Osphena

Serious side effects have been reported with Osphena. See the "Osphena Precautions" section. 

Common side effects of Osphena include the following:

• hot flashes
• vaginal discharge
• muscle spasms
• increased sweating

This is not a complete list of Osphena side effects. Ask your doctor or pharmacist for more information. 

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. 

Before taking Osphena, tell your doctor about all of your medical conditions. Especially tell your doctor if:

• are allergic to Osphena or any of its ingredients
• have any unusual vaginal bleeding. Vaginal bleeding after menopause may be a warning sign of cancer of the lining of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
• have any other medical conditions such as severe liver problems.
• are going to have surgery or will be on bed rest. Your healthcare provider will let you know if you need to stop taking Osphena
• are pregnant or plan to become pregnant. 
• are breast feeding. It is not known if Osphena can pass into your breast milk.

Tell you doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. 

Take Osphena exactly how your healthcare provider tells you to take it.

• Take Osphena by mouth 1 time each day with food.
• You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether or not you still need treatment with Osphena.

It is recommended you have a pelvic exam, breast exam and mammogram (breast x-ray) every year unless your healthcare provider tells you something else.

If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram (breast x-ray), you may need to have breast exams more often.

If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or use tobacco, you may have a higher chance of getting heart disease. 

If you have a uterus, talk with your healthcare provider about whether the addition of a progestin is right for you.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;

• chest pain, sudden cough, wheezing, rapid breathing, coughing up blood;

• pain, swelling, warmth, or redness in one or both legs; or

• any unusual vaginal bleeding.

Common side effects may include:

• hot flashes;

• vaginal discharge;

• increased sweating; or

• muscle spasm.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Metabolized mainly in the liver by CYP isoenzymes 3A4 and 2C9; other CYP isoenzymes (2C19, 2B6) also involved in metabolism.1 10 11 12

Weak inhibitor of CYP2B6, 2C9, 2C19, 2C8, 2D6, and 3A4 in vitro.1 11

Not a clinically important substrate for P-glycoprotein (P-gp) transport system in vitro.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors (potent or moderate) of CYP3A4, 2C9, and/or 2C19: Possible pharmacokinetic interaction (increased plasma concentrations and AUC of ospemifene).1 10 11 12 Concomitant use with drugs that inhibit both CYP3A4 and 2C9 may increase risk of ospemifene-related adverse reactions.1

Inducers (potent or moderate) of CYP3A4, 2C9, and/or 2C19: Possible pharmacokinetic interaction (decreased plasma concentrations and AUC of ospemifene).1 Concomitant use may decrease efficacy of ospemifene.1

Substrates of CYP2B6, 2C9, 2C19, 2C8, 2D6, and 3A4: Clinically important pharmacokinetic interactions unlikely.1 11

Protein-bound Drugs

Concomitant use with other highly protein-bound drugs may lead to increased exposure of ospemifene or the other drug.1

Specific Drugs

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

• Tell all of your health care providers that you take Osphena. This includes your doctors, nurses, pharmacists, and dentists.
• If you are having surgery, talk with your doctor.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Chest pain.
• Shortness of breath.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Feeling very tired or weak.
• Very bad headache.
• Swelling, warmth, numbness, change of color, or pain in a leg or arm.
• Very bad vaginal bleeding.

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 (8.7), and Clinical Pharmacology (12.3)].

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)]

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

The following adverse reactions have been identified during post-approval use of ospemifene. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: allergic conditions including hypersensitivity, angioedema

Skin and Subcutaneous Tissue Disorders: rash, rash erythematous, rash generalized, pruritus, urticaria

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 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 (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.

The effectiveness and safety of Osphena on moderate to severe symptoms of vulvar and vaginal atrophy in postmenopausal women were examined in three placebo-controlled clinical trials (two 12-week efficacy trials and one 52-week long-term safety trial). In the three placebo-controlled trials, a total of 787 women received placebo and 1102 women received 60 mg Osphena.

The first clinical trial was a 12-week, randomized, double-blind, placebo-controlled, parallel-group study that enrolled 826 generally healthy postmenopausal women between 41 to 81 years of age (mean 59 years of age) who at baseline had ≤5 percent superficial cells on a vaginal smear, a vaginal pH >5.0, and who identified at least one moderate to severe vaginal symptom that was considered the most bothersome to her (vaginal dryness, pain during intercourse [dyspareunia], or vaginal irritation/itching). Treatment groups included 30 mg Osphena (n=282), 60 mg Osphena (n=276), and placebo (n=268). All women were assessed for improvement in the mean change from Baseline to Week 12 for the co-primary efficacy variables of: most bothersome symptom (MBS) of vulvar and vaginal atrophy (defined as the individual moderate to severe symptom that was identified by the woman as most bothersome at baseline), percentage of vaginal superficial and vaginal parabasal cells on a vaginal smear, and vaginal pH. Following completion of 12-weeks, women with an intact uterus were allowed to enroll in a 40-week double-blind extension study, and women without an intact uterus were allowed to enroll in a 52-week open-label extension study.

The second clinical trial was a 12-week, randomized, double-blind, placebo-controlled, parallel-group study that enrolled 919 generally healthy postmenopausal women between 41 to 79 years of age (mean 59 years of age) who at baseline had ≤5 percent superficial cells on a vaginal smear, a vaginal pH >5.0, and who identified either moderate to severe vaginal dryness (dryness cohort) or moderate to severe dyspareunia (dyspareunia cohort) as most bothersome to her at baseline. Treatment groups included 60 mg Osphena (n=463) and placebo (n=456). Primary endpoints and study conduct were similar to those in Trial 1.

The third clinical trial was a 52-week, randomized, double-blind, placebo-controlled, long-term safety study that enrolled 426 generally healthy postmenopausal women between 49 to 79 years of age (mean 62 years of age) with an intact uterus. Treatment groups included 60 mg Osphena (n=363) and placebo (n=63).

Effects on Dyspareunia

In the 1st and 2nd clinical trial, the modified intent-to-treat population of women treated with Osphena when compared to placebo, demonstrated a statistically significant improvement (least square mean change from Baseline to Week 12) in the moderate to severe most bothersome symptom (MBS) of dyspareunia (1st trial p=0.0012, 2nd trial p<0.0001). See Table 2. A statistically significant increase in the proportion of superficial cells and a corresponding statistically significant decrease in the proportion of parabasal cells on a vaginal smear was also demonstrated (p<0.0001 for both). The mean reduction in vaginal pH between baseline and Week 12 was also statistically significant (p<0.0001).

Osphena (ospemifene) is a non-estrogen medication that reverses certain changes in vaginal tissue that are caused by menopause.

Osphena is used to relieve pain during sexual intercourse in menopausal women. Ospemifene is not a pain medication.

Osphena may also be used for purposes not listed in this medication guide.

Do not use Osphena if you are pregnant, or may become pregnant.

You should not use this medication if you have unusual vaginal bleeding, breast or uterine cancer, or a history of heart attack, stroke, or blood clot.

Osphena may increase your risk of developing endometrial hyperplasia, a condition that may lead to cancer of the uterus. Report any unusual vaginal bleeding to your doctor right away.

Osphena may also increase your risk of a stroke or blood clot. Talk with your doctor about your individual risks.

Get emergency medical help if you have any of these signs of an allergic reaction to Osphena: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;

• chest pain, sudden cough, wheezing, rapid breathing, coughing up blood;

• pain, swelling, warmth, or redness in one or both legs; or

• any unusual vaginal bleeding.

Common Osphena side effects may include:

• hot flashes;

• vaginal discharge;

• increased sweating; or

• muscle spasm.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.