Amerge (Naratriptan)

AMERGE®

Glaxo Wellcome

Naratriptan HCl

5-HT1 Receptor Agonist – Migraine Therapy

Action And Clinical Pharmacology: Naratriptan has been demonstrated to be a selective agonist for a vascular 5-hydroxytryptamine1 receptor subtype (probably a member of the 5-HT1B/1D family) with little or no binding affinity for 5-HT2/3 receptor subtypes, alpha1-, alpha2-, or beta-adrenergic; dopamine1; dopamine2; muscarinic; or benzodiazepine receptors. Naratriptan did not exhibit agonist or antagonist activity in ex vivo assays of 5-HT4 and 5-HT7 receptor-mediated activities.

The therapeutic activity of naratriptan in migraine is generally attributed to its agonist activity at 5-HT1B/5-HT1D receptors. Two current theories have been proposed to explain the efficacy of 5-HT1 receptor agonists in migraine. One theory suggests that activation of 5-HT1 receptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is believed to be correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT1 receptors on perivascular fibers of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. These theories are not mutually exclusive.

Pharmacokinetics: Absorption: Naratriptan is well absorbed, with 74% oral bioavailability in females and 63% in males. After oral administration, the absorption is rapid and peak concentrations are obtained in 2 to 5 hours. A 2-period crossover study was performed in 15 female migraine patients who received naratriptan as a single 2.5 mg tablet during a migraine attack, followed 3 to 7 days later by another 2.5 mg treatment during a non-migraine period. During a migraine attack, absorption is slower, although exposure (AUC) and elimination half-life are not significantly affected.

Plasma levels of naratriptan increase in a dose-proportional manner consistent with linear pharmacokinetics over a 1 to 10 mg dose range. The absorption and elimination are independent of the dose. Administration with food does not appreciably influence the pharmacokinetics of naratriptan. Repeat administration of naratriptan (up to 10 mg once daily for 5 days) does not result in drug accumulation.

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 Cmax 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 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 Cmax (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).

Clinical Studies: Therapeutic Clinical Trials: Four double-blind, placebo-controlled, dose-ranging clinical trials evaluated the safety and efficacy of naratriptan at oral doses ranging from 0.1 to 10 mg in a total of 3 160 adult patients with migraine attacks characterized by moderate or severe pain. The minimal effective dose was 1.0 mg. In 3 of the 4 clinical trials, a higher overall rate of headache relief was achieved with a 2.5 mg dose. Single doses of 5 mg and higher are not recommended due to an increased incidence of adverse events. Onset of significant headache relief (defined as no or mild pain) became apparent at 60 to 120 minutes after these doses. Naratriptan also relieved the nausea, phonophobia, and photophobia associated with migraine attacks.

In study 1, patients were randomised to receive placebo or a particular dose of naratriptan for the treatment of a single migraine attack according to a parallel group design, whereas, in study 2, patients were randomised to receive each of the treatments for separate migraine attacks according to a crossover design. In both studies, patients who achieved headache relief at 240 minutes post-dose, but experienced a worsening of severity between 4 and 24 hours post-dosing were permitted to take a second dose of double-blind medication identical to the first.

Significant headache relief was sustained over 24 hours. Data from four placebo controlled studies (n=3 160) 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.

Indications And Clinical Uses: For the acute treatment of migraine attacks with or without aura.

Naratriptan is not for use in the management of hemiplegic, basilar, or ophthalmoplegic migraine (see Contraindications). Safety and efficacy have not been established for cluster headache which is present in an older, predominantly male population.

Contra-Indications: Naratriptan is contraindicated in patients with history, symptoms, or signs of ischemic cardiac, cerebrovascular or peripheral vascular syndromes, valvular heart disease or cardiac arrhythmias (especially tachycardias). In addition, patients with other significant underlying cardiovascular diseases (e.g., atherosclerotic disease, congenital heart disease) should not receive naratriptan. Ischemic cardiac syndromes include, but are not limited to, angina pectoris of any type (e.g., stable angina of effort and vasospastic forms of angina such as the Prinzmetal’s variant), all forms of myocardial infarction, and silent myocardial ischemia. Cerebrovascular syndromes include, but are not limited to, strokes of any type as well as transient ischemic attacks (TIAs). Peripheral vascular disease includes, but is not limited to, ischemic bowel disease, or Raynaud’s syndrome (see Warnings).

