb, fingers or hand over the Yellow Needle Guard. </paragraph></td><td colspan="2" styleCode="Rrule"><renderMultiMedia referencedObject="MM3"/></td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Step 1 &#x2013; Inspect Auto-injector and Gather Supplies</content></td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">1A &#x2013; Remove Auto-injector from the carton</content></td></tr><tr><td colspan="2" styleCode="Lrule"><content styleCode="bold">1B &#x2013; Check the Expiration Date on the Auto-injector</content></td><td colspan="2" styleCode="Rrule"><renderMultiMedia referencedObject="MM4"/></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule"/><td colspan="2" styleCode="Rrule"><content styleCode="bold">Do not</content>use if the expiration date has passed. </td></tr><tr><td colspan="2" styleCode="Lrule"><content styleCode="bold">1C &#x2013; Inspect the medicine through the Medicine Viewing Window</content> Inspect the appearance of ZEMBRACE SymTouch Auto-injector medicine through the medicine window. It must be a clear, colorless to pale yellow solution. </td><td colspan="2" styleCode="Rrule"><renderMultiMedia referencedObject="MM5"/></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule"/><td align="left" colspan="2" styleCode="Rrule"><content styleCode="bold">Do not</content>inject the medicine if the solution looks discolored or cloudy or contains lumps, flakes, or particles.

tyleCode="Rrule"><renderMultiMedia referencedObject="MM5"/></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule"/><td align="left" colspan="2" styleCode="Rrule"><content styleCode="bold">Do not</content>inject the medicine if the solution looks discolored or cloudy or contains lumps, flakes, or particles. </td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule"><content styleCode="bold">1D &#x2013; Gather the following supplies</content> <list listType="ordered" styleCode="Arabic"><item>Auto-injector</item><item>Alcohol Swab</item><item>Sterile Cotton Ball or Gauze</item><item>Puncture-Resistant Sharps Container</item></list></td><td colspan="2" styleCode="Rrule"><renderMultiMedia referencedObject="MM6"/></td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Step 2 &#x2013; Choose and Prepare Your Injection Site</content></td></tr><tr><td colspan="2" styleCode="Lrule"><content styleCode="bold">2A &#x2013; Choose your injection site</content> The recommended injection sites are the sides of the thighs and the arms. </td><td colspan="2" styleCode="Rrule"><renderMultiMedia referencedObject="MM7"/></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule"/><td align="left" colspan="2" styleCode="Rrule"><content styleCode="bold"><content styleCode="underline">Caution</content>: Do not </content>inject where your skin is scarred, bruised, tender, red or near any open wound. </td></tr><tr><td colspan="2" styleCode="Lrule"><content styleCode="bold">2B &#x2013; Clean the injection site with an alcohol swab</content></td><td colspan="2" styleCode="Rrule"><renderMultiMedia referencedObject="MM8"/></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule"/><td colspan="2" styleCode="Rrule"><content styleCode="bold">Do not</content>touch injection site area after cleaning. </td></tr><tr><td colspan="2" styleCode="Lrule"><content styleCode="bold">2C &#x2013; Remove the Red Cap</content> Hold the body of the Auto-injector in one hand and pull the Red Cap straight off. </td><td colspan="2" styleCode="Rrule"><renderMultiMedia referencedObject="MM9"/></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule"/><td align="left" colspan="2" styleCode="Rrule"><content styleCode="bold">Warning: Do not</content>put or press thumb, fingers or hand over the Yellow Needle Guard, doing so may result in a needle stick injury </td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Step 3 &#x2013; Inject the Medicine</content></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule"><content styleCode="bold">3A &#x2013; Place Auto-injector straight on your injection site</content> Place the Auto-injector straight on your injection site (90 degrees) with the Yellow Needle Guard end gently pressed against your skin. </td><td colspan="2" styleCode="Rrule"><renderMultiMedia referencedObject="MM10"/></td></tr><tr><td colspan="2" styleCode="Lrule"><content styleCode="bold">3B &#x2013; Perform Injection</content> Press and hold the Auto-injector down against your skin. You will hear the first &quot;Click 1&quot; as the injection starts. Continue to hold the device down until you hear the second &quot;Click 2.&quot; Wait 5 seconds before you remove the Auto-injector! After &quot;Click 2,&quot; continue to hold down and slowly count to 5 to make sure you receive your full dose.

