Naratriptan

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 Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 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 to 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 in adult patients with migraine. Only reactions that occurred at a frequency of 2% or more in groups treated with naratriptan 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 and at a Frequency Greater Than Placebo Percent of Patients Reporting Adverse Reaction Naratriptan 1 mg (n=627) Naratriptan 2.5 mg (n=627) Placebo (n=498) Atypical Sensation Paresthesias (all types) 2 1 4 2 1 <1 Gastrointestinal Nausea 6 4 7 5 5 4 Neurological Dizziness Drowsiness Malaise/Fatigue 4 1 1 2 7 2 2 2 3 1 <1 1 Pain and Pressure Sensation Throat/Neck Symptoms 2 1 4 2 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.

4 CONTRAINDICATIONS Naratriptan is 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 [see 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 (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 (angioedema and anaphylaxis seen) ( 4 ) • Severe renal or hepatic impairment ( 4 )

11 DESCRIPTION Naratriptan Tablets, USP contains naratriptan hydrochloride, USP, a selective 5-HT 1B/1D receptor agonist. Naratriptan hydrochloride 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 crystalline powder that is readily soluble in water . Each naratriptan tablet 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: colloidal silicon dioxide, croscarmellose sodium, lactose (anhydrous), magnesium stearate, and microcrystalline cellulose. chem

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 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 is 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 is 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 )] .

1 INDICATIONS AND USAGE Naratriptan is indicated for the acute treatment of migraine attacks 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, reconsider the diagnosis of migraine before naratriptan is administered to treat any subsequent attacks. • Naratriptan is not indicated for the prevention of migraine attacks. • Safety and effectiveness of naratriptan have not been established for cluster headache. Naratriptan is 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 )

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 )] , and therefore monitoring of patients after overdose with naratriptan 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.

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 )] .

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics In the anesthetized dog, naratriptan has been shown to reduce the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance. While the effect on blood flow was selective for the carotid arterial bed, increases in vascular resistance of up to 30% were seen in the coronary arterial bed. Naratriptan has also been shown to inhibit trigeminal nerve activity in rat and cat. In 10 subjects with suspected CAD undergoing coronary artery catheterization, there was a 1% to 10% reduction in coronary artery diameter following subcutaneous injection of 1.5 mg of naratriptan [see Contraindications ( 4 )] . 12.3 Pharmacokinetics Absorption: Naratriptan is well absorbed, with about 70% oral bioavailability. Following administration of a 2.5-mg tablet, the peak concentrations are obtained in 2 to 3 hours. After administration of 1- or 2.5-mg tablets, the C max is somewhat (about 50%) higher in women (not corrected for milligram-per-kilogram dose) than in men. During a migraine attack, absorption is slower, with a T max of 3 to 4 hours. Food does not affect the pharmacokinetics of naratriptan. Naratriptan displays linear kinetics over the therapeutic dose range. Distribution: The steady-state volume of distribution of naratriptan is 170 L. Plasma protein binding is 28% to 31% over the concentration range of 50 to 1,000 ng/mL. Metabolism: In vitro , naratriptan is metabolized by a wide range of cytochrome P450 isoenzymes into a number of inactive metabolites. Elimination: Naratriptan is predominantly eliminated in urine, with 50% of the dose recovered unchanged and 30% as metabolites in urine. The mean elimination half-life of naratriptan is 6 hours. The systemic clearance of naratriptan is 6.6 mL/min/kg. The renal clearance (220 mL/min) exceeds glomerular filtration rate, indicating active tubular secretion. Repeat administration of naratriptan tablets does not result in drug accumulation. Special Populations: Age: A small decrease in clearance (approximately 26%) was observed in healthy elderly subjects (65 to 77 years) compared with younger subjects, resulting in slightly higher exposure [see Use in Specific Populations ( 8.5 )]. Race: The effect of race on the pharmacokinetics of naratriptan has not been examined. Renal Impairment: Clearance of naratriptan was reduced by 50% in subjects with moderate renal impairment (creatinine clearance: 18 to 39 mL/min) compared with the normal group. Decrease in clearances resulted in an increase of mean half-life from 6 hours (healthy) to 11 hours (range: 7 to 20 hours). The mean C max increased by approximately 40%. The effects of severe renal impairment (creatinine clearance: ≤15 mL/min) on the pharmacokinetics of naratriptan have not been assessed [see Contraindications ( 4 )] . Hepatic Impairment: Clearance of naratriptan was decreased by 30% in subjects with moderate hepatic impairment (Child-Pugh Grade A or B). This resulted in an approximately 40% increase in the half-life (range: 8 to 16 hours). The effects of severe hepatic impairment (Child-Pugh Grade C) on the pharmacokinetics of naratriptan have not been assessed [see Contraindications ( 4 )] . Drug Interaction Studies: From population pharmacokinetic analyses, coadministration of naratriptan and fluoxetine, beta-blockers, or tricyclic antidepressants did not affect the clearance of naratriptan. Oral Contraceptives: Oral contraceptives reduced clearance by 32% and volume of distribution by 22%, resulting in slightly higher concentrations of naratriptan. Hormone replacement therapy had no effect on pharmacokinetics in older female patients. Monoamine Oxidase and P450 Inhibitors: Naratriptan does not inhibit monoamine oxidase (MAO) enzymes and is a poor inhibitor of P450; metabolic interactions between naratriptan and drugs metabolized by P450 or MAO are therefore unlikely. Smoking: Smoking increased the clearance of naratriptan by 30%. Alcohol : In normal volunteers, co-administration of single doses of naratriptan tablets and alcohol did not result in substantial modification of naratriptan pharmacokinetic parameters.

