n in the OSPHENA Treatment Group (60 mg Once Daily) and at Frequency ≥1.0% in the Double-Blind, Controlled Clinical Trials with OSPHENA vs. Placebo Ospemifene 60 mg
(N=1242)
% Placebo
(N=958)
%
Vascular Disorders
Hot flush 7.5 2.6
Reproductive System and Breast Disorders
Vaginal discharge
Genital discharge 3.8
1.3 0.3
0.1
Musculoskeletal and Connective Tissue Disorders
Muscle spasms 3.2 0.9
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis 1.6 0.6
7. DRUG INTERACTIONS
OSPHENA is primarily metabolized by CYP3A4 and CYP2C9. CYP2C19 and other pathways contribute to the metabolism of ospemifene.
7.1 Estrogens and estrogen agonist/antagonist
OSPHENA should not be used concomitantly with estrogens and estrogen agonists/antagonists. The safety of concomitant use of OSPHENA with estrogens and estrogen agonists/antagonists has not been studied.
7.2 Fluconazole
Fluconazole, a moderate CYP3A / strong CYP2C9 / moderate CYP2C19 inhibitor, should not be used with OSPHENA. Fluconazole increases the systemic exposure of ospemifene by 2.7-fold. Administration of fluconazole with ospemifene may increase the risk of OSPHENA-related adverse events [see Clinical Pharmacology (12.3)].
7.3 Rifampin
Rifampin, a strong CYP3A4 / moderate CYP2C9 / moderate CYP2C19 inducer, decreases the systemic exposure of ospemifene by 58%. Therefore, co-administration of OSPHENA with drugs such as rifampin which induce CYP3A4, CYP2C9 and/or CYP2C19 activity would be expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect [see Clinical Pharmacology (12.3)].
7.4 Ketoconazole
Ketoconazole, a strong CYP3A4 inhibitor increases the systemic exposure of ospemifene by 1.4-fold. Administration of ketoconazole chronically with ospemifene may increase the risk of OSPHENA-related adverse reactions [see Clinical Pharmacology (12.3)].
7.5 Warfarin
Repeated administration of ospemifene had no effect on the pharmacokinetics of a single 10 mg dose of warfarin. No study was conducted with multiple doses of warfarin. The effect of ospemifene on clotting time such as the International Normalized Ratio (INR) or prothrombin time (PT) was not studied [see Clinical Pharmacology (12.3)].
7.6 Highly Protein-Bound Drugs
Ospemifene is more than 99% bound to serum proteins and might affect the protein binding of other drugs. Use of OSPHENA with other drug products that are highly protein bound may lead to increased exposure of either that drug or ospemifene [see Clinical Pharmacology (12.3)].
7.7 Multiple Enzyme Inhibition
Co-administration of OSPHENA with a drug known to inhibit CYP3A4 and CYP2C9 isoenzymes may increase the risk of OSPHENA-related adverse reactions.
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Teratogenic effects:
Pregnancy Category X [see Contraindications (4)].
Risk Summary
Based on animal data, OSPHENA is likely to increase the risk of adverse outcomes during pregnancy and labor. Adverse findings at maternally toxic doses included embryofetal lethality in rats and rabbits, and neonatal mortality and difficult labor in rats. The reproductive effects observed are consistent with and are considered to be related to estrogen receptor activity of OSPHENA.
Animal Data
The effects of OSPHENA on embryo-fetal development were studied in rats (0.1, 1 or 4 mg/kg/day) and rabbits (3, 10, or 30 m
