Omidenepag

Macular edema, including cystoid macular edema, has been reported during clinical trials in patients with pseudophakia receiving omidenepag. Omidenepag should be used with caution in aphakic patients, in pseudophakic patients, or in patients with known risk factors for macular edema.

Risk Summary

There are no available data on the use of omidenepag in pregnant women. In animal reproduction studies, subcutaneous administration of omidenepag isopropyl to pregnant rabbits throughout the period of organogenesis produced fetal skeletal anomalies at a dose of 24 times the clinical dose, based on estimated plasma C_max. Omidenepag isopropyl was not teratogenic in rats when administered subcutaneously at 1 mg/kg/day, 2,452 times the clinical dose, based on estimated plasma C_max (see Data).

Data

Animal Data

An embryofetal development study was conducted in pregnant rabbits administered omidenepag isopropyl once daily by subcutaneous injection at 0.008, 0.08, or 0.8 mg/kg/day from gestation Day 6 to 18, a period which covers implantation and the period of organogenesis in rabbits. Fetal skeletal anomalies (thoracic misaligned centrum and hemivertebra, fused sternebra, absent rib) were observed at 0.008 mg/kg/day (24 times the maximum recommended human ocular dose [MRHOD], based on estimated plasma C_max). Additional fetal skeletal anomalies were observed at 0.08 mg/kg (absent thoracic arch, fused rib) and 0.8 mg/kg (misaligned and misshapen cervical vertebrae), corresponding to 256 times and 3,696 times the MRHOD based on estimated plasma C_max, respectively. Increases in preimplantation loss and post-implantation loss were observed at 0.8 mg/kg/day. The rabbit maternal, No Observed Adverse Effect Level [NOAEL] was 0.8 mg/kg/day.

An embryofetal development study was conducted in pregnant rats administered omidenepag isopropyl once daily by subcutaneous injection at 0.01, 0.1, or 1 mg/kg/day from gestation Day 6 to 17, to target the period of organogenesis. Omidenepag isopropyl was not found to have any effect on embryo-fetal development in rats at up to 1 mg/kg/day (2,452 times the MRHOD based on estimated plasma C_max). The rat maternal NOAEL was 1 mg/kg/day. In a pre/postnatal development study, treatment of pregnant rats with omidenepag isopropyl subcutaneously from gestation day 6 to lactation day 20 at 0.01, 0.1, or 1 mg/kg/day resulted in no adverse effects. The NOAEL for pre- and postnatal development was 1 mg/kg/day (2,452 times the MRHOD based on estimated plasma C_max).

Risk Summary

There are no data on the presence of omidenepag in human milk, the effects on the breastfed infant, or the effects on milk production. However, systemic exposure to omidenepag following topical ocular administration is low and it is not known whether measurable levels of omidenepag would be present in maternal milk following topical ocular administration. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for omidenepag and any unknown potential adverse effects on the breast-fed child from omidenepag.

Carcinogenesis

Lifetime rodent studies have not been performed to evaluate the carcinogenic potential of omidenepag isopropyl or omidenepag.

In rats dosed by subcutaneous injection daily for 26 weeks, nephroblastoma and a spermatic cord tumor were found at 0.003 mg/kg/day (33 times the RHOD based on the estimated area under the curve [AUC]). Mammary adenocarcinoma and pituitary pars distalis adenomas were observed at 0.03 mg/kg/day (319 fold the RHOD based on the estimated AUC).

Mutagenesis

Omidenepag was not mutagenic in the bacterial reverse mutation (Ames) test and the in vivo mouse micronucleus test. Omidenepag isopropyl was positive (mutagenic and clastogenic) without metabolic activation in the in vitro mouse lymphoma forward mutation assay.

Impairment of Fertility

In a rat fertility and early embryonic development study, daily subcutaneous doses of omidenepag isopropyl did not affect male or female fertility at doses up to 1 mg/kg/day (2,452 times the MRHOD based on estimated plasma C_max).

The rabbit embryofetal development study administered omidenepag isopropyl to pregnant rabbits beginning on gestation day 6, covering the period of implantation. Preimplantation losses were observed at 0.8 mg/kg/day (3,696 times the MRHOD based on estimated plasma C_max). The NOAEL for rabbit preimplantation loss was 0.08 mg/kg/day (256 times the MRHOD based on estimated plasma C_max).

• Pigmentation
• Eyelash changes
• Ocular inflammation
• Macular edema

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to omidenepag in 600 patients for up to 3 months. The most common adverse reactions with incidence ≥1% are conjunctival hyperemia (9%), photophobia (5%), vision blurred (4%), dry eye (3%), instillation site pain (3%), eye pain (2%), ocular hyperemia (2%), punctate keratitis (2%), headache (2%), eye irritation (1%), and visual impairment (1%).