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.

12.2 Pharmacodynamics In the anesthetized dog, naratriptan has been shown to reduce the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance. While the effect on blood flow was selective for the carotid arterial bed, increases in vascular resistance of up to 30% were seen in the coronary arterial bed. Naratriptan has also been shown to inhibit trigeminal nerve activity in rat and cat. In 10 subjects with suspected CAD undergoing coronary artery catheterization, there was a 1% to 10% reduction in coronary artery diameter following subcutaneous injection of 1.5 mg of naratriptan [see Contraindications ( 4 )] .

12.3 Pharmacokinetics Absorption: Naratriptan is well absorbed, with about 70% oral bioavailability. Following administration of a 2.5-mg tablet, the peak concentrations are obtained in 2 to 3 hours. After administration of 1- or 2.5-mg tablets, the C max is somewhat (about 50%) higher in women (not corrected for milligram-per-kilogram dose) than in men. During a migraine attack, absorption is slower, with a T max of 3 to 4 hours. Food does not affect the pharmacokinetics of naratriptan. Naratriptan displays linear kinetics over the therapeutic dose range. Distribution: The steady-state volume of distribution of naratriptan is 170 L. Plasma protein binding is 28% to 31% over the concentration range of 50 to 1,000 ng/mL. Metabolism: In vitro , naratriptan is metabolized by a wide range of cytochrome P450 isoenzymes into a number of inactive metabolites. Elimination: Naratriptan is predominantly eliminated in urine, with 50% of the dose recovered unchanged and 30% as metabolites in urine. The mean elimination half-life of naratriptan is 6 hours. The systemic clearance of naratriptan is 6.6 mL/min/kg. The renal clearance (220 mL/min) exceeds glomerular filtration rate, indicating active tubular secretion. Repeat administration of naratriptan tablets does not result in drug accumulation. Special Populations: Age: A small decrease in clearance (approximately 26%) was observed in healthy elderly subjects (65 to 77 years) compared with younger subjects, resulting in slightly higher exposure [see Use in Specific Populations ( 8.5 )]. Race: The effect of race on the pharmacokinetics of naratriptan has not been examined. Renal Impairment: Clearance of naratriptan was reduced by 50% in subjects with moderate renal impairment (creatinine clearance: 18 to 39 mL/min) compared with the normal group. Decrease in clearances resulted in an increase of mean half-life from 6 hours (healthy) to 11 hours (range: 7 to 20 hours). The mean C max increased by approximately 40%. The effects of severe renal impairment (creatinine clearance: ≤15 mL/min) on the pharmacokinetics of naratriptan have not been assessed [see Contraindications ( 4 )] . Hepatic Impairment: Clearance of naratriptan was decreased by 30% in subjects with moderate hepatic impairment (Child-Pugh Grade A or B). This resulted in an approximately 40% increase in the half-life (range: 8 to 16 hours). The effects of severe hepatic impairment (Child-Pugh Grade C) on the pharmacokinetics of naratriptan have not been assessed [see Contraindications ( 4 )] . Drug Interaction Studies: From population pharmacokinetic analyses, coadministration of naratriptan and fluoxetine, beta-blockers, or tricyclic antidepressants did not affect the clearance of naratriptan. Oral Contraceptives: Oral contraceptives reduced clearance by 32% and volume of distribution by 22%, resulting in slightly higher concentrations of naratriptan. Hormone replacement therapy had no effect on pharmacokinetics in older female patients. Monoamine Oxidase and P450 Inhibitors: Naratriptan does not inhibit monoamine oxidase (MAO) enzymes and is a poor inhibitor of P450; metabolic interactions between naratriptan and drugs metabolized by P450 or MAO are therefore unlikely. Smoking: Smoking increased the clearance of naratriptan by 30%. Alcohol : In normal volunteers, co-administration of single doses of naratriptan tablets and alcohol did not result in substantial modification of naratriptan pharmacokinetic parameters.

