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  药店国别: 美国药房
产地国家: 美国
所属类别: 神经系统药物->头痛药物
处方药:处方药
包装规格: 1毫克/片 9片/盒
计价单位:
  点击放大  
生产厂家中文参考译名:
葛兰素史克
生产厂家英文名:
GLAXOSMITHKLINE
该药品相关信息网址1:
http://www.rxlist.com/amerge-drug.htm
原产地英文商品名:
AMERGE 1mg/tab 9tabs/box
原产地英文药品名:
NARATRIPTAN HYDROCHLORIDE
原产地英文化合物名称:
N-Methyl-2-[3-(1-methyl-4-piperidyl)-1H-indol-5-yl]-ethanesulfonamide Hydrochloride
中文参考商品译名:
AMERGE 1毫克/片 9片/盒
中文参考药品译名:
盐酸那拉曲坦
原产地国家批准上市年份:
1998/02/10
英文适应病症1:
The treatment of migraine
英文适应病症2:
Neurovascular headache
临床试验期:
完成
中文适应病症参考翻译1:
治疗偏头痛
中文适应病症参考翻译2:
神经血管性头痛
药品信息:

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 详细处方信息以本药内容附件PDF文件(201053119261527.pdf)的“原文Priscribing Information”为准
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部分中文AMERGE处方资料(仅供参考)
 

盐酸那拉曲坦 Naratriptan Hydrochloride

别名:N-Methyl-2-[3-(1-methyl-4-piperidyl)-1H-indol-5-yl]-ethanesulfonamide Hydrochloride; Naramig; Amerge;

分子式:C17H26ClN3O2S

分子量:371.93

作用:治偏头痛的,或神经血管性头痛。在头痛发作时才能服用,不发时不用。 此药是选择性激动5-羟色胺受体的药物,而5-羟色胺属于化学递质,存在于脑血管内、脑干神经核内、三叉神经内,可以舒张血管、抑制炎性渗透等作用,所以可以减轻头痛。

适应症:抗偏头痛药

药理作用:药理作用在血管收缩功能性研究中,那拉曲坦表现出与舒马普坦相似的体外药理作用,但是效力更强。本品对5-ht1d受体、5ht1a受体、5ht3受体分别表现出高度的、较低的和弱的亲和力。可以引起狗的基底动脉、中部大脑动脉和隐静脉的收缩, ec50值分别为110、68和51nmol/l,活性与5-ht相近。它也能抑制狗的经神经传导的隐静脉的收缩, ec50值为10nmol/l。那拉曲坦对小鼠主动脉上的5 -ht2受体既没表现出激动作用也没表现出拮抗作用,不能松弛已由α-甲基5-ht引起收缩的乳猪的腔静脉(5-ht1受体),也不能引起豚鼠升结肠(5-ht4受体)的收缩。所有这些都提示了它对颅内血管上的5-ht1受体的选择性。对麻醉的狗进行体内试验,那拉曲坦产生剂量依赖(1~300μ g/kg,iv)的效力持久的颈动脉血流量的降低,同时增加了颈动脉的血管阻力,cd50值(能产生最大的血管收缩作用的一半需要的剂量)为(19±3)μ g/kg。据报道,舒马普坦为(39±8)μg/kg。本品并不增加动脉血压,但与轻微的剂量依赖的心动过缓有关。 

AMERGE®
(naratriptan hydrochloride) Tablets

DRUG 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; hypromellose; lactose; magnesium stearate; microcrystalline cellulose; triacetin; and titanium dioxide, iron oxide yellow (2.5-mg tablet only), and indigo carmine aluminum lake (FD&C Blue No. 2) (2.5-mg tablet only) for coloring.

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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 CONTRAINDICATIONS). Safety and effectiveness of AMERGE Tablets have not been established for cluster headache, which is present in an older, predominantly male population.

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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 4 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 CONTRAINDICATIONS and CLINICAL PHARMACOLOGY). In patients with mild to moderate renal impairment, the maximum daily dose should not exceed 2.5 mg over a 24-hour period and a lower starting dose should be considered.

Hepatic Impairment: The use of AMERGE is contraindicated in patients with severe hepatic impairment (Child-Pugh grade C) because of decreased clearance (see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY). In patients with mild or moderate hepatic impairment, the maximum daily dose should not exceed 2.5 mg over a 24-hour period and a lower starting dose should be considered (see CLINICAL PHARMACOLOGY).

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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 debossed 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 debossed 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).

