FDA label 3f40b0b0-2268-46c3-9388-1451a6c0e1fa

WARNINGS 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-HT 1B/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-HT 1 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 medical history, 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 physician’s office or similar 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 naratriptan tablets in these patients with risk factors. It is recommended that patients who are intermittent long-term users of 5-HT 1 agonists, including naratriptan tablets, and who have or acquire risk factors predictive of CAD, as described above, undergo periodic cardiovascular evaluation as they continue to use 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-HT 1 agonists. Considering the extent of use of 5-HT 1 agonists in patients with migraine, the incidence of these events is extremely low. Premarketing Experience With 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-HT 1 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-HT 1 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 Serotonin syndrome may occur with triptans, including naratriptan, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).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 can occur within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Treatment with naratriptan should be discontinued if serotonin syndrome is suspected. 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-HT 1 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 ).

ADVERSE REACTIONS Serious cardiac events, including some that have been fatal, have occurred following the use of 5-HT 1 agonists. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS , WARNINGS , and PRECAUTIONS ). Incidence in Controlled Clinical Trials The most common adverse events were paresthesias, dizziness, drowsiness, malaise/fatigue, and throat/neck symptoms, which occurred at a rate of 2% and at least 2 times placebo rate. Since patients treated only 1 to 3 headaches in the controlled clinical trials, the opportunity for discontinuation of therapy in response to an adverse event was limited. In a long-term, open-label study where patients were allowed to treat multiple migraine attacks for up to 1 year, 15 patients (3.6%) discontinued treatment due to adverse events. Table 2 lists adverse events that occurred in 5 placebo-controlled clinical trials of approximately 1,752 exposures to placebo and naratriptan tablets in adult migraine patients. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Only events that occurred at a frequency of 2% or more in the group treated with naratriptan tablets 2.5 mg and were more frequent in that group than in the placebo group are included in Table 2. From this table, it appears that many of these adverse events are dose related. Table 2. Treatment-Emergent Adverse Events Reported by at Least 2% of Patients in Placebo-Controlled Migraine Trials Adverse Event Type Placebo (n = 498) Naratriptan Tablets 1 mg (n = 627) Naratriptan Tablets 2.5 mg (n = 627) Atypical sensation Paresthesias (all types) 1% < 1% 2% 1% 4% 2% Gastrointestinal Nausea 5% 4% 6% 4% 7% 5% Neurological Dizziness Drowsiness Malaise/fatigue 3% 1% <1% 1% 4% 1% 1% 2% 7% 2% 2% 2% Pain and pressure sensation Throat/neck symptoms 2% 1% 2% 1% 4% 2% One event (vomiting) present in more than 1% of patients receiving naratriptan tablets occurred more frequently on placebo than on naratriptan 2.5 mg. Naratriptan tablets are generally well tolerated. Most adverse reactions were mild and transient. The incidence of adverse events in placebo-controlled clinical trials was not affected by age or weight of the patients, duration of headache prior to treatment, presence of aura, use of prophylactic medications, or tobacco use. There was insufficient data to assess the impact of race on the incidence of adverse events. Other Events Observed in Association With the Administration of Naratriptan Tablets In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. Because the reports include events observed in open and uncontrolled studies, the role of naratriptan tablets in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients reporting an event divided by the total number of patients (n = 3,557) exposed to oral naratriptan doses up to 10 mg. All reported events are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those occurring in at least 1/100 patients, infrequent adverse events are those occurring in 1/100 to 1/1,000 patients, and rare adverse events are those occurring in fewer than 1/1,000 patients. Atypical Sensations: Frequent were warm/cold temperature sensations. Infrequent were feeling strange and burning/stinging sensation. Cardiovascular: Infrequent were palpitations, increased blood pressure, tachyarrhythmias, and abnormal ECG (PR prolongation, QT c prolongation, ST/T wave abnormalities, premature ventricular contractions, atrial flutter, or atrial fibrillation), and syncope. Rare were bradycardia, varicosities, hypotension, and heart murmurs. Ear, Nose, and Throat: Frequent were ear, nose, and throat infections. Infrequent were phonophobia, sinusitis, upper respiratory inflammation, and tinnitus. Rare were allergic rhinitis; labyrinthitis; ear, nose, and throat hemorrhage; and hearing difficulty. Endocrine and Metabolic: Infrequent were thirst and polydipsia, dehydration, and fluid retention. Rare were hyperlipidemia, hypercholesterolemia, hypothyroidism, hyperglycemia, glycosuria and ketonuria, and parathyroid neoplasm. Eye: Frequent was photophobia. Infrequent was blurred vision. Rare were eye pain and discomfort, sensation of eye pressure, eye hemorrhage, dry eyes, difficulty focusing, and scotoma. Gastrointestinal: Frequent were hyposalivation and vomiting. Infrequent were dyspeptic symptoms, diarrhea, gastrointestinal discomfort and pain, gastroenteritis, and constipation. Rare were abnormal liver function tests, abnormal bilirubin levels, hemorrhoids, gastritis, esophagitis, salivary gland inflammation, oral itching and irritation, regurgitation and reflux, and gastric ulcers. Hematological Disorders: Infrequent was increased white cells. Rare were thrombocytopenia, quantitative red cell or hemoglobin defects, anemia, and purpura. Lower Respiratory Tract: Infrequent were bronchitis, cough, and pneumonia. Rare were tracheitis, asthma, pleuritis, and airway constriction and obstruction. Musculoskeletal: Infrequent were muscle pain, arthralgia and articular rheumatism, muscle cramps and spasms, joint and muscle stiffness, tightness, and rigidity. Rare were bone and skeletal pain. Neurological: Frequent was vertigo. Infrequent were tremors, cognitive function disorders, sleep disorders, and disorders of equilibrium. Rare were compressed nerve syndromes, confusion, sedation, hyperesthesia, coordination disorders, paralysis of cranial nerves, decreased consciousness, dreams, altered sense of taste, neuralgia, neuritis, aphasia, hypoesthesia, motor retardation, muscle twitching and fasciculation, psychomotor restlessness, and convulsions. Non-Site Specific: Infrequent were chills and/or fever, descriptions of odor or taste, edema and swelling, allergies, and allergic reactions. Rare were spasms and mobility disorders. Pain and Pressure Sensations: Frequent were pressure/tightness/heaviness sensations. Psychiatry: Infrequent were anxiety, depressive disorders, and detachment. Rare were aggression and hostility, agitation, hallucinations, panic, and hyperactivity. Reproduction: Rare were lumps of female reproductive tract, breast inflammation, inflammation of vagina, inflammation of fallopian tube, breast discharge, endometrium disorders, decreased libido, and lumps of breast. Skin: Infrequent were sweating, skin rashes, pruritus, and urticaria. Rare were skin erythema, dermatitis and dermatosis, hair loss and alopecia, pruritic skin rashes, acne and folliculitis, allergic skin reactions, macular skin/rashes, skin photosensitivity, photodermatitis, skin flakiness, and dry skin. Urology: Infrequent were bladder inflammation and polyuria and diuresis. Rare were urinary tract hemorrhage, urinary urgency, pyelitis, and urinary incontinence. Observed During Clinical Practice: The following section enumerates potentially important adverse events that have occurred in clinical practice and that have been reported spontaneously to various surveillance systems. The events enumerated represent reports arising from both domestic and nondomestic use of naratriptan. These events do not include those already listed in the ADVERSE REACTIONS section above. Because the reports cite events reported spontaneously from worldwide postmarketing experience, frequency of events and the role of naratriptan in their causation cannot be reliably determined. Cardiovascular : Angina, myocardial infarction (see WARNINGS ). Gastrointestinal : Colonic ischemia (see WARNINGS ). Lower Respiratory : Dyspnea. Miscellaneous : Hypersensitivity, including anaphylaxis/anaphylactoid reactions, in some cases severe (e.g., circulatory collapse) (see WARNINGS ). Neurologic: Cerebral vascular accident, including transient ischemic attack, subarachnoid hemorrhage, and cerebral infarction (see WARNINGS ); serotonin syndrome.

