Zolmitriptan

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

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

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 ) Do not break zolmitriptan orally disintegrating tablets ( 2.2 ) 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, 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 in the treatment of an average of more than three migraines in a 30-day period has not been established. 2.2 Administration of Zolmitriptan Orally Disintegrating Tablets Instruct patients not to break zolmitriptan orally disintegrating tablets because they are not functionally-scored. Administration with liquid is not necessary. Orally disintegrating tablets are packaged in a blister pack. Instruct patients not to remove the tablet from the blister until just prior to dosing. Subsequently, instruct patients to peel the blister pack open, and to place the orally disintegrating tablet on the tongue, where it will dissolve and it will be swallowed with the saliva. 2.3 Dosing in Patients with Hepatic Impairment The recommended dose of zolmitriptan 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. The use of zolmitriptan orally disintegrating tablets is not recommended in patients with moderate or severe hepatic impairment because these orally disintegrating tablets should not be broken in half [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 ) ]. 2.4 Dosing in Patients taking Cimetidine If zolmitriptan is coadministered with cimetidine, limit the maximum single dose of zolmitriptan 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 Orally Disintegrating Tablets: 2.5 mg and 5 mg ( 3 ) 2.5 mg tablets are white/mottled white to cream white, round, flat-faced uncoated tablet, debossed with '715' on one side and plain on other the side. 5 mg tablets are white/mottled white to cream white round, biconvex, beveled, uncoated tablet, debossed with '717' on one side and plain on the other side.

4 CONTRAINDICATIONS 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 ( 4 ) Zolmitriptan orally disintegrating 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 ), Clinical Pharmacology ( 12.3 ) ]. Known hypersensitivity to zolmitriptan (angioedema and anaphylaxis seen) [see Adverse Reactions ( 6.2 ) ].

6 ADVERSE REACTIONS 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 Zydus Pharmaceuticals(USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 )]. Arrthymias [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 )]. Risks in Patients with Phenylketonuria [see Warnings and Precautions ( 5.9 )]. 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* * Only adverse reactions that were at least 2% more frequent in a zolmitriptan group compared to the placebo group are included. 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% 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 …

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 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 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 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 coadministration 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 are used concomitantly, limit the maximum single dose of zolmitriptan 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 Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of zolmitriptan 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 zolmitriptan and any potential adverse effects on the breastfed infant from zolmitriptan or from the underlying maternal condition. 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 identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly pa …

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 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 orally disintegrating 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 molecular formula is C 16 H 21 N 3 O 2 , representing a molecular weight of 287.36. Zolmitriptan, USP is white to off-white crystalline powder that is freely soluble to soluble in methanol and soluble in water, sparingly soluble in dichloromethane, practically insoluble in toluene. Each zolmitriptan orally disintegrating tablet USP, intended for oral administration,contains 2.5 mg or 5 mg of zolmitriptan USP. In addition, each tablet contains the following inactive ingredients: anhydrous citric acid, aspartame, colloidal silicon dioxide, crospovidone, gelatin, magnesium stearate,mannitol, microcrystalline cellulose, orange flavor, polacrilin potassium and sodium stearyl fumarate. Structural Formula

10 OVERDOSAGE There is no experience with acute overdose of zolmitriptan. Clinical study subjects who received single 50 mg oral doses of zolmitriptan commonly experienced sedation. There is no specific antidote to zolmitriptan. 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 is 3 hours [see Clinical Pharmacology ( 12.1 ) ]; therefore, monitor patients after overdose with zolmitriptan 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 Orally Disintegrating Tablets USP, 2.5 mg are white/mottled white to cream white, round, flat-faced, uncoated tablet, debossed with '715' on one side and plain on the other side and are supplied as follows: NDC 68382-715-06 in bottle of 30 tablets with child-resistant closure NDC 68382-715-16 in bottle of 90 tablets with child-resistant closure NDC 68382-715-01 in bottle of 100 tablets NDC 68382-715-10 in bottle of 1000 tablets NDC 68382-715-86 in unit-dose blister cartons of 6 (1 x 6) unit dose tablets NDC 68382-715-77 in unit-dose blister cartons of 100 (10 x 10) unit dose tablets Zolmitriptan Orally Disintegrating Tablets USP, 5 mg are white/mottled white to cream white, round, biconvex, beveled, uncoated tablet, debossed with '717' on one side and plain on the other side and are supplied as follows: NDC 68382-717-06 in bottle of 30 tablets with child-resistant closure NDC 68382-717-16 in bottle of 90 tablets with child-resistant closure NDC 68382-717-01 in bottle of 100 tablets NDC 68382-717-10 in bottle of 1000 tablets NDC 68382-717-82 in unit-dose blister cartons of 3 (1 x 3) unit dose tablets NDC 68382-717-77 in unit-dose blister cartons of 100 (10 x 10) unit dose tablets Storage and Handling Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. Protect from light and moisture. Dispense in a tight, light-resistant closed container.