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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 2 times placebo rate. Since patients treated only 1 to 3 headaches in the controlled clinical trials, the opportunity for discontinuation of therapy in response to an adverse event was limited. In a long-term, open-label study where patients were allowed to treat multiple migraine attacks for up to 1 year, 15 patients (3.6%) discontinued treatment due to adverse events.

One event (vomiting) present in more than 1% of patients receiving AMERGE Tablets 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 = 3,557) exposed to oral naratriptan doses up to 10 mg. All reported events are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those occurring in at least 1/100 patients, infrequent adverse events are those occurring in 1/100 to 1/1,000 patients, and rare adverse events are those occurring in fewer than 1/1,000 patients.

Atypical Sensations: Frequent were warm/cold temperature sensations. Infrequent were feeling strange and burning/stinging sensation.

Cardiovascular: Infrequent were palpitations, increased blood pressure, tachyarrhythmias, and abnormal ECG (PR prolongation, 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 thro at infections. Infrequent were phonophobia, sinusitis, upper respiratory inflammation, and tinnitus. Rare were allergic rhinitis; labyrinthitis; ear, nose, and throat hemorrhage; and hearing difficulty.

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

Eye: Frequent was photophobia. Infrequent was blurred vision. Rare were eye pain and discomfort, sensation of eye pressure, eye hemorrhage, dry eyes, difficulty focusing, and scotoma.

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

Hematological Disorders: Infrequent was increased white cells. Rare were thrombocytopenia, quantitative red cell or hemoglobin defects, anemia, and purpura.

Lower Respiratory Tract: Infrequent were bronchitis, cough, and pneumonia. Rare were tracheitis, asthma, pleuritis, and airway constriction and obstruction.

Musculoskeletal: Infrequent were muscle pain, arthralgia and articular rheumatism, muscle cramps and spasms, joint and muscle stiffness, tightness, and rigidity. Rare were bone and skeletal pain.

Neurological: Frequent was vertigo. Infrequent were tremors, cognitive function disorders, sleep disorders, and disorders of equilibrium. Rare were compressed nerve syndromes, confusion, sedation, hyperesthesia, coordination disorders, paralysis of cranial nerves, decreased consciousness, dreams, altered sense of taste, neuralgia, neuritis, aphasia, hypoesthesia, motor retardation, muscle twitching and fasciculation, psychomotor restlessness, and convulsions.

Non-Site Specific: Infrequent were chills and/or fever, descriptions of odor or taste, edema and swelling, allergies, and allergic reactions. Rare were spasms and mobility disorders.

Pain and Pressure Sensations: Frequent were pressure/tightness/heaviness sensations.

Psychiatry: Infrequent were anxiety, depressive disorders, and detachment. Rare were aggression and hostility, agitation, hallucinations, panic, and hyperactivity.

Reproduction: Rare were lumps of female reproductive tract, breast inflammation, inflammation of vagina, inflammation of fallopian tube, breast discharge, endometrium disorders, decreased libido, and lumps of breast.

Skin: Infrequent were sweating, skin rashes, pruritus, and urticaria. Rare were skin erythema, dermatitis and dermatosis, hair loss and alopecia, pruritic skin rashes, acne and folliculitis, allergic skin reactions, macular skin/rashes, skin photosensitivity, photodermatitis, skin flakiness, and dry skin.

Urology: Infrequent were bladder inflammation and polyuria and diuresis. Rare were urinary tract hemorrhage, urinary urgency, pyelitis, and urinary incontinence.

Observed During Clinical Practice: The following section enumerates potentially important adverse events that have occurred in clinical practice and that have been reported spontaneously to various surveillance systems. The events enumerated represent reports arising from both domestic and nondomestic use of naratriptan. These events do not include those already listed in the ADVERSE REACTIONS section above. Because the reports cite events reported spontaneously from worldwide postmarketing experience, frequency of events and the role of naratriptan in their causation cannot be reliably determined.

Cardiovascular: Angina, myocardial infarction (see WARNINGS).

Gastrointestinal: Colonic ischemia (see WARNINGS).

Lower Respiratory: Dyspnea.

Miscellaneous: Hypersensitivity, including anaphylaxis/anaphylactoid reactions, in some cases severe (e.g., circulatory collapse) (see WARNINGS).

Neurologic: Cerebral vascular accident, including transient ischemic attack, subarachnoid hemorrhage, and cerebral infarction (see WARNINGS); serotonin syndrome.

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).

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DRUG INTERACTIONS
Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported during combined use of SSRIs or SNRIs and triptans (see WARNINGS).

Ergot-Containing Drugs: 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).