r skin. You will hear the first &quot;Click 1&quot; as the injection starts. Continue to hold the device down until you hear the second &quot;Click 2.&quot; Wait 5 seconds before you remove the Auto-injector! After &quot;Click 2,&quot; continue to hold down and slowly count to 5 to make sure you receive your full dose. </td><td colspan="2" styleCode="Rrule"><renderMultiMedia referencedObject="MM11"/></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule"/><td align="left" colspan="2" styleCode="Rrule"><content styleCode="bold"><content styleCode="underline">Important</content>: To receive your full dose, always hold the Auto-injector down on your injection site for additional time after you hear the second click. This allows all of the medicine to be delivered. </content></td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule"><content styleCode="bold">3C &#x2013; Remove Auto-injector from skin</content> Remove the Auto-injector by lifting it straight away from your skin. The Yellow Needle Guard will drop down and lock over the needle. </td><td colspan="2" styleCode="Rrule"><renderMultiMedia referencedObject="MM12"/></td></tr><tr styleCode="Botrule"><td colspan="4" styleCode="Lrule Rrule"><content styleCode="bold">Step 4 &#x2013; Confirm Injection and Dispose the Auto-injector</content></td></tr><tr><td colspan="2" styleCode="Lrule"><content styleCode="bold">4A &#x2013; Confirm Red Color in Medicine Viewing Window</content> Look to confirm that the Red Plunger Rod has filled the Medicine Viewing Window. This means you received the full dose. </td><td colspan="2" styleCode="Rrule"><renderMultiMedia referencedObject="MM13"/></td></tr><tr><td colspan="2" styleCode="Lrule"/><td align="left" colspan="2" styleCode="Rrule"><content styleCode="bold"><content styleCode="underline">Caution</content></content>: Call your healthcare provider if the Red Plunger Rod has not filled the Medicine Viewing Window. This may mean that only a partial dose was delivered. </td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule"/><td align="left" colspan="2" styleCode="Rrule"><content styleCode="bold">Do not</content>try to reuse the Auto-injector. </td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule"><content styleCode="bold">4B &#x2013; Disposal of the Auto-injector</content> Put your used Auto-injector, caps, needles, and sharps in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. Do not recycle your used sharps disposal container. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic; can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out; upright and stable during use; leak-resistant; and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA&apos;s website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. If needed, make sure you get a refill of your Auto-injector.

ou live in, go to the FDA&apos;s website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. If needed, make sure you get a refill of your Auto-injector. </td><td colspan="2" styleCode="Rrule"><renderMultiMedia referencedObject="MM14"/></td></tr><tr><td colspan="2" styleCode="Lrule"><content styleCode="bold">4C &#x2013; Treat Injection Site</content></td><td colspan="2" styleCode="Rrule"/></tr><tr><td colspan="2" styleCode="Lrule">Treat the injection site with a cotton ball, gauze pad or bandage, as needed.</td><td colspan="2" styleCode="Rrule"/></tr><tr><td colspan="2" styleCode="Lrule"><content styleCode="bold">Do not</content>rub the injection site. </td><td colspan="2" styleCode="Rrule"/></tr><tr><td colspan="2" styleCode="Lrule">Manufactured for <content styleCode="bold">UPSHER-SMITH LABORATORIES, LLC</content> Maple Grove, MN 55369 </td><td colspan="2" styleCode="Rrule"/></tr><tr><td colspan="2" styleCode="Lrule">ZEMBRACE and SymTouch are registered trademarks of Upsher-Smith Laboratories, LLC.</td><td colspan="2" styleCode="Rrule"/></tr><tr><td colspan="2" styleCode="Lrule">This product may be covered by one or more U.S. patent(s). See www.uslpatents.com.</td><td colspan="2" styleCode="Rrule"/></tr></tbody></table>

1 INDICATIONS AND USAGE ONZETRA ® Xsail ® is indicated for the acute treatment of migraine with or without aura in adults. ONZETRA Xsail is a serotonin 5-HT 1B/1D receptor agonist (triptan) indicated for the 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 ) Limitations of Use Use only if a clear diagnosis of migraine has been established. If a patient has no response to the first migraine attack treated with ONZETRA Xsail, reconsider the diagnosis of migraine before treatment of subsequent attacks with ONZETRA Xsail. ONZETRA Xsail is not indicated for the prevention of migraine attacks. Safety and effectiveness of ONZETRA Xsail have not been established for the treatment of cluster headache.

2 DOSAGE AND ADMINISTRATION Recommended dose: 22 mg, administered by use of one nosepiece (11 mg) in each nostril ( 2.1 ) Maximum dose in a 24-hour period should not exceed two doses (44 mg) separated by at least 2 hours ( 2.1 ) 2.1 Dosing Information The recommended dosage of ONZETRA is 22 mg of sumatriptan nasal powder (2 nosepieces), administered using the Xsail breath-powered delivery device. If the migraine has not resolved by 2 hours after taking ONZETRA Xsail, or returns after a transient improvement, a second dose of 22 mg may be administered at least 2 hours after the first dose. The maximum recommended dose that may be given in 24 hours is two doses of ONZETRA Xsail (44 mg/4 nosepieces) or one dose of ONZETRA Xsail and one dose of another sumatriptan product, separated by at least 2 hours. The safety of treating an average of more than 4 headaches in a 30 day period has not been established. 2.2 Administration Instructions The recommended dose of 22 mg is administered by using one 11 mg nosepiece in each nostril [see Patient Counseling Information (17) ] . For administration of ONZETRA Xsail, the patient removes the clear device cap from the reusable delivery device, then removes a disposable nosepiece from its foil pouch and clicks the nosepiece into the device body. The patient then fully presses and promptly releases the white piercing button on the device body to pierce the capsule inside the nosepiece. The white piercing button should only be pressed once and released prior to administration to each nostril. The nosepiece is then inserted into the nostril so that it makes a tight seal. Keeping the nosepiece in the nose, the device is rotated to place the mouthpiece into the mouth. The patient blows forcefully through the mouthpiece to deliver the sumatriptan powder into the nasal cavity. Vibration (e.g., a rattling noise) may occur, and indicates that the patient is blowing forcefully, as directed. Once the medication in the first nosepiece has been administered, the patient removes and discards the nosepiece. The same process must then be repeated using a second 11 mg nosepiece into the other nostril to administer the remainder of the total recommended 22 mg dose [see Patient Counseling Information (17) ] .