Because naratriptan can give rise to increases in blood pressure, it is contraindicated in patients with uncontrolled or severe hypertension (see Warnings).

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because naratriptan may also cause coronary vasospasm and these effects may be additive, the use of naratriptan within 24 hours before or after treatment with other 5-HT1 receptor agonists, or ergotamine-containing drugs or their derivatives (e.g., dihydroergotamine, methysergide) is contraindicated.

Naratriptan is contraindicated in patients with hemiplegic, basilar, or ophthalmoplegic migraine.
Naratriptan is contraindicated in patients with severe renal impairment (creatinine clearance
Naratriptan is contraindicated in patients with severe hepatic impairment (Child-Pugh grade C) (see Pharmacology and Dosage).
Naratriptan is contraindicated in patients with hypersensitivity to naratriptan or any component of the formulation.

Manufacturers’ Warnings In Clinical States: Naratriptan 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: Amerge has been associated with transient chest and/or neck pain and tightness which may resemble angina pectoris. In rare cases, the symptoms have been identified as being the likely result of coronary vasospasm or myocardial ischemia. Rare cases of serious coronary events or arrhythmia have occurred following use of another 5-HT1 agonist. Naratriptan should not be given to patients who have documented ischemic or vasospastic coronary artery disease (see Contraindications). It is strongly recommended that naratriptan not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoking, obesity, diabetes, strong family history of CAD, female who is surgically or physiologically postmenopausal, or male who is 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 unknown. If, during the cardiovascular evaluation, the patient’s medical history or electrocardiographic 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 considered to have a satisfactory cardiovascular evaluation, the first dose of naratriptan should be administered 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 ECGs in patients with risk factors during the interval immediately following naratriptan administration on the first occasion of use. However, an absence of drug-induced cardiovascular effects on the occasion of the initial dose does not preclude the possibility of such effects occurring with subsequent administrations.

Intermittent long-term users of naratriptan who have or acquire risk factors predictive of CAD, as described above, should receive periodic interval cardiovascular evaluations over the course of treatment.

If symptoms consistent with angina occur after the use of naratriptan, ECG evaluation should be carried out to look for ischemic changes.

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. 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 Naratriptan: Among approximately 3 500 patients with migraine who participated in premarketing clinical trials of naratriptan, 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, TIA).

Special Cardiovascular Pharmacology Studies: In subjects (n=10) with suspected coronary artery disease undergoing angiography, naratriptan at a s.c. dose of 1.5 mg produced an 8% increase in aortic blood pressure, an 18% increase in pulmonary artery blood pressure, and an 8% increase in systemic vascular resistance. In addition, mild chest pain or tightness was reported by 4 subjects. Clinically significant increases in blood pressure were experienced by 3 of the subjects (2 of whom also had chest pain/discomfort). Diagnostic angiogram results revealed that 9 subjects had normal coronary arteries and 1 had insignificant coronary artery disease.

Migraine patients (n=35) free of cardiovascular disease were subjected to assessments of myocardial perfusion by positron emission tomography while receiving s.c. naratriptan 1.5 mg in the absence of a migraine attack. Naratriptan was associated with a reduced coronary vasodilatory reserve (approximately 10%), increased coronary resistance (approximately 20%), and decreased hyperemic myocardial blood flow (approximately 10%). The relevance of these findings to the use of recommended oral doses of naratriptan is not known.

Hypersensitivity: Rare hypersensitivity (anaphylaxis/anaphylactoid) reactions may occur in patients receiving 5-HT1 agonists such as 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). Owing to the possibility of cross-reactive hypersensitivity reactions, naratriptan should not be used in patients having a history of hypersensitivity to sumatriptan or chemically-related 5-HT1 receptor agonists. As naratriptan contains a sulfonamide component, there is a theoretical risk of hypersensitivity reactions in patients with known hypersensitivity to sulfonamides.

Other Vasospasm-Related Events: 5-HT1 agonists may cause vasospastic reactions other than coronary artery vasospasm. Extensive postmarket experience has shown the use of another 5-HT1 agonist to be associated with rare occurrences of peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea.

Increases in Blood Pressure: Elevations in blood pressure have been reported following use of naratriptan.

Precautions: Cardiovascular: Discomfort in the chest, neck, throat, and jaw (including pain, pressure, heaviness, tightness) has been reported after administration of naratriptan. Because 5-HT1 agonists 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 variant angina before receiving additional doses, 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).

