毒理性
◉ 母乳喂养期间使用总结：有限的数据表明，系统给药的Tacrolimus在母乳中的含量较低，可能不会对哺乳婴儿产生不利影响。美国和欧洲的专家和指南认为，在母乳喂养期间使用Tacrolimus可能是安全的。如果在此期间使用此药物，应监测仅以母乳喂养的婴儿，可能包括测量血清水平以排除毒性的担忧。
局部Tacrolimus的风险较低，因为其在局部应用后吸收不良，大多数患者的峰值血药浓度低于2 mcg/L。确保婴儿的皮肤不直接接触已治疗的皮肤区域。如果要治疗乳房，首选其他药物；在哺乳期间不要涂抹在乳头区域。最新的欧洲指南允许在哺乳后立即涂抹Tacrolimus，并在哺乳前轻轻仔细清洁乳头。
◉ 对哺乳婴儿的影响：一名婴儿在母亲Tacrolimus治疗期间全程至至少2.5个月大时仅以母乳喂养，此时婴儿在身体和神经方面发育正常。婴儿的胸腺超声检查正常。
国家移植妊娠登记处报告了1991年至2011年间收集的数据，这些数据来自移植后母乳喂养婴儿的母亲。共有68位移植母亲（大多数是肾脏或肝脏移植）在母乳喂养总共83名婴儿期间使用了Tacrolimus。哺乳期从1周到1.5年不等，对儿童的随访时间从几周到16年不等。所有婴儿或儿童均未报告问题。截至2013年12月，共有92位母亲母乳喂养了125名婴儿，最长26个月，婴儿未出现明显不良反应。
六位在怀孕期间因器官移植而服用Tacrolimus的妇女的哺乳婴儿（4名完全哺乳，2名部分哺乳）哺乳了45至180天，并随访了2至30个月。这些母亲哺乳期间平均每日Tacrolimus剂量为9.6毫克（每日剂量范围为4.5至15毫克）。其中四位母亲还每天服用100至150毫克的硫唑嘌呤，一位服用地尔硫卓，一位服用15毫克的泼尼松和75毫克的阿司匹林。尽管一名婴儿在继续哺乳期间出现了短暂的血小板增多症，但没有任何婴儿出现明确的Tacrolimus相关副作用。发育里程碑正常，未发现感染模式。
两名患有系统性红斑狼疮的妇女在怀孕和哺乳期间每天服用3毫克的Tacrolimus以及30或40毫克的泼尼松。出生三年后，两个孩子都很健康。哺乳期的持续时间未说明。
在一项为期25年的女性肝移植案例系列中，一名妇女在服用Tacrolimus期间哺乳了她的婴儿（哺乳程度未说明）。未发现新生儿并发症。
一名患有肝移植的妇女在哺乳期间持续使用Belatacept 10毫克/千克每月，缓释Tacrolimus（Envarsus和Veloxis）2毫克每日，硫唑嘌呤25毫克每日，泼尼松2.5毫克每日。她哺乳了婴儿一年（哺乳程度未说明）。婴儿的生长和认知里程碑正常。
一项澳大利亚案例系列报告了3名心脏移植妇女共有5名婴儿，在母亲Tacrolimus治疗期间均接受了哺乳（哺乳程度未说明）。每日剂量范围为3至13毫克。在出院前未报告婴儿不良反应。
一名对依那西普耐药的类风湿性关节炎妇女在怀孕期间直到37周时每两周服用200毫克的Sarilumab。她还每天服用10毫克的泼尼松和3毫克的Tacrolimus。她在38周时分娩了一名健康的婴儿并哺乳了她的婴儿。产后继续服用泼尼松，Tacrolimus在产后7天重新开始服用，Sarilumab在产后28天重新开始服用。母亲在产后6个月继续哺乳。婴儿在满六个月后接种了多种活疫苗，包括卡介苗，未出现不良反应。
◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发布信息。
◉ Summary of Use during Lactation:Limited data indicate that amounts of systemically administered tacrolimus are low in breastmilk and probably do not adversely affect the breastfed infant. United States and European experts and guidelines consider tacrolimus to be probably safe to use during breastfeeding. Exclusively breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels to rule out toxicity if there is a concern.
Topical tacrolimus presents a low risk to the nursing infant because it is poorly absorbed after topical application and peak blood concentrations are less than 2 mcg/L in most patients. Ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. If the breast is to be treated, an alternate drug is preferred; do not apply to the nipple area while nursing. A newer European guideline allows tacrolimus to be applied just after nursing, with the nipples cleaned gently and carefully before nursing.
◉ Effects in Breastfed Infants:One infant was exclusively breastfed during maternal tacrolimus therapy throughout gestation to at least 2.5 months of age at which time the infant was developing normally physically and neurologically. An ultrasound examination of the infant's thymus was normal.
The National Transplantation Pregnancy Registry reported data gathered from 1991 to 2011 on mothers who breastfed their infants following organ transplantation. A total of 68 mothers with transplants (mostly kidney or liver) used tacrolimus while breastfeeding a total of 83 infants. Duration of nursing ranged from 1 week to 1.5 years and follow-up of the children ranged from weeks to 16 years. There were no reports of problems in any of the infants or children. As of December 2013, a total of 92 mothers had breastfed 125 infants for as long as 26 months with no apparent adverse effects in infants.
The breastfed infants of six women who took tacrolimus during pregnancy for organ transplantation were breastfed (4 exclusive, 2 partial) for 45 to 180 days and followed for periods of 2 to 30 months. The mothers' mean daily tacrolimus dosage during breastfeeding was 9.6 mg daily (range 4.5 to 15 mg daily). Four mothers were also taking azathioprine 100 to 150 mg daily, one was taking diltiazem, and one was taking prednisolone 15 mg and aspirin 75 mg daily. None of the infants had any clear tacrolimus-related side effects, although one had transient thrombocytosis that resolved despite continued breastfeeding. Developmental milestones were normal and no pattern of infections was noted.
Two mothers with systemic lupus erythematosus were reported who took tacrolimus 3 mg daily during pregnancy and lactation as well as prednisolone 30 or 40 mg daily. Three years after birth, both children were healthy. The durations of lactation were not stated.
In a case series of women who had liver transplants over a 25-year period, one woman breastfed (extent not stated) her infant while taking tacrolimus. No neonatal complications were noted.
A mother with a liver transplant was maintained on belatacept 10 mg/kg monthly, slow-release tacrolimus (Envarsus and Veloxis) 2 mg daily, azathioprine 25 mg daily, and prednisone 2.5 mg daily. She breastfed her infant for a year (extent not stated). The infant’s growth and cognitive milestones were normal.
An Australian case series reported 3 women with heart transplants who had a total of 5 infants, all of whom were breastfed (extent not stated) during maternal tacrolimus therapy. Daily dosages ranged from 3 to 13 mg daily. No adverse infant effects were reported up to the times of discharge.
A woman with rheumatoid arthritis refractory to etanercept took sarilumab 200 mg every two weeks during pregnancy until 37 weeks of gestation. She was also taking prednisolone 10 mg and tacrolimus 3 mg daily. She delivered a healthy infant at 38 weeks of gestation and breastfed her infant. Prednisolone was continued postpartum, tacrolimus was restarted at 7 days postpartum, and sarilumab was restarted at 28 days postpartum. The mother continued to breastfeed until 6 months postpartum. The infant was vaccinated with multiple live vaccines after reaching six months old, including the Bacille-Calmette-Guerin vaccine, with no adverse effects.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
来源:Drugs and Lactation Database (LactMed)
