Naratriptan

12.1 Mechanism of Action Naratriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (including substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of naratriptan 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.

1 INDICATIONS AND USAGE Naratriptan tablets are indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use: Use only if a clear diagnosis of migraine has been established. If a patient has no response to the first migraine attack treated with naratriptan tablets reconsider the diagnosis of migraine before naratriptan tablets are administered to treat any subsequent attacks. Naratriptan tablets are not indicated for the prevention of migraine attacks. Safety and effectiveness of naratriptan tablets have not been established for cluster headache. Naratriptan Tablets are serotonin (5-HT 1B/1D ) receptor agonists (triptan) indicated for the acute treatment of migraine with or without aura in adults. (1) Limitations of Use: Use only if a clear diagnosis of migraine has been established. (1) Not indicated for the prophylactic therapy of migraine attacks. (1) Not indicated for the treatment of cluster headache. (1)

2 DOSAGE AND ADMINISTRATION Recommended dose: 1 mg or 2.5 mg. ( 2.1 ) May repeat dose after 4 hours if needed; not to exceed 5 mg in any 24- hour period. ( 2.1 ) Mild or moderate renal or hepatic impairment: recommended starting dose is 1 mg not to exceed 2.5 mg in any 24-hour period. ( 2.2 , 2.3 ) 2.1 Dosing Information The recommended dose of naratriptan tablets is 1 mg or 2.5 mg. If the migraine returns or if the patient has only partial response, the dose may be repeated once after 4 hours, for a maximum dose of 5 mg in a 24-hour period. The safety of treating an average of more than 4 migraine attacks in a 30-day period has not been established. 2.2 Dosage Adjustment in Patients With Renal Impairment Naratriptan tablets are contraindicated in patients with severe renal impairment (creatinine clearance: <15 mL/min) because of decreased clearance of the drug [see Contraindications (4) , Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. In patients with mild to moderate renal impairment, the maximum daily dose should not exceed 2.5 mg over a 24-hour period and a 1-mg starting dose is recommended [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. 2.3 Dosage Adjustment in Patients With Hepatic Impairment Naratriptan tablets are contraindicated in patients with severe hepatic impairment (Child-Pugh Grade C) because of decreased clearance [see Contraindications (4) , Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. In patients with mild or moderate hepatic impairment (Child-Pugh Grade A or B), the maximum daily dose should not exceed 2.5 mg over a 24-hour period and a 1-mg starting dose is recommended [ see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ].

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail 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, 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 [s ee 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) ] Hypersensitivity reactions [see Contraindications (4) , Warnings and Precautions (5.9) ] Most common adverse reactions (≥2% and >placebo) were paresthesias, nausea, dizziness, drowsiness, malaise/fatigue, and throat/neck symptoms. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a long-term open-label trial where patients were allowed to treat multiple migraine attacks for up to 1 year, 15 patients (3.6%) discontinued treatment due to adverse reactions. In controlled clinical trials, the most common adverse reactions were paresthesias, dizziness, drowsiness, malaise/fatigue, and throat/neck symptoms, which occurred at a rate of 2% and at least 2 times placebo rate. Table 1 lists the adverse reactions that occurred in 5 placebo-controlled clinical trials of approximately 1,752 exposures to placebo and naratriptan tablets in adult patients with migraine. Only reactions that occurred at a frequency of 2% or more in groups treated with naratriptan tablets 2.5 mg and that occurred at a frequency greater than the placebo group in the 5 pooled trials are included in Table 1. Table 1. Adverse Reactions Reported by at Least 2% of Patients Treated With Naratriptan Tablets and at a Frequency Greater Than Placebo Adverse Reaction Percent of Patients Reporting Naratriptan Tablets 1 mg (n = 627) Naratriptan Tablets 2.5 mg (n = 627) Placebo (n = 498) Atypical sensation 2 4 1 Paresthesias (all types) 1 2 <1 Gastrointestinal 6 7 5 Nausea 4 5 4 Neurological 4 7 3 Dizziness 1 2 1 Drowsiness 1 2 <1 Malaise/fatigue 2 2 1 Pain and pressure sensation 2 4 2 Throat/neck symptoms 1 2 1 The incidence of adverse reactions in controlled clinical trials was not affected by age or weight of the patients, duration of headache prior to treatment, presence of aura, use of prophylactic medications, or tobacco use. There were insufficient data to assess the impact of race on the incidence of adverse reactions.

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 naratriptan within 24 hours of each other is contraindicated. 7.2 Other 5-HT 1 Agonists Concomitant use of other 5-HT 1B/1D agonists (including triptans) within 24 hours of treatment with naratriptan is contraindicated because the risk of vasospastic reactions may be additive. 7.3 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of serotonin syndrome have been reported during co-administration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7) ].