Zolmitriptan

Recent Major Changes Dosage and Administration ( 2.1 , 2.3 , 2.4 ) 09/2012 Warnings and Precautions ( 5.6 ) 09/2012

1 INDICATIONS AND USAGE 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 )

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 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 tabletsin 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) ] .

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 tabletsin 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) ] .

3 DOSAGE FORMS AND STRENGTHS 2.5 mg Tablets: Yellow colored, round, biconvex, film-coated tablets debossed with ‘C’ and ‘C’ on either side of the score line on one side and ‘37’ on the other side (functionally-scored). 5 mg Tablets: Pink colored, round, biconvex, film-coated tablets debossed with ‘CC’ on one side and ‘51’ on the other side (not scored). Tablets: 2.5 mg functionally-scored (3) Tablets: 5 mg (not scored) (3)

4 CONTRAINDICATIONS 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 )

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 Avéma 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 zolmitriptan tablets 1 mg, 2.5 mg, or 5 mg dose groups in the controlled clinical trials of zolmitriptan tablets 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 tablets 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 Tablets 1 mg (n=163) Zolmitriptan Tablets 2.5 mg (n=498) Zolmitriptan Tablets 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 tablet 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 tablets in their causation cannot be reliably determined. Furthermore, variabil …

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 zolmitriptan tablets 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 zolmitriptan tablets 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 zolmitriptan tablets 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 zolmitriptan tablets are used concomitantly, limit the maximum single dose of zolmitriptan tablets to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ] .

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 tablets 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 zolmitriptan tablets 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 zolmitriptan tablets 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 zolmitriptan tablets are used concomitantly, limit the maximum single dose of zolmitriptan tablets to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS The following adverse reactions are described elsewhere in other sections of the prescribing information: Myocardial Ischemia, Myocardial Infarction, and Prinzmetal 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 ) ]. Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) 8.1 Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women; therefore, zolmitriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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. 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. 8.3 Nursing Mothers It is not known whether zolmitriptan is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from zolmitriptan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In rats, oral dosing with zolmitriptan resulted in levels in milk up to 4 times higher than in plasma. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. Therefore, zolmitriptan is not recommended for use in patients under 18 years of age. One randomized, placebo-controlled clinical trial of zolmitriptan 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 zolmitriptan compared to placebo in the treatment of migraine in adolescents. Adverse reactions in the adolescent patients treated with zolmitriptan were similar in nature and frequency to those reported in clinical trials in adults treated with zolmitriptan. Zolmitriptan has not been studied in pediatric patients less than 12 years old. In the postmarketing experience with triptans, including zolmitriptan, there were no additional adverse reactions seen in pediatric patients that were not seen in adults. 8.5 Geriatric Use Clinical studies of zolmitriptan 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 id …

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 zolmitriptan tablets 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 Zolmitriptan tablets, USP 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-5yl]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. Zolmitriptan is a white to off-white crystalline powder that is practically insoluble in water. Zolmitriptan 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. In addition, following inactive ingredients are also present as components of the film coat: hypromellose, titanium dioxide, polyethylene glycol 4000, yellow iron oxide (2.5 mg strength) and hypromellose, titanium dioxide, talc, polyethylene glycol 6000 and red iron oxide (5 mg strength). Structure

10 OVERDOSAGE There is no experience with acute overdose of zolmitriptan tablets. Clinical study subjects who received single 50 mg oral doses of zolmitriptan tablets commonly experienced sedation. There is no specific antidote to zolmitriptan tablets. 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 zolmitriptan tablets is 3 hours [see Clinical Pharmacology ( 12.1 ) ]; therefore, monitor patients after overdose with zolmitriptan tablets 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/STORAGE AND HANDLING Zolmitriptan tablet, USP 2.5 mg Tablets – Yellow colored, round, biconvex film-coated tablets debossed with “497” on one side and functionally-scored on the other side and are supplied in Cartons (NDC 69462-497-76) containing one blister pack of 6 unit-dose tablets (NDC 68462-497-40). Zolmitriptan tablet, USP 5 mg Tablets – Pink colored, round, biconvex film-coated tablets debossed with “498” on one side and plain on the other side and are supplied in cartons (NDC 68462-498-33) containing one blister pack of 3 unit-dose tablets (NDC 68462-498-40). Store zolmitriptan tablets at 20°C to 25°C (68°F to 77°F); [see USP Controlled Room Temperature]. Protect from light and moisture.