Eletriptan HBR

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.

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.

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-hydroxytryptamine1 (5-HT1) 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)].

Eletriptan hydrobromide should only be used where a clear diagnosis of migraine has been established. 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina Eletriptan hydrobromide is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of eletriptan hydrobromide. Some of these reactions occurred in patients without known CAD. Eletriptan hydrobromide may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD. Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving eletriptan hydrobromide. Do not use eletriptan hydrobromide if there is evidence of CAD or coronary artery vasospasm [see CONTRAINDICATIONS (4)]. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first eletriptan hydrobromide dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following administration of eletriptan hydrobromide. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of eletriptan hydrobromide. 5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm including ventricular tachycardia and ventricular fibrillation leading to death have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue eletriptan hydrobromide if these disturbances occur. Eletriptan hydrobromide is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see CONTRAINDICATIONS (4)]. 5.3 Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure Sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with eletriptan hydrobromide and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. Eletriptan hydrobromide is contraindicated in patients with CAD or Prinzmetal’s variant angina [see CONTRAINDICATIONS (4)]. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical of migraine, other potentially serious neurological conditions need to be excluded. Eletriptan hydrobromide is contraindicated in patients with a history of stroke or TIA [see CONTRAINDICATIONS (4)]. 5.5 Other Vasospasm Reactions Eletriptan hydrobromide may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of a vasospastic reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before receiving additional eletriptan hydrobromide doses [see CONTRAINDICATIONS (4)]. 5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g. ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused acute migraine drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. 5.7 Serotonin Syndrome Serotonin syndrome may occur with eletriptan hydrobromide, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors [see DRUG INTERACTIONS (7.3)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue eletriptan hydrobromide if serotonin syndrome is suspected. 5.8 Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with eletriptan hydrobromide. Eletriptan hydrobromide is contraindicated in patients with uncontrolled hypertension [see CONTRAINDICATIONS (4)]. 5.9 Anaphylactic/Anaphylactoid Reactions There have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving eletriptan hydrobromide. 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. Eletriptan hydrobromide is contraindicated in patients with a history of hypersensitivity reaction to eletriptan hydrobromide [see CONTRAINDICATIONS (4)].

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 within 24 hours of each other is contraindicated. Concomitant use of other 5-HT1 agonists within 24 hours of eletriptan hydrobromide treatment is contraindicated [see CONTRAINDICATIONS (4)]. 7.2 CYP3A4 Inhibitors Potent CYP3A4 inhibitors significantly increase the exposure of eletriptan hydrobromide. Eletriptan hydrobromide 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)].

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)] 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 in short-term placebo-controlled trials, the most common adverse reactions reported with treatment with eletriptan hydrobromide 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 a eletriptan hydrobromide 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 and More Than Placebo Adverse Reaction Type Placebo (n=988) Eletriptan Hydrobromide 20 mg (n=431) Eletriptan Hydrobromide 40 mg (n=1774) Eletriptan Hydrobromide 80 mg (n=1932) 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 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. 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. Neurological: seizure Digestive: vomiting

8.1 Pregnancy Risk Summary Available human data on the use of eletriptan hydrobromide 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/m2 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/m2 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/m2 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/m2 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 and any potential adverse effects on the breastfed child from eletriptan hydrobromide or from the underlying maternal condition. Infant exposure can be minimized by avoiding breastfeeding for 24 hours after treatment. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. The efficacy of eletriptan hydrobromide tablets (40 mg) in patients 11 to 17 was not established in a randomized, placebo-controlled trial of 274 adolescent migraineurs [see CLINICAL STUDIES (14)]. Adverse reactions observed were similar in nature to those reported in clinical trials in adults. Postmarketing experience with other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse reactions that are similar in nature to those reported rarely in adults. Long-term safety of eletriptan was studied in 76 adolescent patients who received treatment for up to one year. A similar profile of adverse reactions to that of adults was observed. The long-term safety of eletriptan in pediatric patients has not been established. 8.5 Geriatric Use Blood pressure was increased to a greater extent in elderly subjects than in young subjects. The pharmacokinetic disposition of eletriptan in the elderly is similar to that seen in younger adults [see CLINICAL PHARMACOLOGY (12.3)]. In clinical trials, there were no apparent differences in efficacy or the incidence of adverse reactions between patients under 65 years of age and those 65 and above. 8.6 Hepatic Impairment The effect of severe hepatic impairment on eletriptan hydrobromide metabolism has not been evaluated. Eletriptan hydrobromide is not recommended for use in patients with severe hepatic impairment [see CLINICAL PHARMACOLOGY (12.3)].