3 DOSAGE FORMS AND STRENGTHS ONZETRA Xsail is supplied as a disposable nosepiece containing a capsule and a reusable delivery device body. Each capsule contains 11 mg sumatriptan base (equivalent to 15.4 mg of sumatriptan succinate nasal powder) in a clear, hypromellose capsule with 825 printed on one side. Capsule in disposable nosepiece: 11 mg sumatriptan as the succinate salt. For use with the Xsail breath-powered delivery device only.

4 CONTRAINDICATIONS ONZETRA Xsail is contraindicated in patients with: Ischemic coronary artery disease (CAD) (e.g., angina pectoris, history of myocardial infarction, or silent ischemia) or coronary artery vasospasm, including Prinzmetal's angina or in patients with other significant underlying cardiovascular diseases [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 and 7.3) ]. Concurrent administration of an MAO-A inhibitor or recent use (within 2 weeks) 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 (5.9) ]. Severe hepatic impairment [see Clinical Pharmacology (12.3) ] History of coronary artery disease (CAD) or coronary 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 )

5 WARNINGS AND PRECAUTIONS Myocardial ischemia/infarction and Prinzmetal's angina : Perform cardiac evaluation in patients with multiple cardiovascular risk factors ( 5.1 ) Arrhythmias : Discontinue ONZETRA Xsail if occurs ( 5.2 ) Chest/throat/neck/jaw pain, tightness, pressure, or heaviness : Generally not myocardial ischemia; evaluate high risk patients for CAD ( 5.3 ) Cerebral hemorrhage, subarachnoid hemorrhage, and stroke : Discontinue ONZETRA Xsail if occurs ( 5.4 ) Gastrointestinal ischemia and infarction events, peripheral vasospastic reactions : Discontinue ONZETRA Xsail if occurs ( 5.5 ) Medication overuse headache : Detoxification may be necessary ( 5.6 ) Serotonin syndrome : Discontinue ONZETRA Xsail if occurs ( 5.7 ) Seizures : Use with caution in patients with epilepsy or a lowered seizure threshold ( 5.10 ) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina The use of ONZETRA Xsail is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of sumatriptan. Some of these reactions occurred in patients without known CAD. 5-HT 1 agonists, including ONZETRA Xsail, may cause coronary artery vasospasm (Prinzmetal's angina), even in patients without a history of CAD. Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving ONZETRA Xsail. If there is evidence of CAD or coronary artery vasospasm, ONZETRA Xsail is contraindicated . For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of ONZETRA Xsail in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of ONZETRA Xsail. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of ONZETRA Xsail. 5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT 1 agonists. Discontinue ONZETRA Xsail if these disturbances occur. ONZETRA Xsail is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders . 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure Sensations of tightness, pain, pressure, and heaviness in the chest, throat, neck, and jaw commonly occur after treatment with 5-HT 1 agonists including other products containing sumatriptan and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of ONZETRA Xsail is contraindicated in patients with known CAD and those with Prinzmetal's variant angina. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have occurred in patients treated with 5-HT 1 agonists including other products containing sumatriptan, and some have resulted in fatalities.

ients with known CAD and those with Prinzmetal's variant angina. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have occurred in patients treated with 5-HT 1 agonists including other products containing sumatriptan, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). ONZETRA Xsail is contraindicated in patients with a history of stroke or TIA. Discontinue ONZETRA Xsail if a cerebrovascular event occurs. Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, exclude other potentially serious neurological conditions. 5.5 Other Vasospasm Reactions 5-HT 1 agonists, including ONZETRA Xsail, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of a non-coronary vasospastic reaction following the use of any 5-HT 1 agonist, rule out a vasospastic reaction before using ONZETRA Xsail . Transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists including sumatriptan. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists have not been clearly established. 5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, nonsteroidal anti-inflammatory drugs or combinations of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. 5.7 Serotonin Syndrome Serotonin syndrome may occur with triptans, including ONZETRA Xsail, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.4) ] . Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue ONZETRA Xsail if serotonin syndrome is suspected. 5.8 Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT 1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with ONZETRA Xsail. ONZETRA Xsail is contraindicated in patients with uncontrolled hypertension. 5.9 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients receiving sumatriptan.

