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Pregnancy: Risk summary: There are no adequate or well-controlled clinical studies in pregnant women using ciclosporin. There is a moderate amount of data on the use of ciclosporin in pregnant patients from post-marketing experience, including published literature. Pregnant women receiving immunosuppressive therapies after transplantation, including ciclosporin and ciclosporin-containing regimens, are at risk of premature delivery (<37 weeks). The data have not demonstrated a higher incidence of miscarriages, major birth defects, or maternal events as compared to the rates seen in the general population (see Human data as follows).
Embryo-fetal developmental (EFD) studies in rats and rabbits with ciclosporin have shown embryo-fetal toxicity at dose levels below the maximum recommended human dose (MRHD) based on body surface area (BSA) (see Animal data as follows).
Sandimmun Neoral should not be used during pregnancy unless the expected benefit to the mother outweighs the potential risk to the fetus. The ethanol content should also be taken into account in pregnant women (see Precautions).
Data: Human data: Published data from National Transplantation Pregnancy Registry (NTPR), described pregnancy outcomes in female kidney (482), liver (97), and heart (43) transplant recipients receiving ciclosporin. The data indicated successful pregnancies with a live birth rate of 76% and 76.9%, and 64% in kidney, liver, and heart transplant recipients, respectively. Premature delivery (<37 weeks) was reported in 52%, 35%, and 35% of kidney, liver, and heart transplant recipients, respectively.
The rates of miscarriages and major birth defects were reported to be comparable to the rates observed in the general population. A potential direct effect of ciclosporin on maternal hypertension, preeclampsia, infections, or diabetes could not be excluded given the limitations inherent to registries and postmarketing safety reporting.
A limited number of observations in children exposed to ciclosporin in utero is available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal.
Animal data: Three EFD studies (two oral and one intravenous) are available in rats. In oral EFD studies, pregnant rats were administered with ciclosporin either at doses of 10, 17, 30, 100 and 300 mg/kg/day or 4, 10 and 25 mg/kg/day from gestation day (GD) 6 to 15 or from GD 7 to 17, respectively. Maternal toxicity characterized by mortality, clinical signs of toxicity and impaired body weight gain were observed at 30 mg/kg/day and above. Ciclosporin was embryo- and fetotoxic as indicated by increased embryonic mortality and reduced fetal weight together with skeletal retardations in rats at 25 mg/kg/day and above. In addition, ventricular septal defect was observed at 25 mg/kg/day in fetuses. The no observed effect level (NOEL) for both dams and fetus was 17 mg/kg/day (below the MRHD based on BSA) after oral administration. In the other oral study, the NOEL for dams and fetuses were 10 and 4 mg/kg/day (below the MRHD based on BSA), respectively. In the IV EFD study, rats were administered with 3, 6 and 12 mg/kg/day of ciclosporin from GD 7 to 17. An increase in post implantation loss was observed at 12 mg/kg/day; ventricular septal defect was observed at 6 mg/kg/day and above in fetuses. The NOEL for dams and fetus were 6 and 3 mg/kg/day (below the MRHD based on BSA), respectively, after IV administration.
In rabbits, ciclosporin was orally administered at dose levels of 10, 30, 100 or 300 mg/kg/day from GD 6 to 18. At 100 mg/kg/day and above, reduction in body weight gain of dams and at 300 mg/kg/day abortions were observed. Maternal toxicity, embryo-fetotoxicity as indicated by increased pre- and postnatal mortality, reduced fetal weight together with skeletal retardations were observed at 100 mg/kg/day and above. The NOEL for dams and fetuses was 30 mg/kg/day (below the MRHD based on BSA).
In two published research studies, pregnant rabbits exposed to ciclosporin (10 mg/kg/day subcutaneously) during gestation demonstrated maternal toxicity (reduced body weight gain) and kidney changes in pups and adults (reduced numbers of nephrons, renal hypertrophy, systemic hypertension, and progressive renal insufficiency). An increase in fetal resorptions and a decrease in live pups and pup body weight were observed.
In a peri-and postnatal development study in rats, pregnant rats were orally administered with ciclosporin (5, 15 or 45 mg/kg/day) from GD 15 until end of lactation. At 45 mg/kg/day (below the MRHD based on BSA), increased pre and postnatal mortality of offspring and reduced body weight gain of surviving pups were observed. Ciclosporin up to 15 mg/kg/day (below the MRHD based on BSA) had no effect on pregnancy, pre and postnatal development of offspring [83].
Lactation: Risk summary: Ciclosporin is transferred into breast milk. Mothers receiving treatment with Sandimmun Neoral should not breastfeed. Because of the potential of Sandimmun Neoral to cause serious adverse drug reactions in breastfed newborns/infants, a decision should be made whether to abstain from breast-feeding or to abstain from using the medicinal drug, taking into account the benefit of breast-feeding for the newborn/infant and the importance of the medicinal product to the mother.
The milk to maternal blood concentration ratio of ciclosporin was in the range of 0.17 to 1.4. Based on the infant milk intake, the highest estimated ciclosporin dose ingested by fully breast-fed infant was approximately 2% of maternal weight adjusted dose.
The ethanol content of the Sandimmun Neoral formulations should also be taken into account (see Precautions).
Females and males of reproductive potential: Females: There are no special recommendations for women of child-bearing potential.
Fertility: There is limited data on the effect of ciclosporin on human fertility. No impairment in fertility was demonstrated in male and female rats up to 5 mg/kg/day (below MRHD based on BSA) (see Pharmacology: Toxicology: Nonclinical Safety Data under Actions).
