zolmitriptan

1 INDICATIONS AND USAGE Zolmitriptan 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 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 is not indicated for the prevention of migraine attacks. • Safety and effectiveness of zolmitriptan have not been established for cluster headache. • Not recommended in patients with moderate or severe hepatic impairment [ see Dosage and Administration ( 2.2 ) ]. • Zolmitriptan 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 indicated 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 zolmitriptan nasal spray in adult and pediatric patients 12 years of age and older is 2.5 mg. As the individual response to zolmitriptan nasal spray may vary, the dose should be adjusted on an individual basis. The maximum recommended single dose of zolmitriptan is 5 mg. If the migraine has not resolved by 2 hours after taking zolmitriptan, 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 zolmitriptan 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 Zolmitriptan 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 zolmitriptan 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 zolmitriptan is co-administered 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 ( 7.4 ) and Clinical Pharmacology ( 12.3 ) ].

3 DOSAGE FORMS AND STRENGTHS Nasal Spray 2.5 mg and 5 mg. Nasal Spray: 2.5 mg and 5 mg ( 3 )

4 CONTRAINDICATIONS Zolmitriptan 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 zolmitriptan (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 zolmitriptan ( 4 )

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 Perrigo at 1-866-634-9120 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 zolmitriptan 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 zolmitriptan nasal spray. The most common adverse reactions (≥ 5% and > placebo) in any dosage strength in clinical trials for zolmitriptan 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 zolmitriptan 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) Zolmitriptan 2.5 mg (N=224) Zolmitriptan 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 zolmitriptan 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 zolmitriptan 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 rep …

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 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. Therefore, the use of zolmitriptan 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 zolmitriptan 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 zolmitriptan and its active metabolites 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 ( 2.3 ) 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 ) ].

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 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. 8.2 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 Safety and effectiveness of zolmitriptan in pediatric patients under 12 years of age have not been established. The efficacy of zolmitriptan nasal spray in the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in a placebo-controlled study with a total of 81 pediatric patients receiving zolmitriptan 2.5 mg and 229 pediatric patients receiving zolmitriptan 5 mg [ see Clinical Studies ( 14.2 ) ]. In an earlier study with a different design, zolmitriptan 5 mg nasal spray was evaluated in the acute treatment of migraine headache in 171 pediatric patients 12 to 17 years of age. In that study, the efficacy of zolmitriptan nasal spray was not established. The safety of zolmitriptan nasal spray in the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in two placebo-controlled studies with a total of 81 pediatric patients receiving zolmitriptan 2.5 mg and 431 pediatric patients receiving zolmitriptan 5 mg [ see Adverse Reactions ( 6.1 ) ]. The safety profile of zolmitriptan nasal spray in pediatric patients 12 to 17 years of age is similar to the profile observed in adults [ see Adverse Reactions ( 6.1 ) ]. In the postmarketing experience with trip …

12.1 Mechanism of Action Zolmitriptan binds with high affinity to human recombinant 5-HT 1D and 5-HT 1 B 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. Current theories proposed to explain the etiology of migraine headache suggest that symptoms are 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 Nasal Spray, USP contains 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. Zolmitriptan Nasal Spray is supplied as a clear to pale yellow solution of zolmitriptan, buffered to a pH 5.0. Each Zolmitriptan Nasal Spray contains 2.5 mg or 5 mg of zolmitriptan in a 100-μL unit dose aqueous buffered solution containing citric acid, anhydrous, USP, disodium phosphate dodecahydrate USP, benzalkonium chloride solution NF and purified water USP. Zolmitriptan Nasal Spray is hypertonic. The osmolarity of Zolmitriptan Nasal Spray for 2.5 mg is 358 to 396 mOsmol, and for 5 mg is 411 to 455 mOsmol. chemical-structure

10 OVERDOSAGE There is no experience with acute overdose. Clinical study subjects receiving single 50 mg oral doses of zolmitriptan commonly experienced sedation. The elimination half-life of zolmitriptan is 3 hours [ see Clinical Pharmacology ( 12.1 ) ] and therefore monitoring of patients after overdose with zolmitriptan should continue for at least 15 hours or while symptoms or signs persist. 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. It is unknown what effect hemodialysis or peritoneal dialysis has on the plasma concentrations of zolmitriptan.

16 HOW SUPPLIED/STORAGE AND HANDLING The Zolmitriptan Nasal Spray device is a white plastic device, labeled to indicate the nominal dose. Each Zolmitriptan Nasal Spray device administers a single dose of zolmitriptan. Zolmitriptan Nasal Spray, USP is supplied as a clear to pale yellow solution of zolmitriptan, buffered to a pH 5.0. Each Zolmitriptan Nasal Spray device contains 2.5 mg or 5 mg of zolmitriptan in a 100 μL unit dose aqueous buffered solution containing citric acid, anhydrous, USP, disodium phosphate dodecahydrate USP, benzalkonium chloride solution NF and purified water USP. 2.5 mg Zolmitriptan Nasal Spray is supplied in boxes of 6 single-use nasal spray units. (NDC 45802-606-91) 5 mg Zolmitriptan Nasal Spray is supplied in boxes of 6 single-use nasal spray units. (NDC 45802-711-91) Each Zolmitriptan Nasal Spray single dose unit spray supplies 2.5 and 5 mg, respectively, of zolmitriptan. The Zolmitriptan Nasal Spray unit must be discarded after use. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].