Carcinogenesis

Oral carcinogenicity studies of siponimod were performed in mice and rats. There was an increase in malignant lymphoma in females at all doses and in hemangiosarcoma and combined hemangioma and hemangiosarcoma at all doses in males and females. The lowest dose tested is approximately 5 times the recommended human dose (RHD) of 2 mg/day ^{FDA label}.

Mutagenesis

Siponimod was negative in several in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays ^{FDA label}.

Impairment of fertility

When siponimod was administered orally (0, 2, 20, or 200 mg/kg) to male rats (mated with untreated females) before and throughout the mating period, there was a dose-related increase in the precoital interval at any dose. A decrease in implantation sites, an increase in preimplantation loss, and a decrease in the number of viable fetuses were noted at the highest dose tested. The higher no-effect dose for adverse effects on fertility (20 mg/kg) is approximately 100 times the recommended human dose ^{FDA label}.

When siponimod was administered orally (0, 0.1, 0.3, or 1 mg/kg) to female rats (mated with untreated males) prior to and during mating, and continuing to Day 6 of gestation, no effects on fertility were noted up to the highest dose studied (1 mg/kg). Plasma siponimod exposure (AUC) at the highest dose studied is about 16 times that in humans at the recommended human dose ^{FDA label}.

Use in pregnancy and lactation

Siponimod may cause fetal harm, based on the results of animal studies. Because it takes about 10 days to eliminate this drug from the body, women of childbearing potential should use adequate contraception to avoid pregnancy during and for 10 days after the cessation of treatment ^{FDA label}.
No data currently exist regarding the presence of siponimod in human milk ^{FDA label}. A study in lactating rats demonstrated excretion of the drug and/or its metabolites in milk. The benefits nursing should be considered as well as the mother’s clinical requirement for this drug and any possible adverse effects on the breastfed infant from siponimod ^{FDA label}.