Other 5-HT1 Agonists: 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).

Drug/Laboratory Test Interactions:AMERGE Tablets are not kno wn to interfere with commonly employed clinical laboratory tests.

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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-HT1B/1D agonists) to cause coronary vasospasm, naratriptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (see CONTRAINDICATIONS). It is strongly recommended that 5-HT1 agonists (including naratriptan) not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient's 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 3,500 patients with migraine who participated in premarketing clinical trials of naratriptan tablets, 4 patients treated with single oral doses of naratriptan ranging from 1 to 10 mg experienced asymptomatic ischemic ECG changes with at least 1, who took 7.5 mg, likely due to coronary vasospasm.

Cerebrovascular Events and Fatalities With 5-HT1 Agonists: Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).

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

Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome may occur with triptans, including treatment with AMERGE, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with naratriptan and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

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

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

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

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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 variant angina before receiving additional doses of naratriptan, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud syndrome following naratriptan administration should be evaluated for atherosclerosis or predisposition to vasospasm (see CONTRAINDICATIONS and WARNINGS).

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

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

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

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

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

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

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

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

Laboratory Tests: No specific laboratory tests are recomm ended for monitoring patients prior to and/or after treatment with AMERGE Tablets.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Lifetime carcinogenicity studies, 104 weeks in duration, were carried out in mice and rats by oral gavage. There was no evidence of an increase in tumors related to naratriptan administration in mice receiving up to 200 mg/kg/day. That dose was associated with a plasma area-under-the-curve (AUC) exposure that was 110 times the exposure in humans receiving the maximum recommended daily dose of 5 mg. Two rat studies were conducted, 1 using a standard diet and the other a nitrite-supplemented diet (naratriptan can be nitrosated in vitro to form a mutagenic product that has been detected in the stomachs of rats fed a high nitrite diet). Doses of 5, 20, and 90 mg/kg were associated with week 13 AUC exposures that in the standard diet study were 7, 40, and 236 times, respectively, and in the nitrite-supplemented diet study were 7, 29, and 180 times, respectively, the exposure attained in humans given the maximum recommended daily dose of 5 mg. In both studies, there was an increase in the incidence of thyroid follicular hyperplasia in high-dose males and females and in thyroid follicular adenomas in high-dose males. In the standard diet study only, there was also an increase in the incidence of benign c-cell adenomas in the thyroid of high-dose males and females. The exposures achieved at the no-effect dose for thyroid tumors were 40 (standard diet) and 29 (nitrite-supplemented diet) times the exposure achieved in humans receiving the maximum recommended daily dose of 5 mg. In the nitrite-supplemented diet study only, the incidence of benign lymphocytic thymoma was increased in all treated groups of females. It was not determined if the nitrosated product is systemically absorbed. However, no changes were seen in the stomachs of rats in that study.

Mutagenesis: Naratriptan was not mutagenic when tested in 2 gene mutation assays, the Ames test and the in vitro thymidine locus mouse lymphoma assay. It was not clastogenic in 2 cytogenetics assays, the in vitro human lymphocyte assay and the in vivo mouse micronucleus assay. Naratriptan can be nitrosated in vitro to form a mutagenic product (WHO nitrosation assay) that has been detected in the stomachs of rats fed a nitrite-supplemented diet.

Impairment of Fertility: In a reproductive toxicity study in which male and female rats were dosed prior to and throughout the mating period with 10, 60, 170, or 340 mg/kg/day (plasma exposures [AUC] approximately 11, 70, 230, and 470 times, respectively, the human exposure at the maximum recommended daily dose [MRDD] of 5 mg), there was a treatment-related decrease in the number of females exhibiting normal estrous cycles at doses of 170 mg/kg/day or greater and an increase in preimplantation loss at 60 mg/kg/day or greater. In high-dose group males, testicular/epididymal atrophy accompanied by spermatozoa depletion reduced mating success and may have contributed to the observed preimplantation loss. The exposures achieved at the no-effect doses for preimplantation loss, anestrus, and testicular effects were approximately 11, 70, and 230 times, respectively, the exposures in humans receiving the MRDD.

In a study in which rats were dosed orally with 10, 60, or 340 mg/kg/day for 6 months, changes in the female reproductive tract including atrophic or cystic ovaries and anestrus were seen at the high dose. The exposure at the no-effect dose of 60 mg/kg was approximately 85 times the exposure in humans receiving the MRDD.

