WARNINGS AND PRECAUTIONS
Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina
AMERGE 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 AMERGE. Some of these reactions occurred in patients without known CAD. AMERGE may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD.
Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving AMERGE. If there is evidence of CAD or coronary artery vasospasm, AMERGE is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of AMERGE in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of AMERGE. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of AMERGE.
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 AMERGE if these disturbances occur. AMERGE is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.
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 AMERGE and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. 5-HT1 agonists, including AMERGE, are contraindicated in patients with CAD and those with Prinzmetal’s variant angina.
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. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue AMERGE if a cerebrovascular event occurs.
Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical for migraine, exclude other potentially serious neurological conditions. AMERGE is contraindicated in patients with a history of stroke or TIA.
Other Vasospasm Reactions
AMERGE may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before receiving additional doses of AMERGE.
Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established.
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 drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
Serotonin Syndrome
Serotonin syndrome may occur with AMERGE, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors [see Drug Interactions]. 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 AMERGE if serotonin syndrome is suspected.
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 AMERGE. AMERGE is contraindicated in patients with uncontrolled hypertension.
Anaphylactic/Anaphylactoid Reactions
There have been reports of anaphylaxis and anaphylactoid and hypersensitivity reactions, including angioedema, in patients receiving AMERGE. 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. AMERGE is contraindicated in patients with a history of hypersensitivity reaction to AMERGE.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C: There are no adequate and well-controlled trials in pregnant women. AMERGE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In reproductive toxicity studies in rats and rabbits, oral administration of naratriptan was associated with developmental toxicity (embryolethality, fetal abnormalities, pup mortality, offspring growth retardation) at doses producing maternal plasma drug exposures as low as 11 and 2.5 times, respectively, the exposure in humans receiving the maximum recommended daily dose (MRDD) of 5 mg.
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, and increased incidences of embryonic death and fetal variations (major blood vessel variations, supernumerary ribs, incomplete skeletal ossification) were observed 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 this study. 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.
Nursing Mothers
Naratriptan is excreted in rat milk. It is not known whether naratriptan is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from AMERGE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Therefore, AMERGE is not recommended for use in patients younger than 18 years of age.
One controlled clinical trial evaluated AMERGE (0.25 to 2.5 mg) in 300 adolescent migraineurs aged 12 to 17 years who received at least 1 dose of AMERGE 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 AMERGE 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.
Geriatric Use
Clinical trials of AMERGE 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 AMERGE [see Warnings and Precautions].
Renal Impairment
The use of AMERGE 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 Clinical Pharmacology].
Hepatic Impairment
The use of AMERGE 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 recommendedstarting dose is 1 mg, and the maximum daily dose should not exceed 2.5 mg over a 24-hour period [see Dosage and Administration Clinical Pharmacology].
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