WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
Black Box Warning
ConditionName:
See full prescribing information for complete Boxed Warning.
ConditionName:
WARNING: ENDOMETRIAL CANCER AND CARDIOVASCULAR DISORDERS
Endometrial Cancer
OSPHENA is an estrogen agonist/antagonist with tissue selective effects. In the endometrium, OSPHENA has estrogen agonistic effects. There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed and random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)].
Cardiovascular Disorders
There is a reported increased risk of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) who received daily oral conjugated estrogens (CE) [0.625 mg]-alone therapy over 7.1 years as part of the Women's Health Initiative (WHI) [see Warnings and Precautions (5.1)].
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 in placebo [see Warnings and Precautions (5.1)]. The incidence of DVT was 1.45 per thousand women in OSPHENA 60 mg treatment group and 1.04 per thousand women in placebo [see Warnings and Precautions (5.1)]. OSPHENA should be prescribed for the shortest duration consistent with treatment goals and risks for the individual woman.
Overview
Ospemifene is a Selective Estrogen Receptor Modulator that is FDA approved for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hot flush, vaginal discharge, muscle spasms, genital discharge, hyperhidrosis..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
OSPHENA is indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause.
Dosage
OSPHENA is an estrogen agonist/antagonist which has agonistic effects on the endometrium. Generally, when a product with estrogen agonistic effects on the endometrium is prescribed for a postmenopausal woman with a uterus, a progestin should be considered to reduce the risk of endometrial cancer. A woman without a uterus does not need a progestin [see Warnings and Precautions (5.2)].
Use of OSPHENA should be for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.
2.1 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to Menopause
Take one 60 mg tablet with food once daily.
DOSAGE FORMS AND STRENGTHS
OSPHENA tablets are white to off-white, oval, biconvex, film coated tablets containing 60 mg of ospemifene and engraved with "60" on one side.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Ospemifene in adult patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ospemifene in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding FDA-Labeled Use of Ospemifene in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Ospemifene in pediatric patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ospemifene in pediatric patients.
Contraindications
OSPHENA is contraindicated in women with any of the following conditions:
Undiagnosed abnormal genital bleeding
Known or suspected estrogen-dependent neoplasia
Active DVT, pulmonary embolism (PE), or a history of these conditions
Active arterial thromboembolic disease [for example, stroke and myocardial infarctions (MI)], or a history of these conditions
OSPHENA is contraindicated in women who are or may become pregnant. OSPHENA may cause fetal harm when administered to a pregnant woman. Ospemifene was embryo-fetal lethal with labor difficulties and increased pup deaths in rats at doses below clinical exposures, and embryo-fetal lethal in rabbits at 10 times the clinical exposure based on mg/m2. If this drug is used during pregnancy, or if a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to a fetus.
Warnings
ConditionName:
See full prescribing information for complete Boxed Warning.
ConditionName:
WARNING: ENDOMETRIAL CANCER AND CARDIOVASCULAR DISORDERS
Endometrial Cancer
OSPHENA is an estrogen agonist/antagonist with tissue selective effects. In the endometrium, OSPHENA has estrogen agonistic effects. There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed and random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)].
Cardiovascular Disorders
There is a reported increased risk of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) who received daily oral conjugated estrogens (CE) [0.625 mg]-alone therapy over 7.1 years as part of the Women's Health Initiative (WHI) [see Warnings and Precautions (5.1)].
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 in placebo [see Warnings and Precautions (5.1)]. The incidence of DVT was 1.45 per thousand women in OSPHENA 60 mg treatment group and 1.04 per thousand women in placebo [see Warnings and Precautions (5.1)]. OSPHENA should be prescribed for the shortest duration consistent with treatment goals and risks for the individual woman.
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.
5.2 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.
5.3 Severe Hepatic Impairment
OSPHENA should not be used in women with severe hepatic impairment
Adverse Reactions
Clinical Trials Experience
The following serious adverse reactions are discussed elsewhere in the labeling:
Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)]
Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)]
6.1 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 safety of OSPHENA has been assessed in nine phase 2/3 trials (N=1892) with doses ranging from 5 to 90 mg per day. The duration of treatment in these studies ranged from 6 weeks to 15 months. Most women (N=1370) had a treatment period of at least 12 weeks, 409 had at least 52 weeks (1 year) of exposure.
The incidence rates of thromboembolic and hemorrhagic stroke were 0.72 per thousand women (1 reported case of thromboembolic stroke) and 1.45 per thousand women (2 reported cases of hemorrhagic stroke), respectively in OSPHENA 60 mg treatment group and 1.04 and 0 per thousand women, respectively in placebo. The incidence of deep vein thrombosis (DVT) was 1.45 per thousand women in OSPHENA 60 mg treatment group (2 reported cases of DVT) and 1.04 (1 case of DVT) in placebo.
Table 1 lists adverse reactions occurring more frequently in the OSPHENA 60 mg treatment group than in placebo and at a frequency ≥1%.
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ospemifene in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
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.
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.
Pregnancy Category (AUS):
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ospemifene in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Ospemifene during labor and delivery.
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.
Geriatic 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.
Gender
There is no FDA guidance on the use of Ospemifene with respect to specific gender populations.
Race
There is no FDA guidance on the use of Ospemifene with respect to specific racial populations.
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.
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.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ospemifene in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Ospemifene in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Intravenous
Monitoring
There is limited information regarding Monitoring of Ospemifene in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Ospemifene in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
Description
Management
Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Ospemifene in the drug label.
Pharmacology
There is limited information regarding Ospemifene Pharmacology in the drug label.