without a history of hypertension. Monitor blood pressure in patients treated with ONZETRA Xsail. ONZETRA Xsail is contraindicated in patients with uncontrolled hypertension. 5.9 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients receiving sumatriptan. 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. ONZETRA Xsail is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan. 5.10 Seizures Seizures have been reported following administration of sumatriptan. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent. ONZETRA Xsail should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the prescribing information: Myocardial ischemia, myocardial infarction, and Prinzmetal's angina [see Warnings and Precautions (5.1) ] Arrhythmias [see Warnings and Precautions (5.2) ] Chest, throat, neck and/or jaw pain/tightness/pressure [see Warnings and Precautions (5.3) ] Cerebrovascular events [see Warnings and Precautions (5.4) ] Other vasospasm reactions [see Warnings and Precautions (5.5) ] Medication overuse headache [see Warnings and Precautions (5.6) ] Serotonin syndrome [see Warnings and Precautions (5.7) ] Increase in blood pressure [see Warnings and Precautions (5.8) ] Hypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.9) ] Seizures [see Warnings and Precautions (5.10) ] In controlled studies with ONZETRA Xsail, the most common adverse reactions (incidence of ≥ 2% and greater than placebo) were abnormal taste, nasal discomfort, rhinorrhea, and rhinitis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Currax Pharmaceuticals LLC at 1-800-793-2145 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 to the 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 2 placebo-controlled clinical trials in 301 patients with migraine who took at least 1 dose of ONZETRA Xsail or placebo. Only adverse reactions that occurred at a frequency of 2% or more with ONZETRA Xsail and that occurred at a frequency greater than the placebo group are included in Table 1. Table 1: Adverse Reactions Reported by at Least 2% of Patients in 2 Controlled Migraine Trials Percent of Patients Reporting Adverse Reaction ONZETRA N=151 Placebo N=150 Abnormal Taste 20 3 Nasal Discomfort 11 Limited examinations of the nose and throat did not reveal any clinically noticeable injury in these patients. 1 Rhinorrhea 5 2 Rhinitis 2 0 There is insufficient data with ONZETRA Xsail to assess the impact of age, gender, and race on adverse effects. 6.2 Postmarketing Experience The following adverse reaction has been identified during post approval use of ONZETRA Xsail. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. Epistaxis has been identified during post approval use of ONZETRA Xsail as an adverse reaction.

<table width="90%"><caption>Table 1: Adverse Reactions Reported by at Least 2% of Patients in 2 Controlled Migraine Trials </caption><col width="34%" align="left" valign="top"/><col width="33%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule"/><th styleCode="Rrule" colspan="2">Percent of Patients Reporting</th></tr><tr><th styleCode="Lrule Rrule" valign="middle">Adverse Reaction</th><th styleCode="Rrule">ONZETRA N=151</th><th styleCode="Rrule">Placebo N=150</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abnormal Taste</td><td styleCode="Rrule">20</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasal Discomfort</td><td styleCode="Rrule">11<footnote>Limited examinations of the nose and throat did not reveal any clinically noticeable injury in these patients.</footnote></td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rhinorrhea</td><td styleCode="Rrule">5</td><td styleCode="Rrule">2</td></tr><tr><td styleCode="Lrule Rrule">Rhinitis</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0</td></tr></tbody></table>

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 ONZETRA Xsail within 24 hours of each other is contraindicated . 7.2 Monoamine Oxidase Inhibitors MAO-A inhibitors increase systemic exposure by up to 7-fold. Therefore, the use of ONZETRA Xsail 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 ONZETRA Xsail 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) ] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) 8.1 Pregnancy Risk Summary Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see Data ) . In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal ( see Data ). In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9%, and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Several studies have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension 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 to support 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.

edical 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 ONZETRA Xsail. 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 ONZETRA Xsail 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 ONZETRA Xsail. 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 has not been established in pediatric 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.

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 studies, 3 multiple-attack studies) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These studies did not establish the efficacy of oral sumatriptan compared to 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 nasal sumatriptan are not presently available. 8.5 Geriatric Use Clinical trials of ONZETRA Xsail did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience with subcutaneous, oral, and liquid nasal spray sumatriptan has not identified differences in responses between the elderly and younger patients. In general, treatment for an elderly patient should be cautious, reflecting the greater frequency of decreased or abnormal hepatic function, renal function, or cardiac function, more pronounced blood pressure increases, higher risks for unrecognized CAD, and/or 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 ONZETRA Xsail [see Warnings and Precautions (5.1) ]. 8.6 Hepatic Impairment The clearance of oral sumatriptan was reduced in patients with moderate hepatic impairment [see Clinical Pharmacology (12.3) ] . Similar changes can be expected following intranasal administration. The effect of severe hepatic impairment was NOT evaluated using oral formulation. The use of ONZETRA Xsail in patients with severe hepatic impairment is contraindicated [see Contraindications (4) ] .

8.1 Pregnancy Risk Summary Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see Data ) . In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal ( see Data ). In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9%, and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Several studies have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension 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 to support 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.

8.4 Pediatric Use Safety and effectiveness has not been established in pediatric 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 studies, 3 multiple-attack studies) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These studies did not establish the efficacy of oral sumatriptan compared to 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 nasal sumatriptan are not presently available.

8.5 Geriatric Use Clinical trials of ONZETRA Xsail did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience with subcutaneous, oral, and liquid nasal spray sumatriptan has not identified differences in responses between the elderly and younger patients. In general, treatment for an elderly patient should be cautious, reflecting the greater frequency of decreased or abnormal hepatic function, renal function, or cardiac function, more pronounced blood pressure increases, higher risks for unrecognized CAD, and/or 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 ONZETRA Xsail [see Warnings and Precautions (5.1) ].

