友情提示：zavesca为管制药。

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 详细处方信息以本药内容附件PDF文件（201072122554129.pdf）的“原文Priscribing Information”为准
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部分中文zavesca处方资料（仅供参考）

    美格鲁特zavesca(Miglustat)可治疗囊性纤维化与高雪氏病
    法国国家科研中心和普瓦提埃大学的研究人员日前宣布，他们发现一种名为美格鲁特的药物可有效治疗囊性纤维化。  
    囊性纤维化是一种遗传性疾病，主要影响胃肠道和呼吸系统，通常具有慢性梗阻性肺部病变、胰腺外分泌功能不足和汗液电解质异常升高的特征，可威胁患者生命。  
    研究人员在美国最新一期《呼吸细胞和分子生物学杂志》上报告说，他们发现，在病变细胞中注入美格鲁特后，在不停药的前提下可使病变细胞恢复正常。随后进行的小范围临床试验证实，囊性纤维化患者每天被注射小剂量的美格鲁特后，在两个月的治疗过程中，病人的各项参数逐渐恢复正常，不过一旦停药，他们的病情又会加重。
    美格鲁特是一种葡萄糖苷酰鞘氨醇合成酶抑制剂，主要用于治疗另一种罕见的遗传性疾病——高雪氏病。
    zavesca(Miglustat)治疗高雪病的首例药物由美国ACTELION PHARMS公司研制的治疗由葡萄糖酶脑苷脂酶出现功能性缺陷所引起的Ⅰ型高雪病的首例药物美格鲁特(Miglustat)胶囊剂以商品名zavesca于2003年7月获得美国FDA批准。
    高雪病为一种少见的疾病，由于葡萄糖酶脑苷脂酶出现功能性缺陷所致。此酶在人体内参与鞘糖脂葡萄糖鞘脑苷鞘氨醇的降解过程，当鞘糖脂葡萄糖鞘脑苷鞘氨醇的降解受到阻碍时，会使富含此种物质的巨嗜细胞的溶酶体在体内蓄积，发生广泛的病理反应，包括严重贫血、血小板减少、肝脾肿大、骨坏死和骨质减少。在治疗上常采用酶替代方法，美格鲁特用于无法以酶替代治疗的成年患者。
    美格鲁特可降低鞘内糖脂的生物合成率，将葡萄糖苷鞘酶在人体内的浓度降至一个低水平，有助于改善Ⅰ型高雪病患者的肝、脾脏肿大，血色素、血小板计数低下的水平。推荐剂量为1次100mg，1日3次，若患者出现腹泻和震颤等不良反应，剂量可减少为1日1～2次；对轻度肾脏功能受损者(肌酐清除率为50～70ml/min /1.73m2)推荐剂量为1次100mg，1日2次；对轻度肾脏功能受损者(肌酐清除率为50～70ml/min  /1.73m2)推荐剂量为1次100mg，1日2次；对中度肾脏功能受损者(肌酐清除率为30～50ml/min /1.73m2)推荐剂量为1次100mg，1日1次；对重度肾脏功能受损者不宜应用。
    其应用初始的第1个月，常见有震颤、腹泻、胃肠道不适、视力损害、体重减轻、麻木、疼痛、背痛、疲乏、手足烧灼感、肢体沉重、血小板减少等不良反应；对男性有可能影响精子的质量，因此在用药期间尽可能地采取避孕措施，对女性患者在服用期间建议不要怀孕。美格鲁特胶囊剂的规格为每粒100mg。

Zavesca®
(miglustat) Capsules, 100mg

ZAVESCA® (miglustat capsules, 100 mg) is an inhibitor of the enzyme glucosylceramide synthase, which is a glucosyl transferase enzyme responsible for the first step in the synthesis of most glycosphingolipids. ZAVESCA® is an N-alkylated imino sugar, a synthetic analogue of D-glucose.

The chemical name for miglustat is 1,5-(butylimino)-1,5-dideoxy-D-glucitol with the chemical formula C10H21NO4 and a molecular weight of 219.28.

Miglustat is a white to off-white crystalline solid and has a bitter taste. It is highly soluble in water ( > 1000 mg/mL as a free base).

