Naratriptan

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 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 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)] .

3 DOSAGE FORMS AND STRENGTHS 1 mg white to off-white tablets, capsule shaped, film-coated, and debossed with "N" on one side and "1" on the other side 2.5 mg green tablets, capsule shaped, film-coated, and debossed with "N" on one side and "2.5" on the other side Tablets: 1 mg and 2.5 mg (3, 16)

4 CONTRAINDICATIONS Naratriptan tablets are contraindicated in patients with: Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) 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 or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because such patients are at a higher risk of stroke [s ee Warnings and Precautions (5.4)] Peripheral vascular disease [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, ergot-type medication (such as dihydroergotamine or methysergide) [see Drug Interactions (7.1, 7.2)] Hypersensitivity to naratriptan tablets (angioedema and anaphylaxis seen) [see Warnings and Precautions (5.9)] Severe renal or hepatic impairment [see Use in Specific Populations (8.6, 8.7), Clinical Pharmacology (12.3)] History of coronary artery disease or coronary artery vasospasm (4) 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) Hypersensitivity to naratriptan tablets (angioedema and anaphylaxis seen) (4) Severe renal or hepatic impairment (4)

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 [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)] 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 Bionpharma Inc. at 1-888-235-BION or 1-888-235-2466 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 tablets 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 tablets 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)] .

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 use of naratriptan tablets in pregnant women. Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have documented outcomes in women exposed to naratriptan during pregnancy; however, due to small sample sizes, no definitive conclusions can be drawn regarding the risk of birth defects following exposure to naratriptan [see Data] . In animal studies, naratriptan produced developmental toxicity (including embryolethality and fetal abnormalities) when administered to pregnant rats and rabbits. The lowest doses producing evidence of developmental toxicity in animals were associated with plasma exposures 2.5 (rabbit) to 11 (rat) times that in humans at the maximum recommended daily dose (MRDD) [see Data] . In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy. Data Human Data : The numbers of exposed pregnancy outcomes accumulated during the Sumatriptan/Naratriptan/Treximet ® (sumatriptan and naproxen sodium) Pregnancy Registry, a population-based international prospective study that collected data from October 1997 to September 2012, and smaller observational studies, were insufficient to define a level of risk for naratriptan in pregnant women. The Registry documented outcomes of 57 infants and fetuses exposed to naratriptan during pregnancy (52 exposed during the first trimester and 5 exposed during the second trimester). The occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to naratriptan was 2.2% (1/46 [95% CI: 0.1% to 13%]) and during any trimester of exposure was 2% (1/51 [95% CI: 0.1% to 11.8%]). Seven infants were exposed to both naratriptan and sumatriptan in utero, and one of these infants with first-trimester exposure was born with a major birth defect (ventricular septal defect). The sample size in this study had 80% power to detect at least a 3.8 to 4.6 fold increase in the rate of major malformations. In a study using data from the Swedish Medical Birth Register, women who used triptans or ergots during pregnancy were compared with women who did not. Of the 22 births with first-trimester exposure to naratriptan, one infant was born with a malformation (congenital deformity of the hand). Animal Data : When naratriptan was administered to pregnant rats during the period of organogenesis at doses of 10, 60, or 340 mg/kg/day, there was a dose-related increase in embryonic death; incidences of fetal structural variations (incomplete/irregular ossification of skull bones, sternebrae, ribs) were increased at all doses. The maternal plasma exposures (AUC) at these doses were approximately 11, 70, and 470 times the exposure in humans at the MRDD. The high dose was maternally toxic, as evidenced by decreased maternal body weight gain during gestation. A no-effect dose for developmental toxicity in rats exposed during organogenesis was not established. When naratriptan was administered orally (1, 5, or 30 mg/kg/day) to pregnant Dutch rabbits throughout organogenesis, the incidence of a specific fetal skeletal malformation (fused sternebrae) was increased at the high dose, the incidence of fetal variations (major blood vessel variations, supernumerary ribs, incomplete skel …

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 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 Naratriptan tablets, USP contain naratriptan hydrochloride USP, a selective 5-HT 1B/1D receptor agonist. Naratriptan hydrochloride, USP is chemically designated as N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide monohydrochloride, and it has the following structure: The empirical formula is C 17 H 25 N 3 O 2 S•HCl, representing a molecular weight of 371.93. Naratriptan hydrochloride, USP is a white to pale yellow powder that is sparingly soluble in water. Each naratriptan tablet, USP for oral administration contains 1.11 or 2.78 mg of naratriptan hydrochloride USP, equivalent to 1 or 2.5 mg of naratriptan, respectively. Each tablet also contains the inactive ingredients croscarmellose sodium, anhydrous lactose, magnesium stearate, microcrystalline cellulose, opadry white (1 mg tablet) and opadry green (2.5 mg tablet). The components of opadry white are hypromellose, triacetin, and titanium dioxide. The components of opadry green are hypromellose, triacetin, titanium dioxide, iron oxide yellow, and FD&C Blue No. 2. molecular structure

10 OVERDOSAGE Adverse reactions observed after overdoses of up to 25 mg included increases in blood pressure resulting in lightheadedness, neck tension, tiredness, and loss of coordination. Also, ischemic ECG changes likely due to coronary artery vasospasm have been reported. The elimination half-life of naratriptan is about 6 hours [see Clinical Pharmacology (12.3)] , therefore monitoring of patients after overdose with naratriptan tablets should continue for at least 24 hours or while symptoms or signs persist. There is no specific antidote to naratriptan. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of naratriptan.

16 HOW SUPPLIED/STORAGE AND HANDLING Naratriptan tablets, USP containing 1 mg and 2.5 mg of naratriptan (base) as the hydrochloride salt. Naratriptan Tablets USP, 1 mg, are white to off-white colored, capsule shaped, film-coated tablets debossed with “N” on one side and “1” on the other side are supplied as: Carton of 9 Unit-of-Use tablets each with cross perforation and individually labeled NDC 69452-340-72 Naratriptan Tablets USP, 2.5 mg, are green colored, capsule shaped, film-coated tablets debossed with “N” on one side and “2.5” on the other side are supplied as: Carton of 9 Unit-of-Use tablets each with cross perforation and individually labeled NDC 69452-341-72 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].