FDA变更Depo-Provera、Tracleer与Tabloid的安全性标示


  Feb. 2, 2005 - 美国食品药物管理局(FDA)于去年11月核准药物安全性标示变更,建议健康照护专家们下列的变更:medroxyprogesterone acetate(MPA)禁止使用于严重肝脏疾病患者,MPA可能随著使用时间越长,造成显著的骨质流失,且这种改变是不可逆的;bosentan可能降低避孕药物的疗效;因为thioguanine引起肝脏毒性的高风险,因此并不建议长期使用这个药物。
  
  Medroxyprogesterone Acetate(Depo-Provera)与骨质流失有关
  11月17日,FDA核准可注射的medroxyprogesterone acetate(MPA)悬浮液(Depo-Provera避孕注射液,由辉瑞药厂制造),建议有关于这个药物的使用禁忌症与注意事项。
  
  严重肝脏疾病患者禁止使用这个药物。
  
  除此之外,FDA警告使用MPA可能会造成严重的骨密度(BMD)流失,这种现象与使用药物时间的长短有关,而且是不可逆的;FDA表示,目前仍不清楚于青少年时期或是成年早期(骨骼愈合的关键时期)使用这个药物是否会降低最高骨质密度,并增加未来骨质疏松骨折的风险。
  
  有骨质疏松危险因子的妇女应该考虑其它避孕方式,因为MPA的使用可能为有代谢性骨骼疾病病史、慢性酒精以及/或是吸菸、厌食症、长期使用抗凝血药物、类固醇、或是其它可能会降低骨质的药物、或是强烈的骨质疏松症病史患者,带来额外的风险。
  
  MPA的使用只有在使用其它避孕方式失败时,才能使用超过2年;FDA建议长期使用者(超过2年)应该评估BMD,而当阐释青少年的结果时,必须要将年龄与骨骼成熟度考虑进去。
  
  尽管并没有实验指出这样的摄取方式可以降低这些病患骨质流失的情形,但所有使用MPA的妇女都被建议摄取足够的钙与维他命D。
  
  FDA建议,使用MPA之前,应该要将一些因子,如所有年龄层妇女的骨质流失、对青少年最高骨质量的影响、因怀孕以及/或是泌乳降低的BMD,都考虑到风险-利益评估中;处方这些药物给青少年及年轻的成人时应该要特别地注意。
  
  MPA的适应症为预防具有生育潜力的妇女怀孕。
  
  Bosentan(Tracleer)降低荷尔蒙避孕药物的效果
  
  11月24日,FDA核准bosentan(Tracleer锭,由Actelion公司制造)的安全性标示变更,警告同时使用经皮荷尔蒙避孕药物(除了口服、注射及植入剂型)可能会降低避孕药物的效果,在这种情况下,不应该仅依赖药物作为唯一的避孕方式。
  
  安全性标示的变更是由于一项交互作用试验结果显示,共同投予bosentan及口服避孕药物Ortho-Novum(Ortho-McNeil药厂制造)会造成norethindrone(14%)与ethinyl estradiol(31%)的平均浓度下降,甚至有受试者的药物血中浓度分别下降了56%与66%。
  
  FDA建议,当妇女使用bosentan时,应该尝试额外的避孕方法,不能仅依赖荷尔蒙避孕方式。
  
  Bosentan的适应症,包括治疗世界卫生组织分级III或是IV症状的肺动脉高压患者,以改善运动能力与减缓临床上恶化的速度。
  
  Thioguanine(Tabloid)因为肝脏毒性高风险,而不能长期使用
  11月15日,FDA核准thioguanine(Tabloid锭,由葛兰素史克美占药厂制造)的安全性标示变更,警告thioguanine与血管内皮损伤有关的肝脏毒性,使得这药物不适合作为维持、或是长期连续疗法。
  
  已经于大多数接受thioguanine作为急性淋巴母细胞白血病、及其它情况下维持疗法的病患身上观察到这个药物的肝脏毒性。
  
  毒性在临床上以一种静脉阻塞性疾病(胆红素过高、触痛的肝脏肿大、因体液滞留引起的体重增加及腹水)的症候群、或是肝门高压(脾脏肿大、血小板低下、食道静脉曲张)的病征表现。
  
  组织病理的特色,包括肝脏肝门附近的硬化、结节性退化性增生、紫癜性肝炎及肝门附近的纤维化。
  
  接受thioguanine治疗的病患,应被仔细地监测肝门高压的早期病征,如与中性球低下不成比例的血小板低下及肝脏肿大;此外,肝脏酵素的上升与肝脏毒性有关,但是不一定会发生。
  
  FDA建议,thioguanine疗法在有肝脏毒性证据的患者身上应该停用;肝脏毒性的病征与症状可能在停药后消失。
  
  Thioguanine的适应症,为急性非淋巴球性白血病的诱导消退及巩固疗法。

FDA Safety Labeling Changes: D

By Yael Waknine
Medscape Medical News

Feb. 2, 2005 — The U.S. Food and Drug Administration (FDA) approved revisions to drug safety labeling last November, advising healthcare professionals of the following changes: use of medroxyprogesterone acetate (MPA) injection is contraindicated in patients with significant liver disease, and use of MPA injection may result in significant bone loss that increases with duration of use and may not be completely reversible; bosentan may reduce the efficacy of concurrently administered hormonal contraceptives; long-term use of thioguanine is not recommended due to a high risk of hepatotoxicity.

