Eletriptan hydrobromide

1 INDICATIONS AND USAGE Eletriptan hydrobromide 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 eletriptan hydrobromide tablets, reconsider the diagnosis of migraine before eletriptan hydrobromide tablets are administered to treat any subsequent attacks. • Eletriptan hydrobromide tablets are not intended for the prevention of migraine attacks. • Safety and effectiveness of eletriptan hydrobromide tablets have not been established for cluster headache. Eletriptan hydrobromide 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 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 )

2 DOSAGE AND ADMINISTRATION The maximum recommended single dose is 40 mg. In controlled clinical trials, single doses of 20 mg and 40 mg were effective for the acute treatment of migraine in adults. A greater proportion of patients had a response following a 40 mg dose than following a 20 mg dose [see Clinical Studies (14) ] . If the migraine has not resolved by 2 hours after taking eletriptan hydrobromide tablets, or returns after transient improvement, a second dose may be administered at least 2 hours after the first dose. The maximum daily dose should not exceed 80 mg. The safety of treating an average of more than 3 migraine attacks in a 30-day period has not been established. • Single dose: 20 mg or 40 mg ( 2 ) • Maximum single dose: 40 mg ( 2 ) • May repeat dose after 2 hours if needed; not to exceed 80 mg in any 24-hour period ( 2 )

3 DOSAGE FORMS AND STRENGTHS Eletriptan Hydrobromide Tablets are available containing eletriptan hydrobromide equivalent to 20 mg or 40 mg eletriptan (base), respectively. • The 20 mg tablets are orange, film-coated, round, unscored tablets debossed with M on one side of the tablet and EL4 on the other side. • The 40 mg tablets are orange, film-coated, round, unscored tablets debossed with M on one side of the tablet and EL5 on the other side. Tablets: 20 mg and 40 mg ( 3 )

4 CONTRAINDICATIONS Eletriptan hydrobromide 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, transient ischemic attack (TIA), or history or current evidence of hemiplegic or basilar migraine because these 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-hydroxytryptamine 1 (5-HT 1 ) agonist, ergotamine-containing medication, or ergot-type medication such as dihydroergotamine (DHE) or methysergide [see Drug Interactions (7.1) ] . • Hypersensitivity to eletriptan hydrobromide tablets (angioedema and anaphylaxis seen) [see Warnings and Precautions (5.9) ] . • Recent use (i.e., within at least 72 hours) of the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, or nelfinavir [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ] . • History of coronary artery disease (CAD) or coronary artery vasospasm ( 4 ) • Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders ( 4 ) • History of stroke, transient ischemic attack, or history or current evidence of hemiplegic or basilar migraine ( 4 ) • Peripheral vascular disease ( 4 ) • Ischemic bowel disease ( 4 ) • Uncontrolled hypertension ( 4 ) • Within 24 hours of treatment with another 5-HT 1 agonist, or an ergotamine-containing medication ( 4 ) • Hypersensitivity to eletriptan hydrobromide tablets (angioedema and anaphylaxis seen) ( 4 ) • Within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, or nelfinavir ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in other sections of the prescribing information: • Myocardial ischemia and myocardial infarction, and Prinzmetal’s angina [see Warnings and Precautions (5.2) ] • Arrhythmias [see Warnings and Precautions (5.3) ] • Chest, throat, neck, and/or jaw pain/tightness/pressure [see Warnings and Precautions (5.4) ] • 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) and Warnings and Precautions (5.9) ] Most common adverse reactions (≥ 5% and > placebo) were asthenia, nausea, dizziness, and somnolence. These reactions appear to be dose-related. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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. Among 4,597 patients who treated the first migraine headache with eletriptan hydrobromide tablets in short-term placebo-controlled trials, the most common adverse reactions reported with treatment with eletriptan hydrobromide tablets were asthenia, nausea, dizziness, and somnolence. These reactions appear to be dose-related. In long-term open-label studies where patients were allowed to treat multiple migraine attacks for up to 1 year, 128 (8.3%) out of 1,544 patients discontinued treatment due to adverse reactions. Table 1 lists adverse reactions that occurred in the subset of 5,125 migraineurs who received eletriptan doses of 20 mg, 40 mg and 80 mg or placebo in worldwide placebo-controlled clinical trials. Only adverse reactions that were more frequent in an eletriptan hydrobromide tablet treatment group compared to the placebo group with an incidence greater than or equal to 2% are included in Table 1. Table 1: Adverse Reactions Incidence in Placebo-Controlled Migraine Clinical Trials: Reactions Reported by ≥ 2% Patients Treated with Eletriptan Hydrobromide Tablets and More Than Placebo Adverse Reaction Type Placebo (n = 988) Eletriptan Hydrobromide Tablets 20 mg (n = 431) Eletriptan Hydrobromide Tablets 40 mg (n = 1,774) Eletriptan Hydrobromide Tablets 80 mg (n = 1,932) ATYPICAL SENSATIONS Paresthesia 2% 3% 3% 4% Flushing/feeling of warmth 2% 2% 2% 2% PAIN AND PRESSURE SENSATIONS Chest – tightness/pain/pressure 1% 1% 2% 4% Abdominal – pain/discomfort/stomach pain/cramps/pressure 1% 1% 2% 2% DIGESTIVE Dry mouth 2% 2% 3% 4% Dyspepsia 1% 1% 2% 2% Dysphagia – throat tightness/difficulty swallowing 0.2% 1% 2% 2% Nausea 5% 4% 5% 8% NEUROLOGICAL Dizziness 3% 3% 6% 7% Somnolence 4% 3% 6% 7% Headache 3% 4% 3% 4% OTHER Asthenia 3% 4% 5% 10% The frequency of adverse reactions in clinical trials did not increase when up to 2 doses of eletriptan hydrobromide tablets were taken within 24 hours. The incidence of adverse reactions in controlled clinical trials was not affected by gender, age, or race of the patients. Adverse reaction frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis (e.g., SSRIs, beta blockers, calcium channel blockers, tricyclic antidepressants), estrogen replacement therapy or oral contraceptives. 6.2 Postmarketing Experience The following adverse reaction(s) have been identified during post approval use of eletriptan hydrobromide tablets. 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 …