ZAVESCA® is supplied in hard gelatin capsules each containing 100 mg miglustat for oral administration. Each ZAVESCA® 100 mg capsule also contains sodium starch glycolate, povidone (K30), and magnesium stearate. Ingredients in the capsule shell include gelatin and titanium dioxide, and the shells are printed with edible ink consisting of black iron oxide and shellac.

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INDICATIONS
ZAVESCA® is indicated for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g., due to constraints such as allergy, hypersensitivity, or poor venous access).

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DOSAGE AND ADMINISTRATION
Instructions for Administration
Therapy should be directed by physicians who are knowledgeable in the management of Gaucher disease. The recommended dose for the treatment of adult patients with type 1 Gaucher disease is one 100 mg capsule administered orally three times a day at regular intervals.

It may be necessary to reduce the dose to one 100 mg capsule once or twice a day in some patients for adverse effects, such as diarrhea or tremor.

Patients with Renal Insufficiency
In patients with mild renal impairment (adjusted creatinine clearance 50-70 mL/min/1.73 m²), ZAVESCA® administration should commence at a dose of 100 mg twice per day. In patients with moderate renal impairment (adjusted creatinine clearance of 30-50 mL/min/1.73 m²), ZAVESCA® administration should commence at a dose of one 100 mg capsule per day. Use of ZAVESCA® in patients with severe renal impairment (creatinine clearance of < 30 mL/min/1.73 m²) is not recommended.

STORAGE
Store at 20° C to 25° C (68° F to 77° F). Brief exposure to 15° C to 30° C (59° F to 86° F) permitted (see USP Controlled Room Temperature).

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HOW SUPPLIED
ZAVESCA® is supplied in hard gelatin capsules containing 100 mg miglustat. ZAVESCA® 100 mg capsules are white opaque with “OGT 918” printed in black on the cap and “100” printed in black on the body.

ZAVESCA® 100 mg capsules are packed in blister cards. Five blister cards of 18 capsules are supplied in each carton.

NDC 66215-201-90: carton containing 90 capsules
NDC 66215-201-18: blister card containing 18 capsules

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SIDE EFFECTS
The most common serious adverse reaction reported with Zavesca treatment in clinical studies was peripheral neuropathy (see WARNINGS: Peripheral Neuropathy).

The most common treatment-emergent adverse events reported in clinical studies with Zavesca were weight loss, diarrhea, and tremor (see PRECAUTIONS: Tremor, and Diarrhea and Weight Loss). Other common adverse reactions were flatulence, abdominal pain, headache, and influenza-like symptoms.

The most common adverse reaction requiring intervention was diarrhea (see PRECAUTIONS: Diarrhea and Weight Loss). Most episodes of diarrhea were ameliorated by the use of anti-diarrheal medications, and/or the avoidance of high-carbohydrate-content foods, or were noted to decrease over time with continued Zavesca treatment. The next most common adverse reaction requiring intervention was tremor (see PRECAUTIONS: Tremor). In many cases, tremor resolved despite continued Zavesca treatment. Dose reduction of Zavesca may ameliorate tremor, but discontinuation of Zavesca was required in some patients.

The data described below reflect exposure of 80 adult type 1 Gaucher disease patients to Zavesca in two open-label, uncontrolled, monotherapy trials, and one open-label, active-controlled trial. Patients were ages 18 to 69 years at first treatment. The population was nearly evenly distributed by gender.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In two open-label, uncontrolled monotherapy trials, adult type 1 Gaucher disease patients were treated with ZAVESCA® at a starting dose of 100 mg three times daily (dose range 100 to 200 mg three times daily) for up to 12 months in 28 patients [Study 1], or at a dose of 50 mg three times daily for up to 6 months in 18 patients [Study 2]. Table 9 below enumerates adverse events that occurred during the trials in ≥ 5% of patients. Reported adverse events have been classified using standard WHOART terms.

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DRUG INTERACTIONS
While co-administration of ZAVESCA® appeared to increase the clearance of Cerezyme by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of Cerezyme. Combination therapy with Cerezyme (imiglucerase) and ZAVESCA® is not indicated (see CLINICAL PHARMACOLOGY: Drug Interactions).