20230303

7

3 DOSAGE FORMS AND STRENGTHS 1 mg white to off-white round, biconvex tablet debossed with “54” on one side and “227” on the other side. 2.5 mg white to off-white round, biconvex tablet debossed with “54 351” on one side and plain on the other side. Tablets: 1 mg and 2.5 mg ( 3 , 16 )

Naratriptan Naratriptan NARATRIPTAN HYDROCHLORIDE NARATRIPTAN ANHYDROUS LACTOSE SILICON DIOXIDE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE 54;227 Naratriptan Naratriptan NARATRIPTAN HYDROCHLORIDE NARATRIPTAN ANHYDROUS LACTOSE SILICON DIOXIDE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE 54;351

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: In carcinogenicity studies, mice and rats were given naratriptan by oral gavage for 104 weeks. There was no evidence of an increase in tumors related to naratriptan administration in mice receiving up to 200 mg/kg/day. That dose was associated with a plasma (AUC) exposure that was 110 times the exposure in humans receiving the MRDD of 5 mg. Two rat studies were conducted, one using a standard diet and the other a nitrite-supplemented diet (naratriptan can be nitrosated in vitro to form a mutagenic product that has been detected in the stomachs of rats fed a high nitrite diet). Doses of 5, 20, and 90 mg/kg were associated with AUC exposures that in the standard-diet study were 7, 40, and 236 times, respectively, and in the nitrite-supplemented-diet study were 7, 29, and 180 times, respectively, the exposure in humans at the MRDD. In both studies, there was an increase in the incidence of thyroid follicular hyperplasia in high-dose males and females and in thyroid follicular adenomas in high-dose males. In the standard-diet study only, there was also an increase in the incidence of benign c-cell adenomas in the thyroid of high-dose males and females. The exposures achieved at the no-effect dose for thyroid tumors were 40 (standard diet) and 29 (nitrite-supplemented diet) times the exposure achieved in humans at the MRDD. In the nitrite-supplemented diet study only, the incidence of benign lymphocytic thymoma was increased in all treated groups of females. It was not determined if the nitrosated product is systemically absorbed. However, no changes were seen in the stomachs of rats in that study. Mutagenesis: Naratriptan was not mutagenic when tested in in vitro gene mutation (Ames and mouse lymphoma tk ) assays. Naratriptan was also negative in the in vitro human lymphocyte assay and the in vivo mouse micronucleus assay. Naratriptan can be nitrosated in vitro to form a mutagenic product (WHO nitrosation assay) that has been detected in the stomachs of rats fed a nitrite-supplemented diet. Impairment of Fertility: In a reproductive toxicity study in which male and female rats were administered naratriptan orally prior to and throughout the mating period (10, 60, 170, or 340 mg/kg/day; plasma exposures [AUC] approximately 11, 70, 230, and 470 times, respectively, the human exposure at the MRDD), there was a drug-related decrease in the number of females exhibiting normal estrous cycles at doses of 170 mg/kg/day or greater and an increase in pre-implantation loss at 60 mg/kg/day or greater. In high-dose males, testicular/epididymal atrophy accompanied by spermatozoa depletion reduced mating success and may have contributed to the observed pre-implantation loss. The exposures achieved at the no-effect doses for pre-implantation loss, anestrus, and testicular effects were approximately 11, 70, and 230 times, respectively, the exposures in humans at the MRDD. In a study in which rats were dosed orally with naratriptan (10, 60, or 340 mg/kg/day) for 6 months, changes in the female reproductive tract including atrophic or cystic ovaries and anestrus were seen at the high dose. The exposure at the no-effect dose of 60 mg/kg was approximately 85 times that in humans at the MRDD.