7 DRUG INTERACTIONS 7.1 Ergot-Containing Drugs Including Other 5-HT 1B/1D Agonists 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 [DHE] or methysergide) and Eletriptan Hydrobromide Tablets within 24 hours of each other is contraindicated . Concomitant use of other 5-HT 1 agonists within 24 hours of Eletriptan Hydrobromide Tablets treatment is contraindicated [see Contraindications (4) ] . 7.2 CYP3A4 Inhibitors Potent CYP3A4 inhibitors significantly increase the exposure of Eletriptan Hydrobromide Tablets. Eletriptan Hydrobromide Tablets should not be used within at least 72 hours of treatment with potent CYP3A4 inhibitors [see Contraindications (4) and Clinical Pharmacology (12.3) ] . 7.3 Selective Serotonin Reuptake Inhibitors/Serotonin and 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 Available human data on the use of Eletriptan Hydrobromide Tablets in pregnant women are not sufficient to draw conclusions about drug-associated risk for major birth defects and miscarriage. In animal studies, oral administration of eletriptan during pregnancy or throughout pregnancy and lactation was associated with developmental toxicity (decreased fetal and pup weights, increased incidences of fetal structural abnormalities, decreased pup viability) at clinically-relevant doses [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 reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate 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 and gestational hypertension during pregnancy. Data Human Data A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for triptans before pregnancy only. Of the 189 women who redeemed prescriptions for eletriptan during the first trimester, 4 (2.1%) had infants with major congenital malformations, while for the 174 women who redeemed prescriptions for eletriptan before, but not during, pregnancy, 11 (6.3%) had infants with major congenital malformations. Methodological limitations of this study, including small size of the eletriptan population and infrequent events, do not allow for thorough characterization of risk. Animal Data When pregnant rats were administered eletriptan (0, 10, 30, or 100 mg/kg/day) during the period of organogenesis, fetal weights were decreased and the incidences of vertebral and sternebral variations were increased at 100 mg/kg/day (approximately 12 times the maximum recommended human dose [MRHD] of 80 mg/day on a mg/m 2 basis). The 30 and 100 mg/kg/day doses were also maternally toxic, as evidenced by decreased maternal body weight gain during gestation. The no-effect dose for adverse effects on embryofetal development in rats was 30 mg/kg/day, which is approximately 4 times the MRHD on a mg/m 2 basis. When eletriptan (0, 5, 10, or 50 mg/kg/day) was orally administered to pregnant rabbits throughout organogenesis, fetal weights were decreased at 50 mg/kg/day. The incidences of fused sternebrae and vena cava deviations were increased at all doses. Maternal toxicity was not evident at any dose. A no-effect dose for adverse effects on embryofetal development in rabbits was not established; the lowest dose tested (5 mg/kg/day) is similar to the MRHD on a mg/m 2 basis. Oral administration of eletriptan (0, 5, 15, or 50 mg/kg/day) to female rats throughout pregnancy and lactation resulted in a decrease in offspring viability and body weight at the highest dose tested. The no-effect dose for adverse effects on pre- and postnatal development in rats (15 mg/kg/day) is approximately 2 times the MRHD on a mg/m 2 basis. 8.2 Lactation Risk Summary Eletriptan is excreted in human milk. There are no data on the effects of eletriptan on the breastfed infant or the effects of eletriptan on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Eletriptan Hydrobromide Tablets and any potential adverse effects on the breastfed child from Eletriptan Hydrobromide Tablets or from the underlying maternal condition. Infant exposure can be minimized by avoiding …

