ZOLMITRIPTAN

Zolmitriptan tablets, USP contain zolmitriptan, which is a selective 5-hydroxytryptamine 1B/1D (5-HT 1B/1D ) receptor agonist. Zolmitriptan is chemically designated as (4S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone and has the following chemical structure: The molecular formula is C 16 H 21 N 3 O 2 , representing a molecular weight of 287.36 g/mol. Zolmitriptan is a white to off-white powder that is soluble in methanol and acetone, insoluble in water. Zolmitriptan tablets, USP are available as 2.5 mg (yellow) and 5 mg (pink) film-coated tablets for oral administration. The film-coated tablets contain anhydrous lactose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polyethylene glycol 8000, red iron oxide (5 mg tablet), sodium starch glycolate, titanium dioxide and yellow iron oxide (2.5 mg tablet). Structure

Zolmitriptan tablets are indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use • Only use zolmitriptan tablets if a clear diagnosis of migraine has been established. If a patient has no response to zolmitriptan tablets treatment for the first migraine attack, reconsider the diagnosis of migraine before zolmitriptan tablets are administered to treat any subsequent attacks. • Zolmitriptan tablets are not indicated for the prevention of migraine attacks. • Safety and effectiveness of zolmitriptan tablets have not been established for cluster headache. Zolmitriptan tablets are 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 )

• 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 zolmitriptan tablets 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 zolmitriptan tablets 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 zolmitriptan tablets, 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 zolmitriptan tablets 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 zolmitriptan tablets in patients with moderate to severe hepatic impairment is 1.25 mg (one-half of one 2.5 mg zolmitriptan 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 zolmitriptan tablets are co-administered with cimetidine, limit the maximum single dose of zolmitriptan tablets to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Drug Interactions ( 7.5 ), Clinical Pharmacology ( 12.3 ) ].

Zolmitriptan tablets are contraindicated in patients with: • Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), other significant underlying cardiovascular disease, or c oronary 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 zolmitriptan tablets (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 zolmitriptan tablets ( 4 )

The following adverse reactions are described elsewhere in other sections of the prescribing information: • Myocardial Ischemia, Myocardial Infarction, and Prinzmetal Angina [ seeWarnings and Precautions ( 5.1 ) ]. • Arrhythmias [ see Warnings and Precautions ( 5.2 ) ]. • Chest and or Throat, Neck and Jaw Pain/Tightness/Pressure [ seeWarnings and Precautions ( 5.3 ) ]. • Cerebrovascular Events [ see Warnings and Precautions ( 5.4 ) ]. • Other Vasospasm Reactions [ seeWarnings and Precautions ( 5.5 ) ]. • Medication Overuse Headache [ seeWarnings and Precautions ( 5.6 ) ]. • Serotonin Syndrome [ seeWarnings 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 Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 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 zolmitriptan 1 mg, 2.5 mg, or 5 mg dose groups in the controlled clinical trials of zolmitriptan 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 zolmitriptan 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) Zolmitriptan 1 mg (n=163) Zolmitriptan 2.5 mg (n=498) Zolmitriptan 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 zolmitriptan 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 Zolmitriptan 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 zolmitriptan 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. Adverse reaction frequencies were calculated as the number of patients who used zolmitriptan tablets and reported a reaction divided by the total number of patients exposed to zolmitriptan tablets (n=4,027). Reactions were further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: infrequent adverse reactions (those occurring in 1/100 to 1/1,000 patients) and rare adverse reactions (those occurring in less than 1/1,000 patients). General : Infrequent were allergic reactions. Cardiovascular : Infrequent were arrhythmias, hypertension, and syncope. Rare was tachycardia. Neurological : Infrequent were agitation, anxiety, depression, emotional lability and insomnia; Rare were amnesia, hallucinations, and cerebral ischemia. Skin : Infrequent were pruritus, rash and urticaria. Urogenital: Infrequent were polyuria, urinary frequency and urinary urgency. Adverse Reactions with Zolmitriptan Orally Disintegrating Tablets The adverse reaction profile seen with zolmitriptan orally disintegrating tablets was similar to that seen with zolmitriptan tablets. 6.2 Postmarketing Experience The following adverse reactions were identified during post approval use of zolmitriptan. 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: As with other 5-HT 1B/1D agonists, there have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving zolmitriptan. Zolmitriptan is contraindicated in patients with a history of hypersensitivity reaction to zolmitriptan.

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 zolmitriptan within 24 hours of each other is contraindicated [ seeContraindications ( 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 zolmitriptan in patients receiving MAO-A inhibitors is contraindicated [ seeContraindications ( 4 ), Clinical Pharmacology ( 12.3 ) ] . 7.3 5-HT 1B/1D agonists Concomitant use of other 5-HT 1B/1D agonists (including triptans) within 24 hours of zolmitriptan treatment is contraindicated because the risk of vasospastic reactions may be additive [ seeContraindications ( 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) [ seeWarnings 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 [ seeClinical Pharmacology ( 12.3 ) ] . If cimetidine and zolmitriptan are used concomitantly, limit the maximum single dose of zolmitriptan to 2.5 mg, not to exceed 5 mg in any 24-hour period [ seeDosage and Administration ( 2.4 ), Clinical Pharmacology ( 12.3 ) ].