Naratriptan

DESCRIPTION

AMERGE Tablets contain naratriptan as the hydrochloride, which is a selective 5-hydroxytryptamine1 receptor subtype agonist. Naratriptan hydrochloride is chemically designated as N-methyl-3-( 1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide monohydrochloride.

The empirical formula is C₁₇H₂₅N₃O₂S•HCl, representing a molecular weight of 371.93. Naratriptan hydrochloride is a white to pale yellow powder that is readily soluble in water . Each AMERGE Tablet for oral administration contains 1.11 or 2.78 mg of naratriptan hydrochloride equivalent to 1 or 2.5 mg of naratriptan, respectively. Each tablet also contains the inactive ingredients croscarmellose sodium; hydroxypropyl methylcellulose; lactose; magnesium stearate; microcrystalline cellulose; triacetin; and titanium dioxide, iron oxide yellow, and indigo carmine aluminum lake (FD& C Blue No. 2) for coloring.

CLINICAL PHARMACOLOGY

Mechanism of Action

Naratriptan binds with high affinity to 5-HT_1D and 5-HT_1B receptors and has no significant affinity or pharmacological activity at 5-HT_2-4 receptor subtypes or at adrenergic a₁, a₂, or b; dopaminergic D₁ or D₂; muscarinic; or benzodiazepine receptors.

The therapeutic activity of naratriptan in migraine is generally attributed to its agonist activity at 5-HT_{1D/ 1B} receptors. Two current theories have been proposed to explain the efficacy of 5-HT_{1D/ 1B} receptor agonists in migraine. One theory suggests that activation of 5-HT_{1D/ 1B} receptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT_{1D/ 1B} receptors on sensory nerve endings in the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.

In the anesthetized dog, naratriptan has been shown to reduce the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance. While the effect on blood flow was selective for the carotid arterial body increases in vascular resistance of up to 30% were seen in the coronary arterial body Naratriptan has also been shown to inhibit trigeminal nerve activity in rat and cat. In 10 human subjects with suspected coronary artery disease (CAD) undergoing coronary artery catheterization, there was a 1% to 10% reduction in coronary artery diameter following subcutaneous injection of 1.5 mg of naratriptan.

Pharmacokinetics

Naratriptan tablets are well absorbed, with about 70% oral bioavailability. Following administration of a 2.5-mg tablet orally, the peak concentrations are obtained in 2 to 3 hours. After administration of 1-or 2.5-mg tablets, the C_max is somewhat (about 50%) higher in women (not corrected for mg/kg dose) than in men. During a migraine attack, absorption was slower, with a t_max of 3 to 4 hours. Food does not affect the pharmacokinetics of naratriptan. Naratriptan displays linear kinetics over the therapeutic dose range.

The steady-state volume of distribution of naratriptan is 170 L. Plasma protein binding is 28% to 31% over the concentration range of 50 to 1000 ng/mL.

Naratriptan is predominantly eliminated in urine, with 50% of the dose recovered unchanged and 30% as metabolites in urine. In vitro, naratriptan is metabolized by a wide range of cytochrome P450 isoenzymes into a number of inactive metabolites.

The mean elimination half-life of naratriptan is 6 hours. The systemic clearance of naratriptan is 6.6 mL/min/kg. The renal clearance (220 mL/min) exceeds glomerular filtration rate, indicating active tubular secretion. Repeat administration of naratriptan tablets does not result in drug accumulation.

Special Populations

Age: A small decrease in clearance (approximately 26%) was observed in healthy elderly subjects (65 to 77 years) compared to younger patients, resulting in slightly higher exposure (see PRECAUTIONS).

Race: The effect of race on the pharmacokinetics of naratriptan has not been examined.

Renal Impairment: Clearance of naratriptan was reduced by 50% in patients with moderate renal impairment (creatinine clearance 18 to 39 mL/ min) compared to the normal group. Decrease in clearances resulted in an increase of mean half-life from 6 hours (healthy) to 11 hours (range: 7 to 20 hours). The mean Cmax increased by approximately 40%. The effects of severe renal impairment (creatinine clearance </=15 mL/ min) on the pharmacokinetics of naratriptan has not been assessed. (See CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION.)

Hepatic Impairment: Clearance of naratriptan was decreased by 30% in patients with moderate hepatic impairment (Child-Pugh grade A or B). This resulted in an approximately 40% increase in the half-life (range: 8 to 16 hours). The effects of severe hepatic impairment (Child-Pugh grade C) on the pharmacokinetics of naratriptan have not been assessed. (See CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION.)

