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WARNINGS

AMERGE (naratriptan) Tablets should only be used where a clear diagnosis of migraine has been established.

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events

Because of the potential of this class of compounds (5-HT1B/1D agonists) to cause coronary vasospasm, naratriptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (see CONTRAINDICATIONS). It is strongly recommended that 5-HT1 agonists (including naratriptan) not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient's electrocardiographic, or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, naratriptan should not be administered (see CONTRAINDICATIONS).

For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of naratriptan take place in the setting of a medically staffed and equipped facility. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following administration of AMERGE (naratriptan) Tablets, in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of 5-HT1 agonists, including AMERGE (naratriptan) Tablets, and who have or acquire risk factors predictive of CAD, as described above, undergo periodic cardiovascular evaluation as they continue to use AMERGE (naratriptan) Tablets.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to naratriptan.

Cardiac Events and Fatalities Associated With 5-HT1 Agonists

Naratriptan can cause coronary artery vasospasm (see CLINICAL PHARMACOLOGY). Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of 5-HT1 agonists. Considering the extent of use of 5-HT1 agonists in patients with migraine, the incidence of these events is extremely low.

Premarketing Experience With AMERGE (naratriptan) Tablets

Among approximately 3,500 patients with migraine who participated in premarketing clinical trials of naratriptan tablets, 4 patients treated with single oral doses of naratriptan ranging from 1 to 10 mg experienced asymptomatic ischemic ECG changes with at least 1, who took 7.5 mg, likely due to coronary vasospasm.

Cerebrovascular Events and Fatalities With 5-HT1 Agonists

Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported 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 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).

Other Vasospasm-Related Events

5-HT1 agonists may cause vasospastic reactions other than coronary artery spasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported with naratriptan.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome may occur with triptans, including treatment with AMERGE (naratriptan) , particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with naratriptan and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. 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).

Increase in Blood Pressure

In healthy volunteers, dose-related increases in systemic blood pressure have been observed after administration of up to 20 mg of oral naratriptan. At the recommended doses, the elevations are generally small, although an increase of systolic pressure of 32 mmHg was seen in 1 patient following a single 2.5-mg dose. The effect may be more pronounced in the elderly and hypertensive patients. A patient who was mildly hypertensive (the baseline blood pressure was 150/98) experienced a significant increase in blood pressure to 204/144 mmHg 225 minutes after administration of a 10-mg oral dose. Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients receiving 5-HT1 agonists with and without a history of hypertension. Naratriptan is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS).

An 18% increase in mean pulmonary artery pressure and an 8% increase in mean aortic pressure was seen following dosing with 1.5 mg of subcutaneous naratriptan in a study evaluating 10 subjects with suspected CAD undergoing cardiac catheterization.

Hypersensitivity

Hypersensitivity (anaphylaxis/anaphylactoid) reactions may occur in patients receiving naratriptan. Such reactions can be life threatening or fatal. In general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens (see CONTRAINDICATIONS).

PRECAUTIONS

General

Chest discomfort (including pain, pressure, heaviness, tightness) has been reported after administration of 5-HT1 agonists, including AMERGE (naratriptan) Tablets. These events have not been associated with arrhythmias or ischemic ECG changes in clinical trials with AMERGE Tablets. Because naratriptan may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following naratriptan should be evaluated for the presence of CAD or a predisposition to Prinzmetal variant angina before receiving additional doses of naratriptan, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud syndrome following naratriptan administration should be evaluated for atherosclerosis or predisposition to vasospasm (see CONTRAINDICATIONS and WARNINGS).

AMERGE (naratriptan) Tablets should also be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as impaired renal or hepatic function (see CLINICAL PHARMACOLOGY, CONTRAINDICATIONS, and DOSAGE AND ADMINISTRATION).

Care should be taken to exclude other potentially serious neurological conditions before treating headache in patients not previously diagnosed with migraine or who experience a headache that is atypical for them. There have been rare reports where patients received 5-HT1 agonists for severe headaches that were subsequently shown to have been secondary to an evolving neurologic lesion (see WARNINGS).

For a given attack, if a patient has no response to the first dose of AMERGE (naratriptan) , the diagnosis of migraine should be reconsidered before administration of a second dose.

