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Osphena

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Osphena

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiovascular Disorders

Risk factors for cardiovascular disorders, arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus), should be managed appropriately.

Stroke

In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per ten thousand women-years). The increase in risk was demonstrated in year 1 and persisted.

In the clinical trials for OSPHENA (duration of treatment up to 15 months), the incidence rates of thromboembolic and hemorrhagic stroke were 0.72 and 1.45 per thousand women, respectively in OSPHENA 60 mg treatment group and 1.04 and 0 per thousand women in placebo.

Should thromboembolic or hemorrhagic stroke occur or be suspected, OSPHENA should be discontinued immediately.

Coronary Heart Disease

In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo. In the OSPHENA clinical trials, a single MI occurred in a woman receiving 60 mg of ospemifene.

Venous Thromboembolism

In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE), was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per ten thousand women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per ten thousand women-years). The increase in VTE risk was demonstrated during the first 2 years.

In the OSPHENA clinical trials, the incidence of DVT was 1.45 per thousand women in OSPHENA 60 mg treatment group and 1.04 per thousand women in placebo. Should a VTE occur or be suspected, OSPHENA should be discontinued immediately.

If feasible, OSPHENA should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Malignant Neoplasms

Endometrial Cancer

OSPHENA is an estrogen agonist/antagonist with tissue selective effects. In the endometrium, OSPHENA has agonistic effects. In the OSPHENA clinical trials (60 mg treatment group), no cases of endometrial cancer were seen with exposure up to 52 weeks. There was a single case of simple hyperplasia without atypia. Endometrial thickening equal to 5 mm or greater was seen in the OSPHENA treatment groups at a rate of 60.1 per thousand women vs. 21.2 per thousand women for placebo. The incidence of any type of proliferative (weakly plus active plus disordered) endometrium was 86.1 per thousand women in OSPHENA vs. 13.3 per thousand women for placebo. Uterine polyps occurred at an incidence of 5.9 per thousand women vs. 1.8 per thousand women for placebo.

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Adding a progestin to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. The use of progestins with OSPHENA therapy was not evaluated in the clinical trials.

Clinical surveillance of all women using OSPHENA is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

Breast Cancer

OSPHENA 60 mg has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer or with a history of breast cancer.

Severe Hepatic Impairment

OSPHENA should not be used in women with severe hepatic impairment [see Use In Specific Populations, and CLINICAL PHARMACOLOGY].

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION)

Hot Flashes or Flushes

OSPHENA may initiate or increase the occurrence of hot flashes in some women.

Vaginal Bleeding

Inform postmenopausal women of the importance of reporting unusual vaginal bleeding to their healthcare providers as soon as possible [see WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 2-year carcinogenicity study in female mice, ospemifene administration of 100, 400 or 1500 mg/kg/day was well tolerated. No evaluation for carcinogenicity was conducted in male mice. There was significant increase in adrenal subcapsular cell adenomas at 4 and 5 times the human exposure based on AUC, and adrenal cortical tumors at 5 times the human exposure. In the ovary, an increase in sex cord/stromal tumors, tubulostromal tumors, granulosa cell tumors, and luteomas were also seen. These findings occurred at doses 2 to 5 times the human exposure based on AUC, and are probably related to estrogenic/antiestrogenic effect of ospemifene in mice.

In a 2-year carcinogenicity study in rats, ospemifene administration of 10, 50, or 300 mg/kg/day was well tolerated. A significant increase in thymomas was recorded for males and thymomas for females at all ospemifene dose levels, or 0.3 to 1.2 times the human exposure based on AUC. In the liver, an increase in hepatocellular tumors were recorded at for females at all ospemifene dose levels.

Mutagenesis

Ospemifene was not genotoxic in vitro in the Ames test in strains of Salmonella typhimurium or at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells in the absence and in the presence of a metabolic activator system. In in vivo testing, ospemifene was not genotoxic in a standard mouse bone marrow micronucleus test or in a determination of DNA adducts in the liver of rats.

Impairment of Fertility

The effect of ospemifene on fertility was not directly evaluated. In female rats and monkeys, decreases in ovarian and uterine weights, decreased corpora lutea number, increased ovarian cysts, uterine atrophy, and disrupted cycles were observed when given repeated daily oral doses. In male rats, atrophy of the prostate and seminal vesicles was noted. The effects on reproductive organs observed in animals are consistent with the estrogen receptor activity of ospemifene and potential for impairment of fertility.

Use In Specific Populations

Pregnancy

Teratogenic effects

Pregnancy Category X [see CONTRAINDICATIONS

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 mg/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.

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.

Pediatric Use

OSPHENA is not indicated in children. Clinical studies have not been conducted in the pediatric population.

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.

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].

No dose adjustment of OSPHENA is required in women with renal impairment.

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, and CLINICAL PHARMACOLOGY].

No clinically important pharmacokinetic differences with OSPHENA were observed between women with mild to moderate hepatic impairment and healthy women [see CLINICAL PHARMACOLOGY].

No dose adjustment of OSPHENA is required in women with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

Last reviewed on RxList: 3/18/2013
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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