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: In carcinogenicity studies, mice and rats were given naratriptan by oral gavage for 104 weeks. There was no evidence of an increase in tumors related to naratriptan administration in mice receiving up to 200 mg/kg/day. That dose was associated with a plasma (AUC) exposure that was 110 times the exposure in humans receiving the MRDD of 5 mg. Two rat studies were conducted, one using a standard diet and the other a nitrite-supplemented diet (naratriptan can be nitrosated in vitro to form a mutagenic product that has been detected in the stomachs of rats fed a high nitrite diet). Doses of 5, 20, and 90 mg/kg were associated with AUC exposures that in the standard-diet study were 7, 40, and 236 times, respectively, and in the nitrite-supplemented-diet study were 7, 29, and 180 times, respectively, the exposure in humans at the MRDD. In both studies, there was an increase in the incidence of thyroid follicular hyperplasia in high-dose males and females and in thyroid follicular adenomas in high-dose males. In the standard-diet study only, there was also an increase in the incidence of benign c-cell adenomas in the thyroid of high-dose males and females. The exposures achieved at the no-effect dose for thyroid tumors were 40 (standard diet) and 29 (nitrite-supplemented diet) times the exposure achieved in humans at the MRDD. In the nitrite-supplemented diet study only, the incidence of benign lymphocytic thymoma was increased in all treated groups of females. It was not determined if the nitrosated product is systemically absorbed. However, no changes were seen in the stomachs of rats in that study. Mutagenesis: Naratriptan was not mutagenic when tested in in vitro gene mutation (Ames and mouse lymphoma tk ) assays. Naratriptan was also negative in the in vitro human lymphocyte assay and the in vivo mouse micronucleus assay. Naratriptan can be nitrosated in vitro to form a mutagenic product (WHO nitrosation assay) that has been detected in the stomachs of rats fed a nitrite-supplemented diet. Impairment of Fertility: In a reproductive toxicity study in which male and female rats were administered naratriptan orally prior to and throughout the mating period (10, 60, 170, or 340 mg/kg/day; plasma exposures [AUC] approximately 11, 70, 230, and 470 times, respectively, the human exposure at the MRDD), there was a drug-related decrease in the number of females exhibiting normal estrous cycles at doses of 170 mg/kg/day or greater and an increase in pre-implantation loss at 60 mg/kg/day or greater. In high-dose males, testicular/epididymal atrophy accompanied by spermatozoa depletion reduced mating success and may have contributed to the observed pre-implantation loss. The exposures achieved at the no-effect doses for pre-implantation loss, anestrus, and testicular effects were approximately 11, 70, and 230 times, respectively, the exposures in humans at the MRDD. In a study in which rats were dosed orally with naratriptan (10, 60, or 340 mg/kg/day) for 6 months, changes in the female reproductive tract including atrophic or cystic ovaries and anestrus were seen at the high dose. The exposure at the no-effect dose of 60 mg/kg was approximately 85 times that in humans at the MRDD.