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 ONZETRA Xsail is about 3 hours [see Clinical Pharmacology (12.3) ] , and therefore monitoring of patients after overdose with ONZETRA Xsail should continue for at least 15 hours or while symptoms persist. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

11 DESCRIPTION ONZETRA Xsail (sumatriptan nasal powder) uses a disposable, single use nosepiece which is attached by the patient to a delivery device body which has a mouthpiece and a piercing mechanism. The nosepiece contains a hypromellose capsule filled with 11 mg sumatriptan base (as 15.4 mg of sumatriptan succinate) in a dry powder form. Two nosepieces comprise a single 22 mg dose. ONZETRA is for nasal administration with the Xsail device only. The active component of ONZETRA Xsail is sumatriptan, a selective 5-hydroxy-tryptamine receptor subtype 1 (5-HT 1 ) agonist (triptan), as the succinate salt. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure: The empirical formula is C 14 H 21 N 3 O 2 S ∙ C 4 H 6 O 4 , representing a molecular weight of 413.5. Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in saline. The ONZETRA Xsail breath-powered delivery device is used to deliver the dry powder contained in the disposable nosepiece (in a capsule) into the nostril using breath exhaled into the device. The Xsail delivery device has a flexible mouthpiece to adjust to individual anatomic variations. Under standardized in vitro testing, the Xsail device delivers a mean of 10 mg sumatriptan per nosepiece when tested at a flow rate of 30 L/min for 4 seconds (2 L total). The amount of sumatriptan delivered to the nasal cavity will depend on patient factors such as expiratory flow. Delivered dose was measured in patients with migraine headache treated in clinical trials to evaluate the efficacy of the product. In these trials, each nosepiece delivered an average dose of 7.5-8.1 mg, providing a total dose of 15-16.2 mg per treatment episode from two nosepieces. Chemical Structure

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 treated with sumatriptan, 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 injection 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 studies carried out during development of sumatriptan as a treatment for migraine were not accompanied by any clinically significant changes in heart rate. 12.3 Pharmacokinetics Absorption and Bioavailability The mean maximum concentration (C max ) following a 22 mg nasal dose of ONZETRA Xsail was 21 ng/mL (range: 9 to 61 ng/mL), and the AUC 0-∞ was 65 ng∙hr/ml (range: 40 to 107 ng/mL). Peak plasma concentration (T max ) was achieved on average 45 minutes (range: 10 minutes to 2 hours) following ONZETRA Xsail administration. The bioavailability of ONZETRA relative to subcutaneous injection was approximately 19%, primarily due to pre-systemic metabolism and partly due to incomplete absorption. Sumatriptan bioavailability following liquid nasal spray administration is 14%, similar to that after oral administration (15%). Distribution Protein binding of sumatriptan, determined by equilibrium dialysis over the concentration range of 10 to 1000 ng/mL, is 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 (predominately 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 powder by the Xsail device is approximately 3 hours, similar to the half-life seen with sumatriptan nasal spray. Only 3% of a nasal spray dose is excreted in the urine as unchanged sumatriptan; 42% of a nasal spray dose is excreted as the major metabolite, the indole acetic acid analogue of sumatriptan. The total plasma clearance of the nasal spray is approximately 1200 mL/min. Specific Populations Age The pharmacokinetics of oral sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in patients 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. Race 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.

in healthy male subjects (mean age: 30 years). Intranasal sumatriptan has not been evaluated for age differences. Race 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. Renal Impairment The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined. Hepatic Impairment The effect of mild hepatic disease on the pharmacokinetics of sumatriptan has not been evaluated. 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 [see Contraindications (4) ] . 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 study 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 spray dose of sumatriptan did not alter the pharmacokinetics of sumatriptan.

12.2 Pharmacodynamics Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients treated with sumatriptan, 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 injection 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 studies carried out during development of sumatriptan as a treatment for migraine were not accompanied by any clinically significant changes in heart rate.

12.3 Pharmacokinetics Absorption and Bioavailability The mean maximum concentration (C max ) following a 22 mg nasal dose of ONZETRA Xsail was 21 ng/mL (range: 9 to 61 ng/mL), and the AUC 0-∞ was 65 ng∙hr/ml (range: 40 to 107 ng/mL). Peak plasma concentration (T max ) was achieved on average 45 minutes (range: 10 minutes to 2 hours) following ONZETRA Xsail administration. The bioavailability of ONZETRA relative to subcutaneous injection was approximately 19%, primarily due to pre-systemic metabolism and partly due to incomplete absorption. Sumatriptan bioavailability following liquid nasal spray administration is 14%, similar to that after oral administration (15%). Distribution Protein binding of sumatriptan, determined by equilibrium dialysis over the concentration range of 10 to 1000 ng/mL, is 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 (predominately 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 powder by the Xsail device is approximately 3 hours, similar to the half-life seen with sumatriptan nasal spray. Only 3% of a nasal spray dose is excreted in the urine as unchanged sumatriptan; 42% of a nasal spray dose is excreted as the major metabolite, the indole acetic acid analogue of sumatriptan. The total plasma clearance of the nasal spray is approximately 1200 mL/min. Specific Populations Age The pharmacokinetics of oral sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in patients 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. Race 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. Renal Impairment The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined. Hepatic Impairment The effect of mild hepatic disease on the pharmacokinetics of sumatriptan has not been evaluated. 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 [see Contraindications (4) ] . 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.

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 study 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 spray dose of sumatriptan did not alter the pharmacokinetics of sumatriptan.

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, 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 of 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.

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, 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 of 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.