Drug Interactions

In normal volunteers, coadministration of single doses of naratriptan tablets and alcohol did not result in substantial modification of naratriptan pharmacokinetic parameters.

From population pharmacokinetic analyses, coadministration of naratriptan and fluoxetine, beta-blockers, or tricyclic antidepressants did not affect the clearance of naratriptan.

Naratriptan does not inhibit monoamine oxidase (MAO) enzymes and is a p.o. inhibitor of P450; metabolic interactions between naratriptan and drugs metabolized by P450 or MAO are therefore unlikely.

Oral Contraceptives

Oral contraceptives reduced clearance by 32% and volume of distribution by 22%, resulting in slightly higher concentrations of naratriptan. Hormone replacement therapy had no effect on pharmacokinetics in older female patients.

Smoking increased the clearance of naratriptan by 30%.

CLINICAL TRIALS

The efficacy of AMERGE Tablets in the acute treatment of migraine headaches was evaluated in six randomized, double-blind, placebo-controlled studies of which 4 used the recommended dosing regimen and were conducted as outpatient trials. Three of these studies enrolled adult patients who were predominantly female (86%) and Caucasian (96%) with a mean age of 41 (range: 18 to 65). One study enrolled adolescents with a mean age of 14 (range: 12 to 17). In the adolescent study, 54% of the patients were female and 89% were Caucasian. In all studies, patients were instructed to treat at least one moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 4 hours after dosing. Associated symptoms such as nausea, vomiting, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours postdose. A second dose of AMERGE Tablets or other medication was allowed 4 to 24 hours after the initial treatment for recurrent headache. The frequency and time to use of these additional treatments were also determined.

In all 3 trials in adults utilizing the recommended dosage regimen and outpatient use, the percentage of patients achieving headache response 4 hours after treatment, the primary outcome measure, was significantly greater among patients receiving AMERGE compared to those who received placebo. In all studies, response to 2.5 mg was numerically greater than response to 1 mg and in the largest of the three studies, there was a statistically significant greater percentage of patients with headache response at 4 hours in the 2.5-mg group compared to the 1-mg group. The results are summarized in Table 1.

Percentage of Adult Patients With Headache Response (Mild or No Headache) 4 Hours Following Treatment

In the single study in adolescents, 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. Comparisons of drug performance based upon results obtained in different clinical trials are never reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.

For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was a lower incidence of these symptoms 4 hours following administration of 1-and 2.5-mg AMERGE Tablets compared to placebo. Four to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. There is no evidence that doses of 5 mg provide a greater effect than 2.5 mg. There was no evidence to suggest that treatment with AMERGE was associated with an increase in the severity or frequency of migraine attacks. The efficacy of AMERGE Tablets was unaffected by presence of aura; gender, age, or weight of the patient; oral contraceptive use; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants). There was insufficient data to assess the impact of race on efficacy.

INDICATIONS

AMERGE Tablets are indicated for the acute treatment of migraine attacks with or without aura in adults. AMERGE Tablets are not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine (see CONTRA

INDICATIONS

DOSAGE AND ADMINISTRATION

In controlled clinical trials, single doses of 1 and 2.5 mg of AMERGE Tablets taken with fluid were effective for the acute treatment of migraines in adults. A greater proportion of patients had headache response following a 2.5 mg dose than following a 1-mg dose (see CLINICAL TRIALS). Individuals may vary in response to doses of AMERGE Tablets. The choice of dose should therefore be made on an individual basis, weighing the possible benefit of the 2.5-mg dose with the potential for a greater risk of adverse events. If the headache returns or if the patient has only partial response, the dose may be repeated once after 4 hours, for a maximum dose of 5 mg in a 24-hour period. There is evidence that doses of 5 mg do not provide a greater effect than 2.5 mg. The safety of treating, on average, more than four headaches in a 30-day period has not been established.

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. (See CONTRA

INDICATIONS

Hepatic Impairment: The use of AMERGE is contraindicated in patients with severe hepatic impairment (Child-Pugh grade C) because of decreased clearance (see CONTRA

INDICATIONS

HOW SUPPLIED

AMERGE Tablets 1 and 2.5 mg of naratriptan (base) as the hydrochloride. AMERGE Tablets, 1 mg, are white, D-shaped, film-coated tablets embossed with "GX CE3" on one side in blister packs of 9 tablets (NDC 0173-0561-00). AMERGE Tablets, 2.5 mg, are green, D-shaped, film-coated tablets embossed with "GX CE5" on one side in blister packs of 9 tablets (NDC 0173-0562-00).

