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Metabolism and Distribution: In vitro, naratriptan is metabolized by a wide range of cytochrome P₄₅₀ isoenzymes into a number of inactive metabolites. Naratriptan is a poor inhibitor of cytochrome P₄₅₀ isoenzymes, and does not inhibit monoamine oxidase (MAO) enzymes; metabolic interactions between naratriptan and drugs metabolized by P₄₅₀ or MAO are, therefore, unlikely. According to a population pharmacokinetic estimate, naratriptan is distributed into a volume of approximately 261 L.

Protein Binding: Plasma protein binding is low (29%).

Elimination: The elimination half-life generally ranges from 5 to 8 hours. Oral clearance is 509 mL/min in females and 770 mL/min in males. The renal clearance (220 mL/min) exceeds the glomerular filtration rate, suggesting that the drug undergoes active tubular secretion. Naratriptan is predominantly eliminated in urine, with 50% of the dose recovered unchanged and 30% as metabolites.

Special Populations: Age Effects: A study was performed to compare the pharmacokinetics of naratriptan in young (6 female/6 male, 24 to 44 years) and elderly (6 female/6 male, 65 to 77 years) subjects. The subjects received 2 doses each of placebo, 1 mg naratriptan, and 2.5 mg naratriptan separated by 4-hour intervals. A minimum 96-hour period intervened between consecutive treatment days.

Elderly subjects experienced a higher degree of exposure to naratriptan than did younger subjects. Mean C_max and area under the plasma concentration time curve values were 28% and 38% higher, respectively, for the 1 mg treatment group and 15% and 32% higher, respectively, for the 2.5 mg group. Total and renal clearance were decreased by about 30%, while the elimination half-life was increased by about 1 hour.

Elevations in systolic blood pressure at the 2.5 mg dose were more pronounced in the elderly subjects than in the young subjects (mean peak increases of 12 mmHg in elderly versus 2 mmHg in young subjects).

Renal Impairment: Renal excretion is the major route for elimination of naratriptan. A study to compare male and female subjects with mild to moderate renal impairment (n=15, 31 to 58 years; screening creatinine clearance: median 41.2 mL/min, range 18 to 115 mL/min) to gender-matched healthy subjects (n=8, 21 to 47 years) showed a decrease in oral clearance (mean decreased by 50%), resulting in a longer mean half-life (approximately 11 hours, range 7 to 20 hours) and an increase in the mean C_max (approximately 40%). In this study, blood pressure measurements suggested that increased exposure in renally-impaired subjects may be associated with increases in blood pressure which are larger than those seen in healthy subjects receiving the same dose (5 mg) (see Dosage).

Hepatic Impairment: Liver metabolism plays a limited role in the clearance of naratriptan. The pharmacokinetics of a single 2.5 mg dose of naratriptan were determined in subjects with moderate hepatic impairment (Child-Pugh grade A or B, n=8) and gender- and age-matched healthy subjects (n=8). Subjects with hepatic impairment showed a moderate decrease in clearance (approximately 30%) resulting in increases of approximately 40% in the half-life (range 8 to 16 hours) and the area under the plasma concentration time curve (see Dosage).

Significant headache relief was sustained over 24 hours. Data from four placebo controlled studies (n=3160) showed that of the patients who achieved headache relief with naratriptan 2.5 mg, 72% to 83% did not experience recurrence of headache between 4 and 24 hours post-dosing.

Subgroup analyses of the overall population of patients participating in the placebo-controlled trials indicate that the efficacy of naratriptan was unaffected by migraine type (with/without aura), gender, oral contraceptive use, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants).

In a long-term, repeat dose, open study of 417 patients (all were initiated on a 2.5 mg dose of naratriptan but were given the option to titrate down to a 1 mg dose if 2.5 mg was not well tolerated) a total of 15 301 attacks were treated (mean number of treated attacks/patient=36 for the 2.5 mg dose and 8 for the 1 mg dose) over a period of up to 12 months. Headache response was sustained (as judged by the proportion of attacks treated with naratriptan resulting in headache relief). The median percentage of attacks per patient requiring a second dose for headache recurrence was 8%. Of the 417 patients treating attacks, 10 patients opted for a dosage reduction.

The safety and effectiveness of naratriptan have not been adequately studied in individuals over 65 years of age. 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 naratriptan did not include patients over 65 years of age. Its use in this age group is, therefore, not recommended.

The limited metabolism of naratriptan and the wide range of cytochrome P₄₅₀ isoenzymes involved, as determined by in vitro studies, suggest that significant drug interactions with naratriptan are unlikely. Naratriptan did not inhibit MAO enzymes (MAO-A or MAO-B) in vitro. The possibility of pharmacodynamic in vivo interactions between naratriptan and MAO inhibitors has not been investigated.

Ergot-Containing Drugs: Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis for these effects being additive, ergot-containing or ergot-type medications (like dihydroergotamine or methysergide) are contraindicated within 24 hours of naratriptan administration (see Contraindications).

Other 5-HT₁ agonists: The administration of naratriptan with other 5-HT₁ agonists has not been evaluated in migraine patients. As an increased risk of coronary vasospasm is a theoretical possibility with coadministration of 5-HT₁ agonists, use of these drugs within 24 hours of each other is contraindicated.

Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors: Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans (see Warnings).

Hormonal Contraceptives: In a population pharmacokinetic study in migraine patients, hormonal contraceptive use was associated with a 32% decrease in naratriptan clearance.

Tobacco: In a population pharmacokinetic study in migraine patients, tobacco use was associated with a 29% increase in naratriptan clearance.

Alcohol and Food: Clinical studies did not reveal any pharmacokinetic interaction when naratriptan was administered together with alcohol or food.

Naratriptan and/or its metabolites are distributed into the milk of lactating rats (at 2 hours post oral gavage dosing, levels in milk were 3.5 times higher than maternal plasma levels). Therefore, caution should be exercised when considering the administration of naratriptan to nursing women.

In 1 clinical study enrolling 12 subjects, all of whom had experience using oral opiates and other psychoactive drugs, subjective responses typically associated with many drugs of abuse were produced with less intensity during treatment with naratriptan (1 to 5 mg) than with codeine (30 to 90 mg). Long-term studies (12 months) in migraine patients using naratriptan revealed no evidence of increased drug utilization.

Safety and effectiveness of naratriptan have not been studied in children under 12 years of age. Use of the drug in this age group is, therefore, not recommended.

The efficacy of naratriptan at single doses of 0.25, 1.0 and 2.5 mg was not demonstrated to be greater than placebo in adolescents (12 to 17 years). Therefore, the use of the drug in adolescents is not recommended.

The safety of naratriptan for use during human pregnancy has not been established. 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 naratriptan, GlaxoSmithKline Inc. maintains a Naratriptan Pregnancy Registry. Health care providers are encouraged to register patients by calling 1-800-336-2176.

Overuse of acute migraine treatments has been associated with the exacerbation of headache (medication overuse headache, MOH) in susceptible patients. Withdrawal of the treatment may be necessary.

In pigmented rats treated with a single oral dose (10 mg/kg) of radiolabeled naratriptan, radioactivity was detected in the eyes at 3 months postadministration, a finding which suggests that the drug or its metabolites may bind to the melanin of the eye. The possible clinical significance of this finding is unknown. No systematic monitoring of ophthalmologic function was undertaken in clinical trials. Prescribers should consider the possibility of long-term ophthalmologic effects due to accumulation of naratriptan in melanin-rich tissues.

Psychomotor Impairment: In a study of psychomotor function in healthy volunteers, single oral 5 and 10 mg doses of naratriptan were associated with sedation and decreased alertness. Although these doses are higher than those recommended for the treatment of migraine, patients should be cautioned that drowsiness may occur following treatment with naratriptan. They should be advised not to perform skilled tasks (e.g., driving or operating machinery) if drowsiness occurs.

Naratriptan is not known to interfere with commonly employed clinical laboratory tests.

Each white film-coated, D-shaped tablet, embossed GXCE3 on one side, contains: naratriptan (base) 1 mg as the HCl salt. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, titanium dioxide and triacetin. Blister packs of 2, cartons of 4 blisters. Store below 30°C.

Each green film-coated, D-shaped tablet, embossed GXCE5 on one side, contains: naratriptan (base) 2.5 mg as the HCl salt. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropyl methylcellulose, indigo carmine aluminium lake (FD&C Blue No. 2), iron oxide yellow, lactose, magnesium stearate, microcrystalline cellulose, titanium dioxide and triacetin. Blister packs of 2 and 6, cartons of 4 blisters. Store below 30°C.

Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. If concomitant treatment with naratriptan and SSRIs (e.g., fluoxetine, paroxetine, sertraline) or SNRIs (e.g., venlafaxine) 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) (see Precautions, Drug Interactions).

dyspnea (see Precautions).

Infrequent: anxiety and depressive disorders. Rare: aggression, agitation and detachment.

Frequent: migraine. Infrequent: vertigo, tremors, sleep disorders, cognitive function disorders and hyperesthesia. Rare: disorders of equilibrium, decreased consciousness, confusion, sedation, coordination disorders, neuritis, dreams, altered sense of taste, motor retardation, muscle twitching and fasciculation.

colonic ischemia (see Warnings).

Long-Term Safety: In a long-term open study, 417 patients treated 15 301 migraine attacks with naratriptan over a period of up to 1 year. The most common adverse events in descending order of frequency were as follows: nausea (16%); malaise/fatigue (11%); drowsiness (10%); chest sensations{*The term “sensations” encompasses adverse events described as pain and discomfort, pressure, heaviness, constriction, tightness, heat/burning sensation, paresthesia, numbness, tingling, and strange sensations.} (8%); neck/throat/jaw sensations* (8%); paresthesia (7%); head/face sensations* (6%); vomiting (6%); and dizziness (5%). Due to the lack of a placebo arm in this study, the role of naratriptan in causation cannot be reliably determined.