<table ID="secondtable"> <caption>Table 2. Treatment-Emergent Adverse Events Reported by at Least 2% of Patients in Placebo-Controlled Migraine Trials</caption> <thead> <tr> <td align="center" styleCode="Lrule">Adverse Event Type</td> <td align="center" styleCode="Lrule">Placebo (n = 498)</td> <td align="center" styleCode="Lrule">Naratriptan Tablets 1 mg (n = 627) </td> <td align="center" styleCode="Lrule Rrule">Naratriptan Tablets 2.5 mg (n = 627) </td> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule">Atypical sensation Paresthesias (all types)</td> <td styleCode="Lrule" align="center">1% &lt; 1%</td> <td styleCode="Lrule" align="center">2% 1%</td> <td styleCode="Lrule Rrule" align="center">4% 2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Gastrointestinal Nausea</td> <td styleCode="Lrule" align="center">5% 4%</td> <td styleCode="Lrule" align="center">6% 4%</td> <td styleCode="Lrule Rrule" align="center">7% 5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Neurological Dizziness Drowsiness Malaise/fatigue</td> <td styleCode="Lrule" align="center">3% 1% &lt;1% 1%</td> <td styleCode="Lrule" align="center">4% 1% 1% 2%</td> <td styleCode="Lrule Rrule" align="center">7% 2% 2% 2%</td> </tr> <tr> <td styleCode="Lrule">Pain and pressure sensation Throat/neck symptoms</td> <td styleCode="Lrule" align="center">2% 1%</td> <td styleCode="Lrule" align="center">2% 1%</td> <td styleCode="Lrule Rrule" align="center">4% 2%</td> </tr> </tbody> </table>