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 NASAL SPRAY if a clear diagnosis of migraine has been established. If a patient has no response to ZOLMITRIPTAN NASAL SPRAY treatment for the first migraine attack, reconsider the diagnosis of migraine before ZOLMITRIPTAN NASAL SPRAY is administered to treat any subsequent attacks. ZOLMITRIPTAN NASAL SPRAY is not indicated for the prevention of migraine attacks. Safety and effectiveness of ZOLMITRIPTAN NASAL SPRAY 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 intended 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)

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 Amneal Pharmaceuticals at 1-877-835-5472 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 repeated use of zolmitriptan nasal spray. All nasopharyngeal adverse reactions with an incidence of ≥ 2% of patients in any zolmitriptan nasal spray dose groups are included in Table 1. Other Adverse Reactions: 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. Reaction frequencies are calculated as the number of patients who used zolmitriptan nasal spray and reported a reaction divided by the total number of patients exposed to zolmitriptan nasal spray (n=3059). All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients and rare adverse reactions are those occurring in fewer than 1/1,000 patients. General: Infrequent: allergic reactions. Cardiovascular: Infrequent: arrhythmias, hypertension, syncope and tachycardia. Rare: angina pectoris and myocardial infarct. Digestive: Rare: stomatitis. Neurological: Infrequent: agitation, amnesia, anxiety, depression, insomnia, and nervousness. Rare: convulsions. Respiratory: Infrequent: bronchitis, increased cough, dyspnea, epistaxis, laryngeal edema, pharyngitis, rhinitis, and sinusitis. Skin: Infrequent: pruritus, rash, and urticaria. Urogenital: Infrequent: polyuria and urinary urgency. Rare: urinary frequency. Special senses: Infrequent: tinnitus. Rare: conjunctivitis, dry eye, and visual field defect. The adverse reaction profile seen with zolmitriptan nasal spray is similar to that seen with zolmitriptan tablets and zolmitriptan orally disintegrating tablets except for the occurrence of local adverse reactions from the nasal spray (see zolmitriptan tablet/zolmitriptan oral disintegrating tablet Prescribing Information) . Pediatric Patients 12 to 17 Years of Age 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 studies [see Pediatric Use (8.4) and Clinical Studies (14.2) ] . The most common adverse reactions (incidence of ≥ 2% of pediatric patients receiving 2.5 mg and 5 mg zolmitriptan nasal spray and numerically greater than placebo) after a single dose are summarized in Table 2. Dysgeusia (unusual taste) was the most common adverse reaction, with a numerically greater incidence for patients receiving zolmitriptan compared to placebo (10% vs. 2%). Other common adverse reactions were nasal discomfort, dizziness, oropharyngeal pain, and nausea. Table 2 lists the adverse reactions from the pooled placebo-controlled studies that occurred in ≥ 2% of pediatric patients 12 to 17 years of age in either the 2.5 mg or 5 mg zolmitriptan dose groups and with an incidence greater than placebo. Table 2: Adverse reactions in Pooled Placebo-Controlled Studies in Pediatric Patients 12 to 17 years of Age with Migraine Adverse Reaction Placebo (N=437) Zolmitriptan 2.5 mg (N=81) Zolmitriptan 5 mg (N=431) Unusual taste 2% 6% 10% Nasal discomfort 1% 3% 3% Dizziness 1% 0% 2% Oropharyngeal pain 2% 0% 2% Nausea 1% 1% 2% The adverse reaction profile was similar across gender. There were insufficient data to assess the impact of race on the incidence of adverse reactions. 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: 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.