14 CLINICAL STUDIES The efficacy of ONZETRA Xsail for the acute treatment of migraine with or without aura was established in a multicenter, randomized, double-blind, placebo-controlled study (Study 1). Migraineurs enrolled in Study 1 were primarily female (84%) and Caucasian (86%), with a mean age of 42 years (range of 19 to 64). Patients were instructed to treat a moderate to severe migraine headache. Additional medications were allowed as rescue therapy beginning 2 hours after the initial treatment. In Study 1, the proportion of patients who had headache relief defined as a reduction from moderate or severe pain to mild or no pain was assessed at 15, 30, 60, 90 minutes and 2, 24 and 48 hours after treatment with study drug. Associated symptoms of nausea, photophobia, and phonophobia were assessed as secondary endpoints. The proportion of patients who had no headache at 2 hours (120 minutes) was also assessed. The percentage of patients achieving headache relief 2 hours after treatment was significantly greater in the ONZETRA Xsail 22 mg group compared to those who received placebo (see Table 2 and Figure 1 ). 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 ONZETRA Xsail compared with placebo. Table 2: Percentage of Patients With Headache Relief (Primary Efficacy Endpoint), with No Headache, No Nausea, No Photophobia, and No Phonophobia 2 hours Post Treatment with ONZETRA Xsail (Study 1) 2 hours post treatment ONZETRA 22 mg (n=108) Placebo (n=104) Headache Relief 68% p <0.05 versus placebo 45% No Headache 34% 17% No Nausea 82% 79% No Photophobia 52% 40% No Phonophobia 68% 56% Figure 1: Percentage of Patients with Headache Relief within 2 Hours with ONZETRA Xsail The efficacy of ONZETRA Xsail 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 was insufficient data to assess the impact of race on efficacy. Figure 1

<table width="90%" ID="table2"><caption>Table 2: Percentage of Patients With Headache Relief (Primary Efficacy Endpoint), with No Headache, No Nausea, No Photophobia, and No Phonophobia 2 hours Post Treatment with ONZETRA Xsail (Study 1)</caption><col width="34%" align="left" valign="top"/><col width="33%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">2 hours post treatment</th><th styleCode="Rrule">ONZETRA 22 mg (n=108)</th><th styleCode="Rrule">Placebo (n=104)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache Relief</td><td styleCode="Rrule">68%<footnote ID="foot2a"><content styleCode="italics">p</content>&lt;0.05 versus placebo</footnote></td><td styleCode="Rrule">45%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">No Headache</td><td styleCode="Rrule">34% <footnoteRef IDREF="foot2a"/></td><td styleCode="Rrule">17%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">No Nausea</td><td styleCode="Rrule">82%</td><td styleCode="Rrule">79%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">No Photophobia</td><td styleCode="Rrule">52%</td><td styleCode="Rrule">40%</td></tr><tr><td styleCode="Lrule Rrule">No Phonophobia</td><td styleCode="Rrule">68%</td><td styleCode="Rrule">56%</td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ONZETRA Xsail is supplied as a disposable nosepiece containing a capsule and a reusable breath-powered delivery device body. Each capsule contains 11 mg sumatriptan base (equivalent to 15.4 mg of sumatriptan succinate nasal powder) in a clear, hypromellose capsule with 825 printed on one side. ONZETRA Xsail is available in kits containing 8 doses. The following table provides a description of the packaging configurations: Description Contents NDC Code 8 Dose Kit 8 pouches containing 2 nosepieces (22 mg sumatriptan) per pouch. Each nosepiece contains 11 mg sumatriptan 2 breath-powered delivery system bodies 42847-311-08 16.2 Storage and Handling Store at room temperature between 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C to 30°C (59°F to 86°F). Do not store in the refrigerator or freezer. Use nosepiece immediately after removing from foil pouch.

<table width="90%"><col width="20%" align="center" valign="top"/><col width="60%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Description</th><th styleCode="Rrule">Contents</th><th styleCode="Rrule">NDC Code</th></tr></thead><tbody><tr><td styleCode="Lrule Rrule">8 Dose Kit</td><td styleCode="Rrule">8 pouches containing 2 nosepieces (22 mg sumatriptan) per pouch. Each nosepiece contains 11 mg sumatriptan 2 breath-powered delivery system bodies</td><td styleCode="Rrule">42847-311-08</td></tr></tbody></table>

16.2 Storage and Handling Store at room temperature between 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C to 30°C (59°F to 86°F). Do not store in the refrigerator or freezer. Use nosepiece immediately after removing from foil pouch.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Only patients who are able to understand and follow the instructions should use ONZETRA Xsail. Instructions on the proper use of ONZETRA Xsail from a physician or healthcare professional prior to administration for the first time may be helpful. For support, healthcare professionals and patients can call 1-800-793-2145 or see www.ONZETRA.com. Risk of Myocardial Ischemia and/or Infarction, Prinzmetal's Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events Inform patients that triptan medications, including ONZETRA Xsail, may cause serious cardiovascular side effects such as myocardial infarction or stroke, which may result in hospitalization and even death. 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 signs or symptoms are observed. Apprise patients of the importance of this follow-up [see Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.4 , and 5.5) ] . Hypersensitivity Reactions Inform patients that anaphylactic reactions have occurred in patients receiving sumatriptan. 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 Warnings and Precautions (5.9) ]. Concomitant Use with Other Triptans and Ergot Medications Inform patients that use of ONZETRA Xsail 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 ONZETRA Xsail 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) ]. Nursing Mothers 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 may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of ONZETRA Xsail. 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 ONZETRA Xsail with the breath powered device Provide patients with instructions on the proper use of ONZETRA Xsail with the breath powered device. Advise patients that use of the breath powered device is for ONZETRA Xsail only.

