g/kg/day) when treated from implantation through organogenesis. In rabbits, there was an increase in the incidence of total resorptions at 30 mg/kg/day (10 times the human exposure based on surface area mg/m2). Drug-induced malformations were not observed in either rats or rabbits.
The effects of OSPHENA on pre-and postnatal development were studied in pregnant rats (0.01, 0.05, and 0.25 mg/kg/day) treated from implantation through lactation. Pregnant rats given 0.05 or 0.25 mg/kg/day OSPHENA (0.8% to 4% the human exposure based on surface area mg/m2), had a significantly prolonged and difficult gestation, increased post-implantation loss, increased number of dead pups at birth, and an increased incidence of postnatal loss. OSPHENA did not induce adverse effects in the surviving offspring of pregnant rats at drug exposures up to 4% the human exposure.
8.3 Nursing Mothers
It is not known whether OSPHENA is excreted in human breast milk.
In a nonclinical study, ospemifene was excreted in rat milk and detected at concentrations higher than that in maternal plasma.
8.4 Pediatric Use
OSPHENA is not indicated in children. Clinical studies have not been conducted in the pediatric population.
8.5 Geriatric Use
Of the 1892 OSPHENA-treated women enrolled in the nine phase 2/3 trials of OSPHENA, >19 percent were 65 years of age or older. No clinically meaningful differences in safety or effectiveness were observed between these women and younger women less than 65 years of age.
8.6 Renal Impairment
The pharmacokinetics of ospemifene in women with severe renal impairment (CrCL <30 mL/min) was similar to those in women with normal renal function [see Clinical Pharmacology (12.3)].
No dose adjustment of OSPHENA is required in women with renal impairment.
8.7 Hepatic Impairment
The pharmacokinetics of ospemifene has not been studied in women with severe hepatic impairment (Child-Pugh Class C); therefore, OSPHENA should not be used in women with severe hepatic impairment [see Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].
No clinically important pharmacokinetic differences with OSPHENA were observed between women with mild to moderate hepatic impairment and healthy women [see Clinical Pharmacology (12.3)].
No dose adjustment of OSPHENA is required in women with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
10. OVERDOSAGE
There is no specific antidote for OSPHENA.
11. DESCRIPTION
OSPHENA is an estrogen agonist/antagonist. The chemical structure of ospemifene is shown in Figure 1.
Figure 1: Chemical structure
The chemical designation is Z-2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethanol, and has the empirical formula C24H23ClO2, which corresponds to a molecular weight of 378.9. Ospemifene is a white to off-white crystalline powder that is insoluble in water and soluble in ethanol.
Each OSPHENA tablet contains 60 mg of ospemifene. Inactive ingredients include colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, sodium starch glycolate, titanium dioxide, and triacetin.
12. CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
OSPHENA is an estrogen agonist/antagonist with tissue selective effects. Its biological actions are mediated through binding to estrogen receptors. This binding
