ZOMIG

1 INDICATIONS AND USAGE ZOMIG Nasal Spray is indicated for the acute treatment of migraine with or without aura in adults and pediatric patients 12 years of age and older. Limitations of Use Only use ZOMIG if a clear diagnosis of migraine has been established. If a patient has no response to ZOMIG treatment for the first migraine attack, reconsider the diagnosis of migraine before ZOMIG is administered to treat any subsequent attacks. ZOMIG is not indicated for the prevention of migraine attacks. Safety and effectiveness of ZOMIG have not been established for cluster headache. Not recommended in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.2) ] . ZOMIG Nasal Spray is a serotonin (5-HT) 1B/1D receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults and pediatric patients 12 years and older (1) Limitations of Use: Use only after a clear diagnosis of migraine has been established (1) Not intended for the prophylactic therapy of migraine (1) Not indicated for the treatment of cluster headache (1) Not recommended in patients with moderate to severe hepatic impairment (1)

2 DOSAGE AND ADMINISTRATION Recommended starting dose: 2.5 mg (2.1) Maximum single dose: 5 mg (2.1) May repeat dose after 2 hours if needed; not to exceed 10 mg in any 24-hour period (2.1) 2.1 Dosing Information The recommended starting dose for ZOMIG nasal spray in adult and pediatric patients 12 years of age and older is 2.5 mg. As the individual response to ZOMIG nasal spray may vary, the dose should be adjusted on an individual basis. The maximum recommended single dose of ZOMIG is 5 mg. If the migraine has not resolved by 2 hours after taking ZOMIG, or returns after a transient improvement, another dose may be administered at least 2 hours after the previous dose. The maximum daily dose should not exceed 10 mg in any 24-hour period. The safety of ZOMIG in the treatment of an average of more than four headaches in a 30-day period has not been established. 2.2 Dosing in Patients with Hepatic Impairment ZOMIG nasal spray is not recommended in patients with moderate to severe hepatic impairment because of increased zolmitriptan blood levels in these patients and elevation of blood pressure in some of these patients. The recommended dosage of ZOMIG nasal spray in patients with mild hepatic impairment is the same as for patients with normal hepatic function [see Dosage and Administration (2.1) , Warnings and Precautions (5.8) , Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.3 Dosing in Patients taking Cimetidine If ZOMIG is co-administered with cimetidine, limit the maximum single dose of ZOMIG to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Drug Interactions (7.4) and Clinical Pharmacology (12.3)] .

4 CONTRAINDICATIONS ZOMIG is contraindicated in patients with: Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), other significant underlying cardiovascular disease, or coronary artery vasospasm including Prinzmetal's angina [see Warnings and Precautions (5.1) ] Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Warnings and Precautions (5.2) ] History of stroke, transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at higher risk of stroke [see Warnings and Precautions (5.4) ] Peripheral vascular disease (PVD) [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 another 5-HT 1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide) [see Drug Interactions (7.1 , 7.3) ] Concurrent administration of an MAO-A inhibitor or recent discontinuation of a MAO-A inhibitor (that is within 2 weeks) [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ] Known hypersensitivity to ZOMIG (angioedema and anaphylaxis seen) [see Adverse Reactions (6.2) ] History of ischemic heart disease or coronary artery vasospasm (4) Symptomatic 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 ergot-type medication (4) MAO-A inhibitor used in past 2 weeks (4) Hypersensitivity to ZOMIG (4)

5 WARNINGS AND PRECAUTIONS Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors (5.1) Arrhythmias: Discontinue dosing 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 dosing if occurs (5.4) Gastrointestinal ischemic events, peripheral vasospastic reactions: Discontinue dosing if occurs (5.5) Medication Overuse Headache: Detoxification may be necessary (5.6) Serotonin syndrome: Discontinue dosing if occurs (5.7 , 7.5) Increase in blood pressure: very rarely associated with significant events (5.8) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina ZOMIG is contraindicated in patients with ischemic or vasospastic coronary artery disease (CAD). There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of ZOMIG. Some of these reactions occurred in patients without known CAD. 5-HT 1 agonists including ZOMIG 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 ZOMIG. Do not administer ZOMIG if there is evidence of CAD or coronary artery vasospasm [see Contraindications (4) ] . For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administrating the first ZOMIG dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following ZOMIG administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of ZOMIG. 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 ZOMIG if these disturbances occur. Patients with Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders should not receive ZOMIG [see Contraindications (4) ] . 5.3 Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure As with other 5-HT 1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with ZOMIG and is usually non-cardiac in origin. However, if a cardiac origin is suspected, patients should be evaluated. Patients shown to have CAD and those with Prinzmetal's variant angina should not receive 5-HT 1 agonists [see Contraindications (4) ] . 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. Discontinue ZOMIG if a cerebrovascular event occurs. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical for migraine, other potentially serious neurological conditions should be excluded. ZOMIG should not be administered to patients with a history of stroke or transient ischemic attack [see Contraindications (4) ] . 5.5 Other Vasospasm Reactions 5-HT 1 agonists, including ZOMIG, 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 vasospasm reaction following the use of any 5-HT 1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional ZOMIG doses [see Contraindications (4) ] . 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, or a combination of 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 ZOMIG, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions (7.5) ] . 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 rapidly occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. ZOMIG treatment should be discontinued if serotonin syndrome is suspected [see Drug Interactions (7.5) and Patient Counseling Information (17) ] . 5.8 Increase in Blood Pressure Significant elevations in systemic blood pressure have been reported in patients treated with 5-HT 1 agonists including patients without a history of hypertension. Very rarely these increases in blood pressure have been associated with significant clinical events. In healthy subjects treated with 5 mg of ZOMIG oral tablet, an increase of 1 and 5 mm Hg in the systolic and diastolic blood pressure, respectively, was seen. In a study of patients with moderate to severe liver impairment, 7 of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a dose of 10 mg of ZOMIG oral tablet. As with all triptans, blood pressure should be monitored in ZOMIG-treated patients. ZOMIG is contraindicated in patients with uncontrolled hypertension [see Contraindications (4) ] .