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WARNINGS
Peripheral Neuropathy
Cases of peripheral neuropathy have been reported in patients treated with ZAVESCA®. All patients receiving ZAVESCA® treatment should undergo baseline and repeat neurological evaluations at approximately 6-month intervals. Patients who develop symptoms such as numbness and tingling should have a careful re-assessment of the risk/benefit of ZAVESCA® therapy, and cessation of treatment may be considered.

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PRECAUTIONS
General
Therapy should be directed by physicians knowledgeable in the management of patients with Gaucher disease.

Tremor
Approximately 30% of patients have reported tremor or exacerbation of existing tremor on treatment. These tremors were described as an exaggerated physiological tremor of the hands. Tremor usually began within the first month of therapy and in many cases resolved within 1 to 3 months during treatment. Dose reduction may ameliorate the tremor, usually within days, but discontinuation with treatment may sometimes be required.

Diarrhea and Weight Loss
Diarrhea and weight loss were common in clinical studies of patients treated with ZAVESCA®, with approximately 85% and up to 65% of treated patients, respectively, reporting these conditions. Diarrhea appears to be the result of the disaccharidase inhibitory activity of ZAVESCA®, with a resultant osmotic diarrhea. It is unclear if weight loss results from the diarrhea and associated gastrointestinal complaints, a decrease in food intake, or a combination of these or other factors. The incidence of weight loss was most evident in the first 12 months of treatment. The incidence of diarrhea was noted to decrease over time with continued ZAVESCA® treatment, and was noted to result in an increase in the use of anti-diarrheal medications, most commonly loperamide. Patients may be instructed to avoid high-carbohydrate-content foods during treatment with ZAVESCA® if they present with diarrhea.

Patients with persistent gastrointestinal events that continue during treatment with Zavesca, and who do not respond to usual interventions (e.g., diet modification), should be evaluated to determine whether significant underlying gastrointestinal disease is present. The safety of treatment with Zavesca has not been evaluated in patients with significant gastrointestinal disease, such as inflammatory bowel disease, and continued treatment of these patients with Zavesca should occur only after consideration of the risks and benefits of continued treatment.

Male Fertility
Male patients should maintain reliable contraceptive methods while taking ZAVESCA®. Studies in the rat have shown that miglustat adversely affects spermatogenesis and sperm parameters, thereby reducing fertility. Until further information is available, it is advised that before seeking to conceive, male patients should cease ZAVESCA® and maintain reliable contraceptive methods for 3 months thereafter (see Carcinogenesis, Mutagenesis, and Impairment of Fertility).

Information for Patients
Patients should be informed of the potential risks and benefits of ZAVESCA® and of alternative modes of therapy. Patients should be advised that diarrhea, gastrointestinal complaints, and weight loss are common side effects of ZAVESCA® therapy, and to adhere to dietary instructions. Patients should also be advised to promptly report any numbness, pain, or burning in the hands and feet, and the development of tremor or worsening in an existing tremor.

Carcinogenesis, Mutagenesis, and Impairment of Fertility
Two-year carcinogenicity studies have been conducted with miglustat in CD-1 mice at oral doses up to 500 mg/kg/day and in Sprague Dawley rats at oral doses up to 180 mg/kg/day. Oral administration of miglustat for 104 weeks produced mucinous adenocarcinomas of the large intestine at 210, 420, and 500 mg/kg/day (about 3, 6, and 7 times the recommended human dose, respectively, based on the body surface area) in male mice and at 420 and 500 mg/kg/day (about 6 and 7 times the recommended human dose, respectively, based on the body surface area) in female mice. The adenocarcinomas were considered rare in CD-1 mice and occurred in the presence of inflammatory and hyperplastic lesions in the large intestine of both males and females. In rats, oral administration of miglustat for 100 weeks produced increased incidences of interstitial cell adenomas of the testis at 30, 60, and 180 mg/kg/day (about 1, 2, and 5 times the recommended human dose, respectively, based on the body surface area).

Miglustat was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including the bacterial reverse mutation (Ames), chromosomal aberration (in human lymphocytes), gene mutation in mammalian cells (Chinese hamster ovary), and mouse micronucleus assays.