Other Adverse Events Observed in Association with Naratriptan: In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. Because some events were observed in open and uncontrolled studies, the role of naratriptan in their causation cannot be reliably determined. All reported events are included except those already listed in Table 3, those too general to be informative, and those not reasonably associated with the use of the drug. Event frequencies are calculated as the number of patients reporting an event divided by the total number of patients (n=2790) exposed to naratriptan. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare adverse events are those occurring in fewer than 1/1000 patients.

Infrequent: photophobia. Rare: eye hemorrhage, dry eyes and difficulty focusing.

Infrequent: thirst and polydipsia, dehydration and fluid retention. Rare: hyperlipidemia, hypercholesterolemia, hypothyroidism, hyperglycemia, glycosuria and ketonuria and parathyroid neoplasm.

Frequent: ear, nose and throat infections. Infrequent: phonophobia, sinusitis, and upper respiratory inflammation. Rare: allergic rhinitis, labyrinthitis, tinnitus, ear, nose and throat hemorrhage and hearing difficulty.

Rare: lumps of female reproductive tract and inflammation of the fallopian tube.

Infrequent: musculoskeletal/muscle pain, muscle cramps and spasms, arthralgia and articular rheumatism. Rare: joint and muscle stiffness, tightness and rigidity.

cerebral vascular accident, including transient ischemic attack, subarachnoid hemorrhage, and cerebral infarction (see Warnings).

hypersensitivity, including anaphylaxis/anaphylactoid reactions, in some cases severe (e.g., circulatory collapse) (see Warnings).

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 Effects 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.

Infrequent: skin photosensitivity, skin rashes, pruritus, sweating and urticaria. Rare: skin erythema, dermatitis and dermatosis, and pruritic skin rash.

Infrequent: urinary infections. Rare: urinary tract hemorrhage, urinary urgency and pyelitis.

Frequent: paresthesia and heat sensations. Infrequent: chills and/or fever, descriptions of odor or taste and feelings of pressure/tightness/heaviness. Rare: allergies and allergic reactions, mobility disorders and faintness.

angina, myocardial infarction (see Precautions and Warnings).

In clinical studies, numerous patients (n=222) and healthy subjects (n=196) have received naratriptan at doses of 5 to 25 mg. In the majority of cases, no serious adverse events were reported. One patient treated with a 7.5 mg dose experienced ischemic ECG changes which were likely due to coronary vasospasm. This event was not associated with a serious clinical outcome. A patient who was mildly hypertensive experienced a significant increase in blood pressure (baseline value of 150/98 to 204/144 mmHg at 225 minutes) beginning 30 minutes after the administration of a 10 mg dose (4 times the maximum recommended single dose). The event resolved with antihypertensive treatment. Administration of 25 mg (10 times the maximum recommended single dose) in 1 healthy male subject increased blood pressure from 120/67 mmHg pretreatment up to 191/113 mmHg at approximately 6 hours postdose and resulted in adverse events including lightheadedness, tension in the neck, tiredness, and loss of coordination. Blood pressure returned to near baseline by 8 hours after dosing without any pharmacological intervention.

The elimination half-life of naratriptan is about 5 to 8 hours (see Pharmacology), and therefore monitoring of patients after overdose with naratriptan should continue for at least 24 hours or longer if symptoms or signs persist. Standard supportive treatment should be applied as required. If the patient presents with chest pain or other symptoms consistent with angina pectoris, ECG monitoring should be performed for evidence of ischemia. Appropriate treatment (e.g., nitroglycerin or other coronary artery vasodilators) should be administered as required.

It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of naratriptan.

In 3 of the 4 studies, optimal rates of headache relief were achieved with a 2.5 mg dose. As patients may vary in their dose-responsiveness, the choice of dose should 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 migraine headache returns, or if a patient has a partial response, the initial dose may be repeated once after 4 hours, for a maximum dose of 5 mg in a 24-hour period.

The safety of treating, on average, more than 4 headaches in a 30-day period has not been established.

Naratriptan tablets should be swallowed whole with fluids. Naratriptan tablets should be taken as early as possible after the onset of a migraine headache, but are effective if taken at a later stage.

If a patient does not respond to the first dose of naratriptan, a second dose should not be taken for the same attack, as it is unlikely to be of benefit.

Renal disease/functional impairment causes prolongation of the half-life of orally administered naratriptan. Consequently, if treatment is deemed advisable in the presence of renal impairment, a maximum single dose of 1 mg should be administered. No more than a total of 2 mg should be taken in any 24-hour period. Repeated dosing in renally impaired patients has not been evaluated (see Pharmacology). Administration of naratriptan in patients with severe renal impairment (creatinine clearance <15 mL/min) is contraindicated (see Contraindications).

Hepatic disease/functional impairment causes prolongation of the half-life of orally administered naratriptan. Consequently, if treatment is deemed advisable in the presence of hepatic impairment, a maximum single dose of 1 mg should be administered. No more than a total of 2 mg should be taken in any 24-hour period (see Pharmacology). Administration of naratriptan in patients with severe hepatic impairment (Child-Pugh grade C) is contraindicated (see Contraindications).

Hypertension: Naratriptan should not be used in patients with uncontrolled or severe hypertension. Patients with mild to moderate controlled hypertension should be treated cautiously at the lowest effective dose.