Binding to Melanin-Containing Tissues

In rats treated with a single oral dose (10 mg/kg) of radiolabeled naratriptan, the elimination half-life of radioactivity from the eye was 90 days, suggesting that naratriptan and/or its metabolites may bind to the melanin of the eye. Because there could be accumulation in melanin-rich tissues over time, this raises the possibility that naratriptan could cause toxicity in these tissues after extended use. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects.

Changes in the Precorneal Tear Film

Dogs receiving oral naratriptan showed transient changes in the precorneal tear film. Corneal stippling was seen at the lowest dose tested, 1 mg/kg/day, and occurred intermittently from day 1 throughout the first 2 to 3 weeks of treatment. Although a no-effect dose was not established, the exposure at the lowest dose tested was approximately 5 times the human exposure after a 5-mg oral dose.

Information for Patients

See PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided for patients.

Patients should be cautioned about the risk of serotonin syndrome with the use of naratriptan or other triptans, especially during combined use with SSRIs or SNRIs.

Laboratory Tests

No specific laboratory tests are recommended for monitoring patients prior to and/or after treatment with AMERGE (naratriptan) Tablets.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity studies, 104 weeks in duration, were carried out in mice and rats by oral gavage. 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 area-under-the-curve (AUC) exposure that was 110 times the exposure in humans receiving the maximum recommended daily dose of 5 mg. Two rat studies were conducted, 1 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 week 13 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 attained in humans given the maximum recommended daily dose of 5 mg. 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 receiving the maximum recommended daily dose of 5 mg. 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 2 gene mutation assays, the Ames test and the in vitro thymidine locus mouse lymphoma assay. It was not clastogenic in 2 cytogenetics assays, 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 dosed prior to and throughout the mating period with 10, 60, 170, or 340 mg/kg/day (plasma exposures [AUC] approximately 11, 70, 230, and 470 times, respectively, the human exposure at the maximum recommended daily dose [MRDD] of 5 mg), there was a treatment-related decrease in the number of females exhibiting normal estrous cycles at doses of 170 mg/kg/day or greater and an increase in preimplantation loss at 60 mg/kg/day or greater. In high-dose group males, testicular/epididymal atrophy accompanied by spermatozoa depletion reduced mating success and may have contributed to the observed preimplantation loss. The exposures achieved at the no-effect doses for preimplantation loss, anestrus, and testicular effects were approximately 11, 70, and 230 times, respectively, the exposures in humans receiving the MRDD.

In a study in which rats were dosed orally with 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 the exposure in humans receiving the MRDD.

Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women; therefore, naratriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

To monitor fetal outcomes of pregnant women exposed to AMERGE, GlaxoSmithKline maintains a Naratriptan Pregnancy Registry. Healthcare providers are encouraged to register patients by calling (800) 336-2176.

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 MRDD of 5 mg.

When pregnant rats were administered naratriptan during the period of organogenesis at doses of 10, 60, or 340 mg/kg/day, there was a dose-related increase in embryonic death, with a statistically significant difference at the highest dose, and 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 doses of 1, 5, or 30 mg/kg/day were given 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 with 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-related material is excreted in the milk of rats. Therefore, caution should be exercised when considering the administration of AMERGE (naratriptan) Tablets to a nursing woman.

Pediatric Use

Safety and effectiveness of AMERGE (naratriptan) Tablets in pediatric patients (younger than 18 years) have not been established.

One randomized, placebo-controlled clinical trial evaluating oral naratriptan (0.25 to 2.5 mg) in pediatric patients aged 12 to 17 years evaluated a total of 300 adolescent migraineurs. This study did not establish the efficacy of oral naratriptan compared to placebo in the treatment of migraine in adolescents (see Clinical Trials). Adverse events observed in this clinical trial were similar in nature to those reported in clinical trials in adults.

Geriatric Use

The use of AMERGE (naratriptan) Tablets in elderly patients is not recommended.

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. Clinical studies of AMERGE (naratriptan) Tablets did not include patients over 65 years of age.

Last reviewed on RxList: 9/3/2010
This monograph has been modified to include the generic and brand name in many instances.

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