ANDA090381

Naratriptan

Naratriptan

0054-0278

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL label1

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events: Inform patients that naratriptan may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring of speech and should ask for medical advice if any indicative sign or symptoms are observed. Apprise patients of the importance of this follow-up [see Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.5 , 5.8 )] . Anaphylactic Reactions: Inform patients that anaphylactic reactions have occurred in patients receiving naratriptan. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens [see Contraindications ( 4 ), Warnings and Precautions ( 5.9 )] . Concomitant Use with Other Triptans or Ergot Medications: Inform patients that use of naratriptan within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) is contraindicated [see Contraindications ( 4 ), Drug Interactions ( 7.1 , 7.2 )] . Serotonin Syndrome: Caution patients about the risk of serotonin syndrome with the use of naratriptan or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions ( 5.7 ), Drug Interactions ( 7.3 )]. Medication Overuse Headache: Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions ( 5.6 )] . Pregnancy: Advise patients to notify their healthcare provider if they become pregnant during treatment or intend to become pregnant [see Use in Specific Populations ( 8.1 )] . Lactation: Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations ( 8.2 )] . Ability to Perform Complex Tasks: Treatment with naratriptan may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of naratriptan. Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 C50000674/02 Revised March 2023

14 CLINICAL STUDIES The efficacy of naratriptan in the acute treatment of migraine headaches was evaluated in 3 randomized, double-blind, placebo-controlled trials in adult patients (Trials 1, 2, 3). These trials enrolled adult patients who were predominantly female (86%) and Caucasian (96%) with a mean age of 41 years (range: 18 to 65 years). In all studies, patients were instructed to treat at least 1 moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 4 hours after dosing. Associated symptoms such as nausea, vomiting, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours postdose. A second dose of naratriptan or other rescue medication to treat migraines was allowed 4 to 24 hours after the initial treatment for recurrent headache. In all 3 trials, the percentage of patients achieving headache response 4 hours after treatment, the primary outcome measure, was significantly greater among patients receiving naratriptan compared with those who received placebo. In all trials, response to 2.5 mg was numerically greater than response to 1 mg and in the largest of the 3 trials, there was a statistically significant greater percentage of patients with headache response at 4 hours in the 2.5-mg group compared with the 1-mg group. The results are summarized in Table 2. Table 2: Percentage of Adult Patients With Headache Response (Mild or No Headache) 4 Hours Following Treatment Naratriptan 1 mg (n=491) Naratriptan 2.5 mg (n=493) Placebo (n=395) Trial 1 50% P <0.05 compared with placebo. 60% 34% Trial 2 52% 66% P <0.05 compared with 1 mg. 27% Trial 3 54% 65% 32% The estimated probability of achieving an initial headache response in adults over the 4 hours following treatment in pooled Trials 1, 2, and 3 is depicted in Figure 1. Figure : Estimated Probability of Achieving Initial Headache Response Within 4 Hours in Pooled Trials 1, 2, and 3 a a The figure shows the probability over time of obtaining headache response (reduction in headache severity from moderate or severe pain to no or mild pain) following treatment with naratriptan. In this Kaplan-Meier plot, patients not achieving response within 240 minutes were censored at 240 minutes. For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was a lower incidence of these symptoms 4 hours following administration of 1-mg and 2.5-mg naratriptan compared with placebo. Four to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other rescue medication. The estimated probability of patients taking a second dose or other rescue medication to treat migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2. Figure : Estimated Probability of Patients Taking a Second Dose of Naratriptan Tablets or Other Medication to Treat Migraine Over the 24 Hours Following the Initial Dose of Study Treatment in Pooled Trials 1, 2, and 3 a a Kaplan-Meier plot based on data obtained in the 3 controlled clinical trials (Trials 1, 2, and 3) providing evidence of efficacy with patients not using additional treatments censored at 24 hours. The plot also includes patients who had no response to the initial dose. Remedication was discouraged prior to 4 hours postdose. There is no evidence that doses of 5 mg provided a greater effect than 2.5 mg. There was no evidence to suggest that treatment with naratriptan was associated with an increase in the severity or frequency of migraine attacks. The efficacy of naratriptan was unaffected by presence of aura; gender, age, or weight of the subject; oral contraceptive use; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants). There was insufficient data to assess the impact of race on efficacy. \\eu.boehringer.com\depts\col\groups\DRA-MA\LABELING\XML Files\Naratriptan HCl Tabs\Labels\naratriptan figure 1.jpg \\eu.boehringer.com\depts\col\groups\DRA-MA\LABELING\XML Files\Naratriptan HCl Tabs\Labels\naratriptan figure 2.jpg

8.5 Geriatric Use Clinical trials of naratriptan did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Naratriptan is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in elderly patients who have reduced renal function. In addition, elderly patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and blood pressure increases may be more pronounced in the elderly. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving naratriptan [see Warnings and Precautions ( 5.1 )] .

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Therefore, naratriptan is not recommended for use in patients younger than 18 years of age. One controlled clinical trial evaluated naratriptan (0.25 to 2.5 mg) in 300 adolescent migraineurs aged 12 to 17 years who received at least 1 dose of naratriptan for an acute migraine. In this study, 54% of the patients were female and 89% were Caucasian. There were no statistically significant differences between any of the treatment groups. The headache response rates at 4 hours (n) were 65% (n=74), 67% (n=78), and 64% (n=70) for placebo, 1-mg, and 2.5-mg groups, respectively. This trial did not establish the efficacy of naratriptan compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in this clinical trial were similar in nature to those reported in clinical trials in adults.