Male rats, given 20 mg/kg/day miglustat by (systemic exposure less than the human therapeutic systemic exposure based on body surface area comparisons, mg/m²) oral gavage 14 days prior to mating, had decreased spermatogenesis with altered sperm morphology and motility and decreased fertility. Decreased spermatogenesis was reversible following 6 weeks of drug withdrawal. A higher dose of 60 mg/kg/day (2 times the human therapeutic systemic exposure based on body surface area comparison, mg/m²) resulted in seminiferous tubule and testicular atrophy/degeneration.

Female rats were given oral gavage doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation. Effects observed at 20 mg/kg/day (systemic exposure less than the human therapeutic systemic exposure, based on body surface area comparisons) included decreased corpora lutea, increased postimplantation loss, and decreased live births.

Pregnancy Category X. See CONTRAINDICATIONS section.

There are no adequate and well-controlled studies of miglustat in pregnant women. ZAVESCA® should not be used during pregnancy.

Labor and Delivery
Studies in pregnant rats exposed to ZAVESCA® during gestation through lactation are associated with dystocia and delayed parturition at systemic exposure 2 times the human therapeutic systemic exposure, based on body surface area comparisons.

Nursing Mothers
It is not known whether miglustat is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from miglustat, ZAVESCA® should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. A decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the lactating woman.

Pediatric Use
The safety and effectiveness of ZAVESCA® have not been evaluated in patients under the age of 18. Treatment with ZAVESCA® is associated with diarrhea and weight loss in approximately 85% and up to 65%, respectively, of adult patients. The effects of ZAVESCA® on growth and development in children have not been evaluated.

Geriatric Use
Clinical studies of ZAVESCA® did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function and of concomitant disease or other drug therapy.

Renal Impairment
Miglustat is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. The clearance of miglustat is decreased by 40 to 60% in patients with mild to moderate renal impairment, and up to 70% in patients with severe renal impairment. As a result of this, dose reductions are recommended for those patients with mild to moderate renal impairment, the reduction being dependent upon the level of their creatinine clearance adjustment. For those patients with severe renal impairment, treatment with miglustat is not recommended. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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OVERDOSE
In the clinical development program for ZAVESCA®, no patient experienced an overdose of study drug. However, ZAVESCA® has been administered at doses of up to 3000 mg/day (approximately 10 times the recommended starting dose administered to Gaucher patients) for up to six months in Human Immunodeficiency Virus (HIV)-positive patients. Adverse events observed in the HIV studies included granulocytopenia, dizziness, and paresthesia. Leukopenia and neutropenia have also been observed in a similar group of patients receiving 800 mg/day or above.

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CONTRAINDICATIONS
ZAVESCA® is contraindicated in patients who have demonstrated hypersensitivity to the active substance or any of the excipients.

Pregnancy Category X
Miglustat may cause fetal harm when administered to a pregnant woman. In female rats given miglustat by oral gavage at doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation day 17 (organogenesis), decreased live births including complete litter loss and decreased fetal weight was observed in the mid- and high-dose groups (systemic exposures ≥ 2 times the human therapeutic systemic exposure based on body surface area comparison). In pregnant rats given miglustat by oral gavage at doses of 20, 60, 180 mg/kg/day from gestation day 6 through lactation (postpartum day 20), dystocia and delayed parturition were observed in the mid- and high-dose groups (systemic exposures ≥ 2 times the human therapeutic systemic exposure, based on body surface area comparison); in addition decreased live births and pup body weights were observed at > 20 mg/kg/day (systemic exposures less than the human therapeutic systemic exposure, based on body surface area comparison).

In pregnant rabbits given miglustat by oral gavage at doses of 15, 30, 45 mg/kg/day during gestation days 6-18 (organogenesis), maternal death and decreased body weight gain were observed at 15 mg/kg/day (systemic exposures less than the human therapeutic systemic exposure, based on body surface area comparisons).

ZAVESCA® is contraindicated in women who are or may become pregnant. If this drug is administered to a woman with reproductive potential, the patient should be apprised of the potential hazard to a fetus.

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 详细处方信息以本药内容附件PDF文件（201072122554129.pdf）的“原文Priscribing Information”为准
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2010年7月22日更新