ELETRIPTAN HYDROBROMIDE: 2,158 Adverse Event Reports & Safety Profile

Eletriptan hydrobromide tablets contain eletriptan hydrobromide, which is a selective 5-hydroxytryptamine 1B/1D (5-HT 1B/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 molecular 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 off white solid that is slightly soluble in water. Each eletriptan hydrobromide Tablet for oral administration contains 24.25 or 48.5 mg of eletriptan hydrobromide equivalent to 20 mg or 40 mg of eletriptan, respectively. Each tablet also contains the inactive ingredients: anhydrous lactose, croscarmellose sodium, FD & C Yellow No. #6 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, titanium dioxide and triacetin. Additionally, each 20 mg tablet contains D & C Yellow #10 aluminum lake and FD & C Blue #2 aluminum lake and each 40 mg tablet contains ferric oxide yellow and ferric oxide red. eletriptan hydrobromide tablet

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 )

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 )

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 )

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 relationship to drug exposure. Neurological: seizure Digestive: vomiting

AND PRECAUTIONS Eletriptan hydrobromide tablets should only be used where a clear diagnosis of migraine has been established.

• Myocardial ischemia/infarction or Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors ( 5.1 )
• Arrhythmias: Discontinue eletriptan hydrobromide tablets if occurs ( 5.2 )
• Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not myocardial ischemia; evaluate high risk patients for CAD ( 5.3 )
• Cerebral hemorrhage, subarachnoid hemorrhage, or stroke: Discontinue eletriptan hydrobromide tablets if occurs ( 5.4 )
• Gastrointestinal ischemia or infarction events, or peripheral vasospastic reactions: Discontinue eletriptan hydrobromide tablets if occurs ( 5.5 )
• Medication overuse headache: Detoxification may be necessary ( 5.6 )
• Serotonin syndrome: Discontinue eletriptan hydrobromide tablets if occurs ( 5.7 , 7.3 )

5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina Eletriptan hydrobromide tablets are 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 tablets. Some of these reactions occurred in patients without known CAD. Eletriptan hydrobromide tablets 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 tablets. Do not use eletriptan hydrobromide tablets if there is evidence of CAD or coronary artery vasospasm <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first eletriptan hydrobromide tablet dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following administration of eletriptan hydrobromide tablets. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of eletriptan hydrobromide tablets.

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-HT 1 agonists. Discontinue eletriptan hydrobromide tablets if these disturbances occur. Eletriptan hydrobromide tablets are contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

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 tablets and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. Eletriptan hydrobromide tablets are contraindicated in patients with CAD or Prinzmetal’s variant angina <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 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 tablets are contraindicated in patients with a history of stroke or TIA <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.5 Other Vasospasm Reactions Eletriptan hydrobromide tablets 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-HT 1 agonist, rule out a vasospastic reaction before receiving additional eletriptan hydrobromide tablet doses <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

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 tablets, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span> . 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 tablets 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-HT 1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with eletriptan hydrobromide tablets. Eletriptan hydrobromide tablets are contraindicated in patients with uncontrolled hypertension <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.9 Anaphylactic/Anaphylactoid Reactions There have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving eletriptan hydrobromide tablets. 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 tablets are contraindicated in patients with a history of hypersensitivity reaction to eletriptan hydrobromide tablets <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

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 tablet treatment is contraindicated <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

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 <span class="opacity-50 text-xs">[see Contraindications (4) and Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> .