ZOMIG

1 INDICATIONS AND USAGE ZOMIG is indicated for the acute treatment of migraine with or without aura in adults. 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. ZOMIG 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 after a clear diagnosis of migraine has been established (1) Not indicated for the prophylactic therapy of migraine (1) Not indicated for the treatment of cluster headache (1)

2 DOSAGE AND ADMINISTRATION Recommended starting dose: 1.25 mg or 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) Moderate or Severe Hepatic Impairment: 1.25 mg recommended (2.3, 8.6) 2.1 Dosing Information The recommended starting dose of ZOMIG is 1.25 mg or 2.5 mg. The 1.25 mg dose can be achieved by manually breaking the functionally-scored 2.5 mg tablet in half. The maximum recommended single dose of ZOMIG is 5 mg. In controlled clinical trials, a greater proportion of patients had headache response following a 2.5 mg or 5 mg dose than following a 1 mg dose. There was little added benefit from the 5 mg dose compared to the 2.5 mg dose, but adverse reactions were more frequent with the 5 mg dose. If the migraine has not resolved by 2 hours after taking ZOMIG, or returns after a transient improvement, a second dose may be administered at least 2 hours after the first dose. The maximum daily dose is 10 mg in any 24-hour period. The safety of ZOMIG in the treatment of an average of more than three migraines in a 30-day period has not been established. 2.3 Dosing in Patients with Hepatic Impairment The recommended dose of ZOMIG in patients with moderate to severe hepatic impairment is 1.25 mg (one-half of one 2.5 mg ZOMIG tablet) because of increased zolmitriptan blood levels in these patients and elevation of blood pressure in some of these patients. Limit the total daily dose in patients with severe hepatic impairment to no more than 5 mg per day. 2.4 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 (7.5), Clinical Pharmacology (12.3)] .

3 DOSAGE FORMS AND STRENGTHS 2.5 mg Tablets: Yellow colored, round, biconvex film-coated tablets debossed with 101 on one side and deep breakline on other side. 5 mg Tablets: Pink colored, round, biconvex film-coated tablets debossed with 102 on one side and plain on the other side. Tablets: 2.5 mg functionally-scored (3) Tablets: 5 mg (not scored) (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 a 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 a monoamine oxidase (MAO)-A inhibitor or recent use 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 coronary artery disease (CAD) or coronary 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 an ergotamine-containing medication (4) Monoamine oxidase (MAO)-A inhibitor used in past 2 weeks (4) Known hypersensitivity to ZOMIG or zolmitriptan orally disintegrating tablets (4)

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere 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 and or Throat, Neck and 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)] . Most common adverse reactions (≥5% and > placebo) were neck/throat/jaw pain/tightness/pressure, dizziness, paresthesia, asthenia, somnolence, warm/cold sensation, nausea, heaviness sensation, and dry mouth (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Avema Pharma Solutions at 1-877-753-3935 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. In a long-term, open-label study where patients were allowed to treat multiple migraine attacks for up to 1 year, 8% (167 out of 2,058) withdrew from the trial because of adverse reaction. The most common adverse reactions (≥5% and > placebo) in these trials were neck/throat/jaw pain, dizziness, paresthesia, asthenia, somnolence, warm/cold sensation, nausea, heaviness sensation, and dry mouth. Table 1 lists the adverse reactions that occurred in ≥ 2% of the 2,074 patients in any one of the ZOMIG 1 mg, 2.5 mg, or 5 mg dose groups in the controlled clinical trials of ZOMIG in patients with migraines (Studies 1, 2, 3, 4, and 5) [see Clinical Studies (14) ] . Only adverse reactions that were at least 2% more frequent in a ZOMIG group compared to the placebo group are included. Several of the adverse reactions appear dose related, notably paresthesia, sensation of heaviness or tightness in chest, neck, jaw, and throat, dizziness, somnolence and possibly asthenia and nausea. Table 1: Adverse Reaction Incidence in Five Pooled Placebo-Controlled Migraine Clinical Trials * Placebo (n=401) ZOMIG 1 mg (n=163) ZOMIG 2.5 mg (n=498) ZOMIG 5 mg (n=1012) ATYPICAL SENSATIONS 6% 12% 12% 18% Paresthesia (all types) 2% 5% 7% 9% Warm/cold sensation 4% 6% 5% 7% PAIN AND PRESSURE SENSATIONS 7% 13% 14% 22% Chest - pain/tightness/pressure and/or heaviness 1% 2% 3% 4% Neck/throat/jaw - pain/tightness/pressure 3% 4% 7% 10% Heaviness other than chest or neck 1% 1% 2% 5% Other- Pressure/tightness/heaviness 0% 2% 2% 2% DIGESTIVE 8% 11% 16% 14% Dry mouth 2% 5% 3% 3% Dyspepsia 1% 3% 2% 1% Dysphagia 0% 0% 0% 2% Nausea 4% 4% 9% 6% NEUROLOGICAL 10% 11% 17% 21% Dizziness 4% 6% 8% 10% Somnolence 3% 5% 6% 8% Vertigo 0% 0% 0% 2% OTHER Asthenia 3% 5% 3% 9% Sweating 1% 0% 2% 3% * Only adverse reactions that were at least 2% more frequent in a ZOMIG group compared to the placebo group are included. There were no differences in the incidence of adverse reactions in controlled clinical trials in the following subgroups: gender, weight, age, use of prophylactic medications, or presence of aura. There were insufficient data to assess the impact of race on the incidence of adverse reactions. Less Common Adverse Reactions with ZOMIG Tablets: 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 quant …