their nose and throat. The symptoms will generally resolve in less than 2 hours. How to Use ONZETRA Xsail with the breath powered device Provide patients with instructions on the proper use of ONZETRA Xsail with the breath powered device. Advise patients that use of the breath powered device is for ONZETRA Xsail only. No other product or substance is approved for use in the breath powered device. Advise patients to remove a disposable nosepiece from the foil pouch, remove the clear device cap from the reusable device, and click the nosepiece into the device body. Advise the patient to fully press and release the white piercing button on the device body to pierce the capsule inside the nosepiece. Instruct the patient to press the white piercing button only once. Advise the patient to insert the nosepiece into the nostril so that it makes a tight seal. The device is then rotated and the mouthpiece inserted between the lips. Instruct the patient to blow forcefully through the mouthpiece to deliver the sumatriptan powder into the nasal cavity. Vibration (e.g., a rattling noise) may occur, and indicates that the patient is blowing forcefully, as directed. Advise the patient to remove and discard the nosepiece in the trash once the medication has been administered. Instruct the patient to follow the same process using a second nosepiece in the other nostril to administer the remainder of the total recommended dose.

ONZETRA and Xsail are registered trademarks of Currax™ Pharmaceuticals LLC in the United States and other countries Distributed by: Currax™ Pharmaceuticals LLC Brentwood, TN 37027 ©2024 Currax™ Pharmaceuticals LLC All rights reserved

Patient Information ONZETRA ® (On ze' trah) Xsail ® (Eks'-seil) (sumatriptan nasal powder) 11 mg Read this Patient Information before you start using ONZETRA Xsail and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. What is the most important information I should know about ONZETRA Xsail? ONZETRA Xsail can cause serious side effects, including: Heart attack and other heart problems. Heart problems may lead to death. Stop taking ONZETRA Xsail and get emergency medical help right away if you have any of the following symptoms of a heart attack: discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw pain or discomfort in your arms, back, neck, jaw or stomach shortness of breath with or without chest discomfort breaking out in a cold sweat nausea or vomiting feeling lightheaded ONZETRA Xsail is not for people with risk factors for heart disease unless a heart exam is done and shows no problem. You have a higher risk for heart disease if you: have high blood pressure have high cholesterol levels smoke are overweight have diabetes have a family history of heart disease What is ONZETRA Xsail? ONZETRA Xsail is a prescription medicine used to treat acute migraine headaches with or without aura in adults. ONZETRA Xsail is not used to treat other types of headaches such as hemiplegic migraines (that make you unable to move on one side of your body) or basilar migraines (rare form of migraine with aura). ONZETRA Xsail is not used to prevent or decrease the number of migraine headaches you have. It is not known if ONZETRA Xsail is safe and effective to treat cluster headaches. It is not known if ONZETRA Xsail is safe and effective in children under 18 years of age. Who should not use ONZETRA Xsail? Do not use ONZETRA Xsail if you have: an allergy to sumatriptan heart problems or history of heart problems narrowing of blood vessels to your legs, arms, stomach or kidney (peripheral vascular disease) uncontrolled high blood pressure severe liver problems hemiplegic migraines or basilar migraines. If you are not sure if you have these types of migraines, ask your healthcare provider. had a stroke, transient ischemic attacks (TIAs) or problems with your blood circulation taken any of the following medicines in the last 24 hours: almotriptan (AXERT ® ) eletriptan (RELPAX ® ) frovatriptan (FROVA ® ) naratriptan (AMERGE ® ) rizatriptan (MAXALT ® , MAXALT-MLT ® ) zolmitriptan (ZOMIG ® , ZOMIG-ZMT ® , ZOMIG ® NASAL SPRAY) sumatriptan (IMITREX ® , IMITREX ® NASAL SPRAY, IMITREX ® INJECTION) sumatriptan and naproxen (TREXIMET ® ) sumatriptan (SUMAVEL ® DOSE PRO ® INJECTION) sumatriptan (ALSUMA ® ) sumatriptan (ZECUITY ® TRANSDERMAL PATCH) ergotamines (CAFERGOT ® , ERGOMAR ® , MIGERGOT ® ) dihydroergotamine (D.H.E. 45 ® , MIGRANAL ® ) Ask your healthcare provider if you are not sure if your medicine is listed above. What should I tell my healthcare provider before taking ONZETRA Xsail?