12.1 Mechanism of Action Eletriptan binds with high affinity to 5-HT 1B , 5-HT 1D and 5-HT 1F receptors, has modest affinity for 5-HT 1A , 5-HT 1E , 5-HT 2B and 5-HT 7 receptors. Migraines are likely 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 Eletriptan Hydrobromide 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 Eletriptan Hydrobromide Tablets (eletriptan hydrobromide) contain eletriptan hydrobromide, which is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Eletriptan hydrobromide is chemically designated as (R)-3-[(1-Methyl-2-pyrrolidinyl)methyl]-5-[2-(phenylsulfonyl)ethyl]-1H-indole monohydrobromide, and it has the following chemical structure: The empirical formula is C 22 H 26 N 2 O 2 S . HBr, representing a molecular weight of 463.43. Eletriptan hydrobromide is a white to light pale colored powder that is readily soluble in water. Each Eletriptan Hydrobromide Tablets Tablet for oral administration contains 25.17 mg or 50.34 mg of eletriptan hydrobromide equivalent to 20 mg or 40 mg of eletriptan, respectively. Each tablet also contains the inactive ingredients microcrystalline cellulose (type 102) NF, lactose monohydrate (super tab 11 SD) NF, croscarmellose sodium USNF, magnesium stearate USP-NF, opadry OY-LS-23016 (orange) which contains HPMC 2910/Hypromellose, Lactose Monohydrate, Titanium Dioxide, Triacetin, FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake and opadry YS-2-19114-A (clear) which contains HPMC 2910/Hypromellose, Triacetin. Chemical Structure

10 OVERDOSAGE The elimination half-life of eletriptan is about 4 hours [see Clinical Pharmacology ( 12.3 )] , therefore monitoring of patients after overdose with eletriptan should continue for at least 20 hours or longer while symptoms or signs persist. There is no specific antidote to eletriptan. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentration of eletriptan.

16 HOW SUPPLIED/STORAGE AND HANDLING Eletriptan hydrobromide Tablets containing 20 mg or 40 mg eletriptan (base) as the hydrobromide salt. Eletriptan Hydrobromide Tablets, 20 mg are orange to mottled orange colored, round shaped, biconvex with beveled edge, film-coated tablets, debossed with "922" on one side and plain on the other side and are supplied as follows: NDC 68382-922-06 in bottle of 30 tablets NDC 68382-922-10 in bottle of 1000 tablets NDC 68382-922-86 in unit-dose blister cartons of 6 (1 x 6) unit-dose tablets NDC 68382-922-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Eletriptan Hydrobromide Tablets, 40 mg are brown colored, round shaped, biconvex with beveled edge, film-coated tablets, debossed with "923" on one side and plain on the other side and are supplied as follows: NDC 68382-923-06 in bottle of 30 tablets NDC 68382-923-05 in bottle of 500 tablets NDC 68382-923-86 in unit-dose blister cartons of 6 (1 x 6) unit-dose tablets NDC 68382-923-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight container.