Neurologic Conditions: Care should be taken to exclude other potentially serious neurologic 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. For newly diagnosed patients or patients presenting with atypical symptoms, the diagnosis of migraine should be reconsidered if no response is seen after the first dose of naratriptan.

Seizures: Caution should be observed if naratriptan is to be used in patients with a history of epilepsy or structural brain lesions which lower the convulsion threshold.

Renal or Hepatic Impairment: Naratriptan should be administered with caution to patients with impaired renal or hepatic function (see Pharmacology, Contraindications and Dosage).

Occupational Hazards: 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.

Drug Interactions: 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.

Other Serotonergic Drugs: Rare postmarketing reports describe patients with weakness, hyperreflexia, and incoordination following the combined use of a selective serotonin reuptake inhibitor (SSRI) and 5-HT1 agonists. If concomitant treatment with naratriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline), tricyclic antidepressant, MAO inhibitor, or other drugs with serotonergic activity is clinically warranted, appropriate observation of the patient for acute and long-term adverse events is advised.

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.

Pregnancy: 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, Glaxo Wellcome Inc. maintains a Naratriptan Pregnancy Registry. Health care providers are encouraged to register patients by calling (800) 722-9292, ext. 39441.

Lactation: 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.

Children: 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.

Adolescents: 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.

Geriatrics: The safety and effectiveness of naratriptan has 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.

Drug/Laboratory Test Interactions : Naratriptan is not known to interfere with commonly employed clinical laboratory tests.

Dependence Liability: 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.

Melanin Binding: 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.

Adverse Reactions: 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).

Experience in Controlled Clinical Trials with Naratriptan: Typical 5-HT1 Agonist Adverse Reactions: As with other 5-HT1 agonists, naratriptan has been associated with sensations of heaviness, pressure, tightness or pain which may be intense. These may occur in any part of the body including the chest, throat, neck, jaw and upper limb.

Acute Safety: The safety and efficacy of the 1 and 2.5 mg doses of naratriptan were investigated in 4 placebo-controlled clinical trials in adult migraine patients. Two of these trials were of parallel group design and involved the treatment of a single migraine attack. A third study was of crossover design and involved the treatment of one migraine attack per dose group. The fourth study was a parallel group trial in which patients treated up to 3 migraine attacks. In all studies, patients who achieved headache relief at 240 minutes postdose, but experienced a worsening of severity between 4 and 24 hours postdosing, were permitted to take a second dose of double-blind medication identical to the first.

The overall incidence of adverse events following doses of naratriptan 1 mg or 2.5 mg (1 or 2 doses) were similar to placebo (28.5 and 30.2% vs 28.9% with placebo). Naratriptan is generally well tolerated and most adverse reactions were mild, transient and self-limiting. The most common adverse events to occur at a higher rate than in the corresponding placebo group were malaise/fatigue (2.4% vs 0.8% with placebo) and neck/throat/jaw sensations (2.1% vs 0.3% with placebo). From this table, it appears that many of these adverse events are dose related.

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* (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. Event frequencies are calculated as the number of patients reporting an event divided by the total number of patients (n=2 790) 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 1/1 000 patients; rare adverse events are those occurring in fewer than 1/1 000 patients.

Cardiovascular: Infrequent: palpitations, increased blood pressure, tachyarrhythmias and abnormal ECGs. Rare: bradycardia, hypotension, varicosities and heart murmur.

Ear, Nose and Throat: 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.

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

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

Gastrointestinal: Frequent: vomiting. Infrequent: dyspeptic symptoms, diarrhea, hyposalivation, gastrointestinal discomfort and pain, gastroenteritis and constipation. Rare: abnormal liver function tests, abnormal bilirubin levels, salivary gland swelling, hemorrhoids, gastritis, esophagitis, oral itching and irritation, regurgitation and reflux and gastic ulcers.

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

Neurology: 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.

Non-Site Specific: 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.

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

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

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

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

Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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 mm Hg 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 mm Hg pretreatment up to 191/113 mm Hg 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.

Dosage And Administration: Naratriptan is recommended only for the acute treatment of migraine attacks. Naratriptan should not be used prophylactically.

Adults: The minimal effective single adult dose of naratriptan is 1 mg. The maximum recommended single dose is 2.5 mg.

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).

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.

Availability And Storage: 1 mg: 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.

2.5 mg: 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.

AMERGE® Glaxo Wellcome Naratriptan HCl 5-HT1 Receptor Agonist – Migraine Therapy

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