7 DRUG INTERACTIONS If co-administered with cimetidine: Maximum single dose of 2.5 mg, not to exceed 5 mg in any 24-hour period. (2.3 , 7.4) 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 ZOMIG within 24 hours of each other is contraindicated [see Contraindications (4) ] . 7.2 MAO-A Inhibitors MAO-A inhibitors increase the systemic exposure of zolmitriptan. Therefore, the use of ZOMIG in patients receiving MAO-A inhibitors is contraindicated [see Contraindications (4) and Clinical Pharmacology (12.3) ] . 7.3 5-HT 1B/1D agonists (e.g. triptans) Concomitant use of other 5-HT 1B/1D agonists (including triptans) within 24 hours of ZOMIG treatment is contraindicated because the risk of vasospastic reactions may be additive [see Contraindications (4) ] . 7.4 Cimetidine Following administration of cimetidine, the half-life and AUC of ZOMIG and its active metabolites were approximately doubled [see Clinical Pharmacology (12.3) ] . If cimetidine and ZOMIG are used concomitantly, limit the maximum single dose of ZOMIG to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] . 7.5 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans [see Warnings and Precautions (5.7) ] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of 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) ] The most common adverse reactions (≥ 5% and > placebo) were: Adults: unusual taste, paresthesia, dizziness, and hyperesthesia (6.1) Pediatrics: unusual taste (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adults Among 460 patients treating 1180 single attacks with ZOMIG nasal spray in a blinded placebo controlled trial (Study 1), there was a low withdrawal rate related to adverse reactions: 5 mg (1.3%), 2.5 mg (0%), and placebo (0.4%). None of the withdrawals were due to a serious event. One patient was withdrawn due to abnormal ECG changes from baseline that were incidentally found 23 days after the last dose of ZOMIG nasal spray. The most common adverse reactions (≥ 5% and > placebo) in any dosage strength in clinical trials for ZOMIG nasal spray were: unusual taste, paresthesia, hyperesthesia, and dizziness. The incidence of adverse reactions was generally dose-related. Table 1 lists the adverse reactions from the controlled clinical trial (Study 1) that occurred in ≥ 2% of patients in either the 2.5 or 5 mg ZOMIG nasal spray dose groups and with an incidence greater than placebo. Table 1: Adverse reactions In a Placebo-Controlled Study In Adult Patients with Migraine (Study 1) Body System Adverse Reaction Placebo (N=228) ZOMIG 2.5 mg (N=224) ZOMIG 5 mg (N=236) Atypical Sensations Hyperesthesia 0% 1% 5% Paraesthesia 6% 5% 10% Warm Sensation 2% 4% 0% Ear/Nose/Throat Disorder/Discomfort of nasal cavity 2% 1% 3% Pain and Pressure Sensations Pain Location Specified 1% 2% 4% Throat Pain 1% 4% 4% Throat Tightness 1% <1% 2% Digestive Dry Mouth <1% 3% 2% Nausea 1% 1% 4% Neurological Dizziness 4% 6% 3% Somnolence 2% 1% 4% Other Unusual Taste 3% 17% 21% Asthenia 1% 3% 3% In Study 1, adverse reactions occurring in ≥ 1% and < 2% of patients in all attacks in either ZOMIG nasal spray dose group and with incidence greater than that of placebo were: abdominal pain, chills, throat pressure, facial edema, chest pressure, palpitation, dysphagia, arthralgia, myalgia, and depersonalization. The incidence of adverse reactions in controlled clinical trials was not affected by gender, weight, or age of the patients (18-39 vs. 40-65 years of age), or presence of aura. There were insufficient data to assess the impact of race on the incidence of adverse reactions. Local Adverse Reactions: Among 460 patients using ZOMIG 2.5 mg or 5 mg in the controlled clinical trial, approximately 3% noted local irritation or soreness at the site of administration. Adverse reactions of any kind, perceived in the nasopharynx (which may include systemic effects of triptans) were severe in about 1% of patients and approximately 57% resolved in 1 hour. Nasopharyngeal examinations, in a subset of patients participating in two long term trials of up to one-year duration, failed to demonstrate any clinically significant changes with repeated use of ZOMIG nasal spray. All nasopharyngeal adverse reactions with an incidence of ≥ 2% of patients in any ZOMIG nasal spray dose groups are included in Table 1. Other Adverse Reactions: In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include reactions observed in open and uncontrolled studies, the role of ZOMIG in their causation cannot be reliably determined. Furthermore, variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction frequencies are calculated as the number of patients who used ZOMIG nasal spray and reported a reaction divided by the total number of patients exposed to ZOMIG nasal spray (n=3059). All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients and rare adverse reactions are those occurring in fewer than 1/1,000 patients. General: Infrequent: allergic reactions. Cardiovascular: Infrequent: arrhythmias, hypertension, syncope and tachycardia. Rare: angina pectoris and myocardial infarct. Digestive: Rare: stomatitis. Neurological: Infrequent: agitation, amnesia, anxiety, depression, insomnia, and nervousness. Rare: convulsions. Respiratory: Infrequent: bronchitis, increased cough, dyspnea, epistaxis, laryngeal edema, pharyngitis, rhinitis, and sinusitis. Skin: Infrequent: pruritus, rash, and urticaria. Urogenital: Infrequent: polyuria and urinary urgency. Rare: urinary frequency. Special senses: Infrequent: tinnitus. Rare: conjunctivitis, dry eye, and visual field defect. The adverse reaction profile seen with ZOMIG nasal spray is similar to that seen with ZOMIG tablets and ZOMIG-ZMT tablets except for the occurrence of local adverse reactions from the nasal spray (see ZOMIG tablet/ZOMIG-ZMT oral disintegrating tablet Prescribing Information) . Pediatric Patients 12 to 17 Years of Age The safety of ZOMIG nasal spray in the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in two studies [see Pediatric Use (8.4) and Clinical Studies (14.2) ] . The most common adverse reactions (incidence of ≥ 2% of pediatric patients receiving 2.5 mg and 5 mg ZOMIG nasal spray and numerically greater than placebo) after a single dose are summarized in Table 2. Dysgeusia (unusual taste) was the most common adverse reaction, with a numerically greater incidence for patients receiving ZOMIG compared to placebo (10% vs. 2%). Other common adverse reactions were nasal discomfort, dizziness, oropharyngeal pain, and nausea. Table 2 lists the adverse reactions from the pooled placebo-controlled studies that occurred in ≥ 2% of pediatric patients 12 to 17 years of age in either the 2.5 mg or 5 mg ZOMIG dose groups and with an incidence greater than placebo. Table 2: Adverse reactions in Pooled Placebo-Controlled Studies In Pediatric Patients 12 to 17years of Age with Migraine Adverse Reaction Placebo (N=437) ZOMIG 2.5 mg (N=81) ZOMIG 5 mg (N=431) Unusual taste 2% 6% 10% Nasal discomfort 1% 3% 3% Dizziness 1% 0% 2% Oropharyngeal pain 2% 0% 2% Nausea 1% 1% 2% The adverse reaction profile was similar across gender. There were insufficient data to assess the impact of race on the incidence of adverse reactions. 6.2 Postmarketing Experience The following adverse reactions were identified during post approval use of ZOMIG. 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. The reactions enumerated include all except those already listed in the Clinical Trials Experience section above or the Warnings and Precautions section. Hypersensitivity Reactions: There have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving ZOMIG. ZOMIG is contraindicated in patients with a history of hypersensitivity reaction to ZOMIG.