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

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

In reproductive toxicity studies in rats and rabbits, oral administration of naratriptan was associated with developmental toxicity (embryolethality, fetal abnormalities, pup mortality, offspring growth retardation) at doses producing maternal plasma drug exposures as low as 11 and 2.5 times, respectively, the exposure in humans receiving the MRDD of 5 mg.

When pregnant rats were administered naratriptan during the period of organogenesis at doses of 10, 60, or 340 mg/kg/day, there was a dose-related increase in embryonic death, with a statistically significant difference at the highest dose, and incidences of fetal structural variations (incomplete/irregular ossification of skull bones, sternebrae, ribs) were increased at all doses. The maternal plasma exposures (AUC) at these doses were approximately 11, 70, and 470 times the exposure in humans at the MRDD. The high dose was maternally toxic, as evidenced by decreased maternal body weight gain during gestation. A no-effect dose for developmental toxicity in rats exposed during organogenesis was not established.

When doses of 1, 5, or 30 mg/kg/day were given to pregnant Dutch rabbits throughout organogenesis, the incidence of a specific fetal skeletal malformation (fused sternebrae) was increased at the high dose, and increased incidences of embryonic death and fetal variations (major blood vessel variations, supernumerary ribs, incomplete skeletal ossification) were observed at all doses (4, 20, and 120 times, respectively, the MRDD on a body surface area basis). Maternal toxicity (decreased body weight gain) was evident at the high dose in this study. In a similar study in New Zealand White rabbits (1, 5, or 30 mg/kg/day throughout organogenesis), decreased fetal weights and increased incidences of fetal skeletal variations were observed at all doses (maternal exposures equivalent to 2.5, 19, and 140 times exposure in humans receiving the MRDD), while maternal body weight gain was reduced at 5 mg/kg or greater. A no-effect dose for developmental toxicity in rabbits exposed during organogenesis was not established.

When female rats were treated with 10, 60, or 340 mg/kg/day during late gestation and lactation, offspring behavioral impairment (tremors) and decreased offspring viability and growth were observed at doses of 60 mg/kg or greater, while maternal toxicity occurred only at the highest dose. Maternal exposures at the no-effect dose for developmental effects in this study were approximately 11 times the exposure in humans receiving the MRDD.

Nursing Mothers: Naratriptan-related material is excreted in the milk of rats. Therefore, caution should be exercised when considering the administration of AMERGE Tablets to a nursing woman.

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

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

Geriatric Use: The use of AMERGE Tablets in elderly patients is not recommended.

Naratriptan is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in elderly patients who have reduced renal function. In addition, elderly patients are more likely to have decreased hepatic function; they are at higher risk for CAD; and blood pressure increases may be more pronounced in the elderly. Clinical studies of AMERGE Tablets did not include patients over 65 years of age.

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OVERDOSE
A patient who was mildly hypertensive experienced a significant increase in blood pressure after administration of a 10-mg dose starting at 30 minutes (baseline value of 150/98 to 204/144 mmHg 225 minutes). This event resolved after treatment with antihypertensive therapy. Oral administration of 25 mg of naratriptan in 1 healthy young 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.

Another subject experienced asymptomatic ischemic ECG changes likely due to coronary artery vasospasm approximately 2 hours following a 7.5-mg oral dose.

The elimination half-life of naratriptan is about 6 hours (see CLINICAL PHARMACOLOGY), and therefore monitoring of patients after overdose with AMERGE Tablets should continue for at least 24 hours or while symptoms or signs persist. There is no specific antidote to naratriptan. 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. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of naratriptan.

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CONTRAINDICATIONS
AMERGE Tablets should not be given to patients with history, symptoms, or signs of ischemic cardiac, cerebrovascular, or peripheral vascular syndromes. In addition, patients with other significant underlying cardiovascular diseases should not receive AMERGE Tablets. 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 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. Peripheral vascular disease includes, but is not limited to, ischemic bowel disease (see WARNINGS).

Because AMERGE Tablets may increase blood pressure, they should not be given to patients with uncontrolled hypertension (see WARNINGS).

AMERGE Tablets are contraindicated in patients with severe renal impairment (creatinine clearance, < 15 mL/min) (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

AMERGE Tablets are contraindicated in patients with severe hepatic impairment (Child-Pugh grade C) (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

AMERGE Tablets should not be administered to patients with hemiplegic or basilar migraine.

AMERGE Tablets should not be used within 24 hours of treatment with another 5-HT1 agonist, an ergotamine-containing or ergot-type medication like dihydroergotamine or methysergide.

AMERGE Tablets are contraindicated in patients with hypersensitivity to naratriptan or any of the components.

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更新日期: 2014-11-05
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