8.1 Pregnancy Risk Summary: There are no adequate data on the developmental risk associated with use of naratriptan 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 13.0%]) and during any trimester of exposure was 2.0% (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 skeletal ossification) was increased at the mid and high doses, and embryonic death was increased at all doses (4, 20, and 120 times, respectively, the MRDD on a body surface area basis). Maternal toxicity (decreased body weight gain) was evident at the high dose. In a similar study in New Zealand White rabbits (1, 5, or 30 mg/kg/day throughout organogenesis), decreased fetal weights and increased incidences of fetal skeletal variations were observed at all doses (maternal exposures equivalent to 2.5, 19, and 140 times exposure in humans receiving the MRDD), while maternal body weight gain was reduced at 5 mg/kg or greater. A no-effect dose for developmental toxicity in rabbits exposed during organogenesis was not established. When female rats were treated orally with naratriptan (10, 60, or 340 mg/kg/day) during late gestation and lactation, offspring behavioral impairment (tremors) and decreased offspring viability and growth were observed at doses of 60 mg/kg or greater, while maternal toxicity occurred only at the highest dose. Maternal exposures at the no-effect dose for developmental effects in this study were approximately 11 times the exposure in humans receiving the MRDD.

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 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 13.0%]) and during any trimester of exposure was 2.0% (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 skeletal ossification) was increased at the mid and high doses, and embryonic death was increased at all doses (4, 20, and 120 times, respectively, the MRDD on a body surface area basis). Maternal toxicity (decreased body weight gain) was evident at the high dose. In a similar study in New Zealand White rabbits (1, 5, or 30 mg/kg/day throughout organogenesis), decreased fetal weights and increased incidences of fetal skeletal variations were observed at all doses (maternal exposures equivalent to 2.5, 19, and 140 times exposure in humans receiving the MRDD), while maternal body weight gain was reduced at 5 mg/kg or greater. A no-effect dose for developmental toxicity in rabbits exposed during organogenesis was not established. When female rats were treated orally with naratriptan (10, 60, or 340 mg/kg/day) during late gestation and lactation, offspring behavioral impairment (tremors) and decreased offspring viability and growth were observed at doses of 60 mg/kg or greater, while maternal toxicity occurred only at the highest dose. Maternal exposures at the no-effect dose for developmental effects in this study were approximately 11 times the exposure in humans receiving the MRDD. 8.2 Lactation Risk Summary: There are no data on the presence of naratriptan in human milk, the effects of naratriptan on the breastfed infant, or the effects of naratriptan on milk production. Naratriptan is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for naratriptan and any potential adverse effects on the breastfed infant from naratriptan or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Therefore, naratriptan is not recommended for use in patients younger than 18 years of age. One controlled clinical trial evaluated naratriptan (0.25 to 2.5 mg) in 300 adolescent migraineurs aged 12 to 17 years who received at least 1 dose of naratriptan for an acute migraine. In this study, 54% of the patients were female and 89% were Caucasian. There were no statistically significant differences between any of the treatment groups. The headache response rates at 4 hours (n) were 65% (n=74), 67% (n=78), and 64% (n=70) for placebo, 1-mg, and 2.5-mg groups, respectively. This trial did not establish the efficacy of naratriptan compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in this clinical trial were similar in nature to those reported in clinical trials in adults. 8.5 Geriatric Use Clinical trials of naratriptan did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Naratriptan is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in elderly patients who have reduced renal function. In addition, elderly patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and blood pressure increases may be more pronounced in the elderly. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving naratriptan [see Warnings and Precautions ( 5.1 )] . 8.6 Renal Impairment The use of naratriptan is contraindicated in patients with severe renal impairment (creatinine clearance: <15 mL/min) because of decreased clearance of the drug. In patients with mild to moderate renal impairment, the recommended starting dose is 1 mg, and the maximum daily dose should not exceed 2.5 mg over a 24-hour period [see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )]. 8.7 Hepatic Impairment The use of naratriptan is contraindicated in patients with severe hepatic impairment (Child-Pugh Grade C) because of decreased clearance. In patients with mild or moderate hepatic impairment (Child-Pugh Grade A or B), the recommended starting dose is 1 mg, and the maximum daily dose should not exceed 2.5 mg over a 24-hour period [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 )].

16 HOW SUPPLIED/STORAGE AND HANDLING Naratriptan Tablets, USP 1 mg tablets are supplied as white to off-white round, biconvex tablets debossed with “54” on one side and “227” on the other side. NDC 0054-0278-03: Bottle of 9 Tablets NDC 0054-0278-25: Bottle of 100 Tablets 2.5 mg tablets are supplied as white to off-white round, biconvex tablets debossed with “54 351” on one side and plain on the other side. NDC 0054-0279-03: Bottle of 9 Tablets NDC 0054-0279-25: Bottle of 100 Tablets Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]