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of ZOMIG in pregnant women. In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals resulted in embryolethality and fetal abnormalities (malformations and variations) at clinically relevant exposures. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated rates of major birth defects (2.2%-2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy. Data Animal Data When zolmitriptan was administered to pregnant rats during the period of organogenesis at oral doses of 100, 400, and 1200 mg/kg/day (plasma exposures (AUCs) ≈280, 1100, and 5000 times the human AUC at the maximum recommended human dose (MRHD) of 10 mg/day), there was a dose-related increase in embryolethality. A no-effect dose for embryolethality was not established. When zolmitriptan was administered to pregnant rabbits during the period of organogenesis at oral doses of 3, 10, and 30 mg/kg/day (plasma AUCs ≈1, 11, and 42 times the human AUC at the MRHD), there were increases in embryolethality and in fetal malformations and variations. The no-effect dose for adverse effects on embryo-fetal development was associated with a plasma AUC similar to that in humans at the MRHD. When female rats were given zolmitriptan during gestation, parturition, and lactation at oral doses of 25, 100, and 400 mg/kg/day (plasma AUCs ≈70, 280, and 1100 times that in human at the MRHD), an increased incidence of hydronephrosis was found in the offspring. The no-effect dose was associated with a plasma AUC ≈280 times that in humans at the MRHD.