Unoprostone

Teratogenic Effects: Pregnancy Category C.

There were no teratogenic effects observed in rats and rabbits up to 5 and 0.3 mg/kg/day (approximately 1000 and 60 fold the recommended human dose of 0.005 mg/kg/day in the rat and rabbit, respectively). There was an increase in the incidence of miscarriages and a decrease in live birth index in rats administered unoprostone isopropyl during organogenesis at subcutaneous doses of 5 mg/kg. There was an increase in incidence of miscarriages and resorptions and a decrease in the number of live fetuses in rabbits administered unoprostone isopropyl during organogenesis at subcutaneous doses of 0.3 mg/kg. The no observable adverse effect level (NOAEL) for embryofetal toxicity in rats and rabbits was 2.0 and 0.1 mg/kg (approximately 400 and 20 fold the recommended human dose of 0.005 mg/kg/day in the rat and rabbit, respectively).

There was an increase in incidence of premature delivery, a decrease in live birth index, and a decrease in weight at birth and through postpartum Day 7 in rats administered unoprostone isopropyl during late gestation through postpartum Day 21 at subcutaneous doses of 1.25 mg/kg. In addition, pups from rats administered 1.25 mg/kg subcutaneously exhibited delayed growth and development characterized by delayed incisor eruption and eye opening. There was an increase in the number of stillborn pups and a decrease in perinatal survival in rats administered unoprostone isopropyl during late gestation through weaning at subcutaneous doses of ≥0.5 mg/kg. The NOAEL for pre and postnatal toxicity in rats was 0.2 mg/kg (approximately 40 fold the recommended human dose of 0.005 mg/kg/day).

There are no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, unoprostone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Unoprostone has been identified in breast milk in rats following intravenous administration. It is not known whether topical ocular administration could result in sufficient systemic absorption to produce detectable quantities in breast milk. Nevertheless, caution should be exercised when unoprostone is administered to a nursing mother.

Unoprostone was not carcinogenic in rats administered oral doses up to 12 mg/kg/day for up to 2 years (approximately 580 and 240 fold the recommended human dose of 0.005 mg/kg/day based on AUC0-24 in male and female rats, respectively).

Under the conditions tested, unoprostone isopropyl and unoprostone free acid were neither mutagenic in an Ames assay nor clastogenic in a chromosome aberration assay in Chinese hamster lung-derived fibroblast cells. Under the conditions tested, unoprostone isopropyl was not genotoxic in a mouse lymphoma mutation assay or clastogenic in an in vivo chromosomal aberration test in mouse bone marrow.

Unoprostone isopropyl did not impair male or female fertility in rats at subcutaneous doses up to 50 mg/kg (approximately 10,000 fold the recommended human dose of 0.005 mg/kg/day).

In clinical studies, the most common ocular adverse events were burning/stinging, burning/stinging upon drug instillation, dry eyes, itching, increased length of eyelashes and injection. These were reported in approximately 10-25% of patients. Approximately 10-14% of patients were observed to have an increase in the length of eyelashes (≥1 mm) at 12 months, while 7% of patients were observed to have a decrease in the length of eyelashes.

Ocular adverse events occurring in approximately 5% to 10% of patients were abnormal vision, eyelid disorder, foreign body sensation, and lacrimation disorder.

Ocular adverse events occurring in approximately 1% to 5% of patients were blepharitis, cataract, conjunctivitis, corneal lesion, discharge from the eye, eye hemorrhage, eye pain, keratitis, irritation, photophobia, and vitreous disorder.

Other ocular adverse events reported in less than 1% of patients were acute elevated intraocular pressure, color blindness, corneal deposits, corneal edema, corneal opacity, diplopia, hyperpigmentation of the eyelid, increased number of eyelashes, iris hyperpigmentation, iritis, optic atrophy, ptosis, retinal hemorrhage, and visual field defect.

The most frequently reported nonocular adverse event associated with the use of unoprostone in the clinical trials was flu syndrome that was observed in approximately 6% of patients. Nonocular adverse events reported in the 1% to 5% of patients were accidental injury, allergic reaction, back pain, bronchitis, cough increased, diabetes mellitus, dizziness, headache, hypertension, insomnia, pharyngitis, pain, rhinitis, and sinusitis.