Store at controlled room temperature, 20° to 25° C (68° to 77° F) (see USP).

SIDE EFFECTS

Serious cardiac events, including some that have been fatal, have occurred following the use of 5-HT1 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 two times placebo rate. Since patients treated only one to three 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 five placebo-controlled clinical trials of approximately 1752 exposures to placebo and AMERGE 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 AMERGE Tablets 2.5-mg treatment group 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.

One event present in more than 1% of patients receiving AMERGE Tablets (vomiting) occurred more frequently on placebo than on naratriptan 2.5 mg. AMERGE 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 AMERGE 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 AMERGE 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 = 3557) 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 1/1000 patients, and rare adverse events are those occurring in fewer than 1/1000 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, QTc 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.

DRUG ABUSE AND DEPENDENCE

In one clinical study enrolling 12 subjects, all of whom had experience using oral opiates and other psychoactive drugs, AMERGE Tablets produced less intense subjective responses ordinarily associated with many drugs of abuse than did codeine (30 to 90 mg).

DRUG INTERACTIONS

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and naratriptan within 24 hours is contraindicated (see CONTRAINDICATIONS). The administration of naratriptan with other 5-HT₁ agonists has not been evaluated in migraine patients. Because their vasospastic effects may be additive, coadministration of naratriptan and other 5-HT₁ agonists within 24 hours of each other is not recommended (see CONTRAINDICATIONS). Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with 5-HTv agonists. If concomitant treatment with naratriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised.

In normal volunteers, coadministration of single doses of naratriptan tablets and alcohol did not result in substantial modification of naratriptan pharmacokinetic parameters. From population pharmacokinetic analyses, coadministration of naratriptan and fluoxetine, beta-blockers, or tricyclic antidepressants did not affect the clearance of naratriptan. Naratriptan does not inhibit monoamine oxidase (MAO) enzymes and is a p.o. inhibitor of P450; metabolic interactions between naratriptan and drugs metabolized by P450 or MAO are therefore unlikely.

Oral Contraceptives

Oral contraceptives reduced clearance by 32% and volume of distribution by 22%, resulting in slightly higher concentrations of naratriptan. Hormone replacement therapy had no effect on pharmacokinetics in older female patients. Smoking increased the clearance of naratriptan by 30%.

WARNINGS

AMERGE 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-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 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 AMERGE Tablets, in these patients with risk factors.

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

Among approximately 3500 patients with migraine who participated in premarketing clinical trials of naratriptan tablets, four patients treated with single oral doses of naratriptan ranging from 1 to 10 mg experienced asymptomatic ischemic ECG changes with at least one, 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 5-HT₁ agonists.

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 one 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 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's 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's syndrome following naratriptan administration should be evaluated for atherosclerosis or predisposition to vasospasm (see CONTRAINDICATIONS and

WARNINGS

AMERGE 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 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 per 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 five 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.

Laboratory Tests

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

Drug Interactions

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and naratriptan within 24 hours is contraindicated (see CONTRAINDICATIONS). The administration of naratriptan with other 5-HT₁ agonists has not been evaluated in migraine patients. Because their vasospastic effects may be additive, coadministration of naratriptan and other 5-HT₁ agonists within 24 hours of each other is not recommended (see CONTRAINDICATIONS). Selective serotonin reuptake inhibitors (SSRIs) (e. g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with 5-HT₁ agonists. If concomitant treatment with naratriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised.

Drug/ Laboratory Test Interactions

AMERGE Tablets are not known to interfere with commonly employed clinical laboratory tests.

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 AUC exposure that was 110 times the exposure in humans receiving the maximum recommended daily dose of 5 mg. Two rat studies were conducted, one 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, and in the nitrite-supplemented diet study were 7, 29, and 180 times, 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 two gene mutation assays, the Ames test and the in vitro thymidine locus mouse lymphoma assay. It was not clastogenic in two 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, Glaxo Wellcome Inc. maintains a Naratriptan Pregnancy Registry. Health care providers are encouraged to register patients by calling (800) 722-9292, ext. 39441.

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 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 MADE 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 Tablets to a nursing woman.

Pediatric Use

Safety and effectiveness of AMERGE Tablets in pediatric patients (less than 18 years of age) 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 PHARMACOLOGY,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 naratriptan in elderly patients is not recommended. AMERGE Tablets are 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 Tablets did not include patients over 65 years of age.