ON) sumatriptan (ALSUMA ® ) sumatriptan (ZECUITY ® TRANSDERMAL PATCH) ergotamines (CAFERGOT ® , ERGOMAR ® , MIGERGOT ® ) dihydroergotamine (D.H.E. 45 ® , MIGRANAL ® ) Ask your healthcare provider if you are not sure if your medicine is listed above. What should I tell my healthcare provider before taking ONZETRA Xsail? Before you use ONZETRA Xsail, tell your healthcare provider about all of your medical conditions, including if you: have high blood pressure have high cholesterol have diabetes smoke are overweight have heart problems or a family history of heart problems or stroke have kidney problems have liver problems have had epilepsy or seizures are not using effective birth control are pregnant or plan to become pregnant. It is not known if ONZETRA Xsail can harm your unborn baby. are breastfeeding or plan to breastfeed. ONZETRA Xsail passes into your breast milk. It is not known if this can harm your baby. Talk with your healthcare provider about the best way to feed your baby if you use ONZETRA Xsail. Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins and herbal supplements. ONZETRA Xsail and certain other medicines can affect each other, causing serious side effects. Especially tell your healthcare provider if you take anti-depressant medicines called: selective serotonin reuptake inhibitors (SSRIs) serotonin norepinephrine reuptake inhibitors (SNRIs) tricyclic antidepressants (TCAs) monoamine oxidase inhibitors (MAOIs) Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine. How should I use ONZETRA Xsail? Before using ONZETRA Xsail, read the Patient Instructions for Use. Certain people should use their first dose of ONZETRA Xsail in their healthcare provider's office or in another medical setting. Ask your healthcare provider if you should use your first dose in a medical setting. Use ONZETRA Xsail exactly as your healthcare provider tells you to use it. Use a full dose (2 nosepieces) to treat your headache. If you do not get any relief after your first full dose, do not use a second dose without first talking with your healthcare provider. If your headache comes back after the first full dose or you only get some relief from your headache, you can use a second full dose 2 hours after the first full dose. Do not take more than a total of 44 mg (two full doses) of ONZETRA Xsail in a 24-hour period. It is not known how using ONZETRA Xsail for a long time affects the nose and throat. If you use too much ONZETRA Xsail, call your healthcare provider or go to the nearest hospital emergency room right away. You should write down when you have headaches and when you take ONZETRA Xsail so you can talk with your healthcare provider about how ONZETRA Xsail is working for you. What should I avoid while taking ONZETRA Xsail? ONZETRA Xsail can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not drive a car, use machinery or do anything where you need to be alert. What are the possible side effects of ONZETRA Xsail? ONZETRA Xsail may cause serious side effects. See " What is the most important information I should know about ONZETRA Xsail? " These serious side effects include: changes in color or sensation in your fingers and toes (Raynaud's syndrome) stomach and intestinal problems (gastrointestinal and colonic ischemic events).

ONZETRA Xsail may cause serious side effects. See " What is the most important information I should know about ONZETRA Xsail? " These serious side effects include: changes in color or sensation in your fingers and toes (Raynaud's syndrome) stomach and intestinal problems (gastrointestinal and colonic ischemic events). Symptoms of gastrointestinal and colonic ischemic events include: sudden or severe stomach pain stomach pain after meals weight loss nausea or vomiting constipation or diarrhea bloody diarrhea fever problems with blood circulation to your legs and feet (peripheral vascular ischemia). Symptoms of peripheral vascular ischemia include: cramping and pain in your legs or hips feeling of heaviness or tightness in your leg muscles burning or aching pain in your feet or toes while resting numbness, tingling or weakness in your legs cold feeling or color changes in 1 or both legs or feet hives (itchy bumps); swelling of your tongue, mouth or throat medication overuse headaches. Some people who use too much sumatriptan may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with ONZETRA Xsail. serotonin syndrome. Serotonin syndrome is a rare but serious problem that can happen in people using ONZETRA Xsail, especially if ONZETRA Xsail is used with anti-depressant medications called SSRIs or SNRIs. Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome: Mental changes such as seeing things that are not there (hallucinations), agitation, or coma Fast heartbeat Changes in blood pressure High body temperature Tight muscles Trouble walking seizures. Seizures have happened in people taking sumatriptan who have never had seizures before. Talk with your healthcare provider about your chance of having seizures while you take ONZETRA Xsail. The most common side effects of ONZETRA Xsail include: unusual or bad taste in your mouth discomfort of your throat or nose runny nose, stuffy nose, and/or postnasal drip Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of ONZETRA Xsail. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ONZETRA Xsail? Store at room temperature, between 68°F to 77°F (20°C to 25°C). Do not store in the refrigerator or freezer. Keep ONZETRA Xsail and all medicines out of the reach of children. General information about the safe and effective use of ONZETRA Xsail. ONZETRA Xsail is to be used only with the Xsail breath-powered device. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use ONZETRA Xsail for a condition for which it was not prescribed. Do not give ONZETRA Xsail to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about ONZETRA Xsail. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ONZETRA Xsail that is written for healthcare professionals. For more information, go to www.ONZETRA.com or call 1-800-793-2145. What are the ingredients in ONZETRA Xsail? Active ingredient: sumatriptan succinate Inactive ingredient: hypromellose (capsule) This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 01/2024

Instructions for Use Read these Instructions for Use which come with ONZETRA ® Xsail ® before you start using it and each time you get a refill. Follow these instructions each time you use ONZETRA Xsail. These Instructions for Use have been approved by the U.S. Food and Drug Administration. ONZETRA and Xsail are registered trademarks of Currax™ Pharmaceuticals LLC in the United States and other countries. The other brands listed are trademarks of their respective owners and are not trademarks of Currax™ Pharmaceuticals LLC. The makers of these brands are not affiliated with and do not endorse Currax™ Pharmaceuticals LLC or its products. U.S. Patent Nos, 6,715,485; 7,975,690; 8,047,202; 8,327,844; 8,550,073; 8,555,877; 8,590,530; 8,875,704; 8,899,229; 8,978,647; 9,108,015; 9,119,932 Distributed by: Currax™ Pharmaceuticals LLC Brentwood, TN 37027 1-800-793-2145 Issued January 2024 ONZ-LC103.01 © 2024 Currax™ Pharmaceuticals LLC. All rights reserved Figure