Medroxyprogesterone Acetate (Depo-Provera) Linked to Bone Loss

On Nov. 17, the FDA approved revisions to the safety labeling for medroxyprogesterone acetate (MPA) injectable suspension (Depo-Provera Contraceptive Injection, made by Pfizer, Inc.), advising of contraindications and warnings associated with its use.

Use of MPA is contraindicated in patients with significant liver disease.

In addition, the FDA warns that use of MPA may result in a significant loss of bone mineral density (BMD) that increases with duration of use and may not be completely reversible. The FDA notes that it is unknown whether use during adolescence or early adulthood (a critical period of bone accretion) will result in reduced peak bone mass and increased risk of future osteoporotic fracture.

Other contraceptive options should be considered in women with risk factors for osteoporosis because the use of MPA may pose additional risk in those with a history of metabolic bone disease; chronic alcohol and/or tobacco use; anorexia nervosa; chronic use of anticonvulsants, corticosteroids, or other drugs that may reduce bone mass; or a strong family history of osteoporosis.

Use of MPA should exceed two years' duration only in those women for whom other methods of birth control are inadequate. The FDA recommends that BMD be evaluated in long-term users (> two years) and that age and skeletal maturity be considered when interpreting results in adolescents.

An adequate intake of calcium and vitamin D is recommended in all women using MPA, although no studies have addressed the effect of such intake on reducing bone loss in these patients.

The FDA advises that factors such as BMD loss in women of all ages, the effect on peak bone mass in adolescents, and decreases in BMD due to pregnancy and/or lactation be considered in a risk-benefit analysis prior to long-term use of MPA. Particular caution is recommended in prescribing for young adults and adolescents.

MPA is indicated for the prevention of pregnancy in women of child-bearing potential.

Bosentan (Tracleer) Decreases Efficacy of Hormonal Contraceptives

On Nov. 24, the FDA approved revisions to the safety labeling for bosentan (Tracleer tablets, made by Actelion, Inc.), warning that concurrent use of transdermal hormonal contraceptives (in addition to oral, injectable, and implantable formulations) may decrease the contraceptives' efficacy and that they should not be relied on as a sole means of contraception.

The labeling has been updated with data from an interaction study showing that concurrent administration of bosentan and the oral hormonal contraceptive Ortho-Novum (made by Ortho-McNeil Pharmaceuticals, Inc.) resulted in mean decreases of norethindrone (14%) and ethinyl estradiol (31%) levels, with individual exposures decreasing by as much as 56% and 66%, respectively.

The FDA recommends that women practice additional methods of contraception and not rely on hormonal contraception alone when taking bosentan.

Bosentan is indicated for the treatment of pulmonary arterial hypertension in patients with World Health Organization class III or IV symptoms to improve exercise ability and decrease the rate of clinical worsening.

Thioguanine (Tabloid) Not for Long-term Use Due to High Risk of Hepatotoxicity

On Nov. 15, the FDA approved revisions to the safety labeling for thioguanine (Tabloid tablets, made by GlaxoSmithKline), warning that thioguanine is not recommended for maintenance or long-term continuous therapy due to a high risk of hepatotoxicity associated with vascular endothelial damage.

Hepatotoxicity has been observed in a high proportion of pediatric patients (particularly in boys) receiving thioguanine as part of maintenance therapy for acute lymphoblastic leukemia and other conditions.

The toxicity presents clinically as a syndrome of hepatic veno-occlusive disease (hyperbilirubinemia, tender hepatomegaly, weight gain due to fluid retention, and ascites) or with signs of portal hypertension (splenomegaly, thrombocytopenia, and esophageal varices). Histopathologic features include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatis, and periportal fibrosis.

Patients receiving thioguanine should be carefully monitored for early indications of portal hypertension, such as thrombocytopenia out of proportion with neutropenia and splenomegaly. Elevated liver enzyme levels have been associated with liver toxicity but do not always occur.

The FDA recommends that thioguanine therapy be discontinued in patients with evidence of hepatotoxicity; signs and symptoms of the condition may reverse upon withdrawal.

Thioguanine is indicated for remission induction and consolidation treatment of acute nonlymphocytic leukemias.

Reviewed by Gary D. Vogin, MD

    
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