Effects on fertility: Fertility studies of paliperidone palmitate have not been performed.
Mating and fertility of male and female rats was not affected at oral paliperidone doses up to 2.5 mg/kg/day [twice the maximum recommended oral clinical dose based on body surface area (mg/m2)]. The 2.5 mg/kg/day dose produced slight maternal toxicity, increased pre-implantation loss and slightly reduced the number of live embryos; the no-effect dose was 0.63 mg/kg/day.
In rat fertility studies with risperidone, which is extensively converted to paliperidone in rats and humans, mating (but not fertility) was impaired at doses 0.2 to 5 times the maximum human dose on a mg/m2 basis, by an effect on females. In repeat dose toxicity studies in beagle dogs, risperidone at doses of 1 to 17 times the maximum human dose on a mg/m2 basis was associated with adverse effects on the male reproductive system (inhibited ejaculation, incomplete spermatogenesis, reduced sperm motility and concentration, reduced gonadal and prostatic weight, prostatic immaturity, decreased serum testosterone). Serum testosterone and sperm parameters partially recovered but remained decreased after treatment was discontinued. No-effect doses were not determined in either rat or dog.
Use in pregnancy - Category C: The safety of intramuscularly-injected paliperidone palmitate or orally-dosed paliperidone during human pregnancy has not been established.
A retrospective observational cohort study based on a US claims database compared the risk of congenital malformations for live births among women with and without antipsychotic use during the first trimester of pregnancy. Paliperidone, the active metabolite of risperidone, was not specifically evaluated in this study. The risk of congenital malformations with risperidone, after adjusting for confounder variables available in the database, was elevated compared to no antipsychotic exposure (relative risk=1.26, 95% CI: 1.02-1.56). No biological mechanism has been identified to explain these findings and teratogenic effects have not been observed in non-clinical studies.
No teratogenicity was observed following a single intramuscular treatment of pregnant rats with paliperidone palmitate in early gestation. The highest dose (160 mg/kg) was maternotoxic and resulted in paliperidone exposure 4-fold the maximal anticipated clinical exposure based on plasma AUC. No teratogenic effect was noted in rats and rabbits following oral administration of paliperidone during the period of organogenesis at respective exposures up to 28- and 17-fold the maximal anticipated clinical exposure, based on plasma AUC. Maternotoxic doses in rabbits were associated with increased fetal mortality. Studies with risperidone also found no teratogenic effects in rats and rabbits following oral administration of risperidone during the period of organogenesis at doses up to nine times the human dose on a mg/m2 basis.
Neonates exposed to antipsychotic drugs (including paliperidone) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases, neonates have required intensive care unit support and prolonged hospitalisation.
INVEGA TRINZA should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Use in lactation: In animal studies with paliperidone and in human studies with risperidone, paliperidone was excreted in the milk. Therefore, women receiving INVEGA TRINZA should not breast-feed infants. Consideration should be given to the long-acting nature of INVEGA TRINZA as nursing infants may be at risk even from INVEGA TRINZA administration long before nursing.
Oral administration of paliperidone to rats from early gestation to lactation was associated with adverse effects in pups (clinical signs, reduced body weight gain and survival, impaired righting reflex) during lactation at doses similar to the maximal recommended clinical dose on a mg/m2 basis; the no-effect dose was less than the clinical dose. In risperidone studies in rats, oral administration of risperidone during late gestation and lactation was associated with increased pup deaths during early lactation at doses 0.2 to 5 times the maximum human dose on a mg/m2 basis (a no-effect dose was not determined) and with reduced pup weight gain at doses five-fold or greater than the maximal recommended human dose on a mg/m2 basis. There were also increases in stillborn rat pups at an oral risperidone dose 2.5 to 5 times the maximum human dose on a mg/m2 basis. It is not known whether these effects of risperidone and paliperidone resulted from a direct effect on the foetuses and pups and/or an effect on the dams.