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 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 and its active N-desmethyl metabolite. Therefore, the use of ZOMIG in patients receiving MAO-A inhibitors is contraindicated [see Contraindications (4), Clinical Pharmacology (12.3)] . 7.3 5-HT1B/1D agonists 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 Selective Serotonin Reuptake Inhibitors and Serotonin Norepinephrine Reuptake Inhibitors Cases of life-threatening serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.7)] . 7.5 Cimetidine Following administration of cimetidine, the half-life and blood levels of zolmitriptan and its active N-desmethyl metabolite 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 (2.4) and Clinical Pharmacology (12.3)] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. 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 (see Data). 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 embryofetal 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. 8.2 Lactation Risk Summary There are no data on the presence of zolmitriptan or its metabolites in human milk, the effects on the breastfed infant, or the effects of zolmitriptan and its metabolites on milk production. In rats, oral dosing with zolmitriptan resulted in levels in milk up to 4 times that in maternal plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOMIG and any potential adverse effects on the breastfed infant from ZOMIG or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. Therefore, ZOMIG is not recommended for use in patients under 18 years of age. One randomized, placebo-controlled clinical trial of ZOMIG tablets (2.5, 5 and 10 mg) evaluated 696 pediatric patients (aged 12 to 17 years) with migraines. This study did not demonstrate the efficacy of ZOMIG compared to placebo in the treatment of migraine in adolescents. Adverse reactions in the adolescent patients treated with ZOMIG were similar in nature and frequency to those reported in clinical trials in adults treated with ZOMIG. ZOMIG has not been studied in pediatric patients less than 12 years old. In the postmarketing experience with triptans, including ZOMIG, there were no additional adverse reactions seen in pediatric patients that were not seen in adults. 8.5 Geriatric Use Clinical studies of ZOMIG did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patie …

12.1 Mechanism of Action Zolmitriptan binds with high affinity to human recombinant 5-HT 1D and 5‐HT 1B receptors, and moderate affinity for 5-HT 1A receptors. The N-desmethyl metabolite also has high affinity for 5‐HT 1B/1D and moderate affinity for 5‐HT 1A receptors. Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of ZOMIG for the treatment of migraine headache is thought to be due to the agonist effects at the 5‐HT 1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

11 DESCRIPTION ZOMIG ® (zolmitriptan) tablets contain zolmitriptan, which is a selective 5‐hydroxytryptamine 1B/1D (5-HT 1B/1D ) receptor agonist. Zolmitriptan is chemically designated as (S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone and has the following chemical structure: The empirical formula is C­ 16 ­H­ 21 ­N­ 3 ­O­­ 2 ­, representing a molecular weight of 287.36. Zolmitriptan is a white to almost white powder that is readily soluble in water. ZOMIG tablets are available as 2.5 mg (yellow) and 5 mg (pink) film-coated tablets for oral administration. The film-coated tablets contain anhydrous lactose, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide, titanium dioxide, polyvinyl alcohol, polyethylene glycol, talc, yellow iron oxide (2.5 mg tablet), and red iron oxide (5 mg tablet). structural figure

10 OVERDOSAGE There is no experience with acute overdose of ZOMIG. Clinical study subjects who received single 50 mg oral doses of ZOMIG commonly experienced sedation. There is no specific antidote to ZOMIG. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system. The elimination half-life of ZOMIG is 3 hours [see Clinical Pharmacology (12.1)] ;therefore, monitor patients after overdose with ZOMIG for at least 15 hours or until symptoms or signs resolve. It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of zolmitriptan.

16 HOW SUPPLIED 2.5 mg Tablets – Yellow colored, round, biconvex film-coated tablets, debossed with 101 on one side and deep breakline on other side and are supplied in carton of 6 (1 x 6) unit-dose tablets (NDC 60846-130-30). 5 mg Tablets – Pink colored, round, biconvex film-coated tablets, debossed with 102 on one side and plain on the other side and are supplied in carton of 3 (1 x 3) unit-dose tablets (NDC 60846-133-60). Store ZOMIG Tablets between 20o to 25oC (68o to 77oF) [see USP Controlled Room Temperature]. Protect from light and moisture.