Pregnancy: Risk summary: There is limited amount of data from the use of DuoTrav or the individual components in pregnant women.
Studies in rats and mice with subcutaneous (s.c.) administration of travoprost during organogenesis have shown reproductive toxicity at the dose of 34 times and 1.7 times, respectively, the maximum recommended ocular human dose (MROHD) based on body surface area (BSA). Reproduction studies in mice, rats and rabbits with orally administered timolol showed no malformations at doses up to 675 times the MROHD based on BSA (see Animal data as follows).
Epidemiological studies have not revealed malformative effects but show a risk for intrauterine growth retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycemia) have been observed in the neonate when systemic beta-blockers have been administered to the mother until delivery.
DuoTrav should not be used during pregnancy unless clearly necessary. However, if DuoTrav is administered during pregnancy up to the time of delivery, the neonate should be carefully monitored during the first days of life.
Animal data: Travoprost: An embryo-fetal study was conducted in pregnant mice administered travoprost once daily by subcutaneous injection during the period of organogenesis. At 1 microgram/kg/day (1.7 times the MROHD, based on BSA), travoprost caused post-implantation loss and decreased fetal weight. The no-observed-effect-level (NOEL) for embryofetal toxicity was 0.3 micrograms/kg/day (0.5 times the MROHD, based on BSA). The maternal NOEL was 1 microgram/kg/day.
An embryo-fetal study was conducted in pregnant rats administered travoprost once daily by s.c. injection during the period of organogenesis. At 10 micrograms/kg/day (34 times the MROHD, based on BSA), travoprost was teratogenic in rats, as evidenced by an increase in the incidence of skeletal malformations as well as external and visceral malformations, including fused sternebrae, domed head and hydrocephaly. Travoprost caused post-implantation loss at 10 micrograms/kg/day. The NOEL for post-implantation loss was 3 micrograms/kg/day (10 times the MROHD based on BSA).
Pre- and postnatal development studies were conducted in rats administered with travoprost once daily by s.c. injection during organogenesis and lactation. At doses of ≥0.12 micrograms/kg/day (0.4 times the MROHD, based on BSA), adverse pregnancy outcomes (embryofetal lethality, abortion, early delivery), low birth weight and developmental delays were observed for F1 offspring. The NOEL for adverse pregnancy outcomes, low birth weight and developmental delay was 0.1 micrograms/kg/day (0.3 times the MROHD, based on BSA). The NOEL for F2 offspring development was 0.36 micrograms/kg/day (1.2 times the MROHD, based on BSA).
Timolol: Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day (675 times the MROHD based on BSA) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1,000 mg/kg/day (13,500 times the MROHD based on BSA) were maternal toxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at 100 mg/kg/day or 5,400 times the MROHD based on BSA, and without apparent maternal toxicity.
Lactation: Risk summary: There is a limited amount of data from the use of DuoTrav Eye Drops, Solution in breast-feeding women.
Timolol is transferred into human breast milk following ocular topical administration. Oral beta-blockers have the potential to cause serious adverse reactions in the breast-fed infant. However, in the case of ocular administration at therapeutic doses, the amounts of timolol present in breast milk are not likely to produce clinical symptoms of beta-blockade in the infant.
It is unknown whether travoprost is transferred into human breast milk after ocular administration. An animal study has shown transfer of travoprost and/or metabolites into milk following subcutaneous administration (see Animal data as follows).
The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for DuoTrav and any potential adverse effects on the breast-fed child from DuoTrav.
Animal data: A study in lactating rats demonstrated that radiolabeled travoprost and/or its metabolites were excreted in milk following subcutaneous administration with highest concentrations of travoprost and/or metabolites observed 6 hours post-dose with a milk to plasma ratio of 11.
Females and males of reproductive potential: Infertility: There are no data on the effects of DuoTrav on human fertility. Fertility studies in rats showed no effect of travoprost or timolol at doses up to 34 times and 4,050 times the MROHD, respectively, based on BSA (see Pharmacology: Toxicology: Non-clinical safety data under Actions).