Ospemifene

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Osphena: 60 mg

Pharmacology

Mechanism of Action

Ospemifene is a selective estrogen receptor modulator (SERM); it activates estrogen pathways in some tissues and blocks estrogen pathways in others, and specifically has agonistic effects on the endometrium. In women with VVA, ospemifene was shown to improve vaginal changes associated with the decrease in natural estrogen production associated with menopause (improves vaginal maturation index, decreases vaginal pH) and significantly decreased the most bothersome moderate-to-severe subjective findings reported by women (vaginal dryness and dyspareunia) after 12 weeks of therapy (Bachmann, 2010).

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 448 L

Metabolism

Hepatic via CYP3A4, 2C9, and 2C19; forms a metabolite (4-hydroxyospemifene)

Excretion

Feces (75%); urine (7%; <0.2% as unchanged drug)

Onset of Action

A significant decrease in vaginal dryness and dyspareunia were observed after 12 weeks of therapy (Bachmann, 2010).

Time to Peak

~2 hours (range: 1-8 hours)

Half-Life Elimination

~26 hours

Protein Binding

>99% bound to serum proteins

Use: Labeled Indications

Dyspareunia: Treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA), due to menopause

Vaginal dryness: Treatment of moderate to severe vaginal dryness, symptoms of VVA, associated with menopause

Note: The International Society for the Study of Women’s Sexual Health and The North American Menopause Society have endorsed the term genitourinary syndrome of menopause (GSM) as new terminology for vulvovaginal atrophy. The term GSM encompasses all genital and urinary signs and symptoms associated with a loss of estrogen due to menopause (Portman 2014).

Contraindications

Hypersensitivity (eg, angioedema, urticaria, rash, pruritus) to ospemifene or any component of the formulation; undiagnosed abnormal genital bleeding; DVT or PE (current or history of); active or history of arterial thromboembolic disease (eg, stroke, MI); estrogen-dependent tumor (known or suspected); women who are or may become pregnant

Dosage and Administration

Dosing: Adult

General dosing guidelines: When treating symptoms of menopause, therapy should be evaluated routinely for appropriate dose, duration, and route of administration for each individual patient based on treatment goals and changes in benefits, risks, and health over time (NAMS 2017).

Dyspareunia, moderate to severe: Postmenopausal females: Oral: 60 mg once daily

Vaginal dryness, moderate to severe: Postmenopausal females: Oral: 60 mg once daily

Dosing: Geriatric

Refer to adult dosing.

Administration

Administer with food.

Storage

Store at controlled room temperature of 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alpelisib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ospemifene. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Estrogen Derivatives: May enhance the adverse/toxic effect of Ospemifene. Estrogen Derivatives may diminish the therapeutic effect of Ospemifene. Avoid combination

Fluconazole: May increase the serum concentration of Ospemifene. Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Rifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Selective Estrogen Receptor Modulators: May enhance the adverse/toxic effect of Ospemifene. Ospemifene may also enhance adverse/toxic effects of other Selective Estrogen Receptor Modulators. Selective Estrogen Receptor Modulators may diminish the therapeutic effect of Ospemifene. Ospemifene may also diminish the therapeutic effects of other Selective Estrogen Receptor Modulators. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

>10%: Endocrine & metabolic: Hot flash (7% to 12%)

1% to 10%:

Central nervous system: Headache (3%)

Dermatologic: Hyperhidrosis (1% to 3%), night sweats (1%)

Genitourinary: Endometrial hyperplasia (10%), vaginal discharge (4% to 6%), endometrial polyps (2%), vaginal hemorrhage (1%)

Neuromuscular & skeletal: Muscle spasm (2% to 5%)

<1%, postmarketing, and/or case reports: Angioedema, benign neoplasm, cerebrovascular accident, cyst, deep vein thrombosis, endometrial carcinoma, erythematous rash, hypersensitivity reaction, malignant neoplasm, myocardial infarction, polyp, pruritus, pulmonary embolism, skin rash, thrombosis, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Breast cancer: Ospemifene has not been adequately studied in women with breast cancer. Use is not currently recommended in women with carcinoma of the breast (known, suspected or history of) and use is contraindicated with an estrogen-dependent tumor.
• Endometrial cancer: [US Boxed Warning]: Ospemifene is an estrogen agonist/antagonist with tissue selective effects. In the endometrium, ospemifene has estrogen agonistic effects. There is a potential increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Undertake adequate diagnostic measures, including directed and random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. For women with an intact uterus using an estrogen without a progestin, the risk of endometrial cancer is dependent upon dose and duration of therapy. Endometrial cancer was not reported in clinical studies of ospemifene (duration ≤52 weeks) and the use of progestins was not evaluated. There is no safety or efficacy data to recommend the addition of a progestin to ospemifene therapy in women with a uterus (current warnings are based on safety data for systemic hormone therapy with unopposed estrogen); evaluate appropriately if postmenopausal vaginal bleeding develops (Simon 2018).

Disease-related concerns:

• Cardiovascular disease: [US Boxed Warning]: The following were reported with ospemifene in clinical trials lasting ≤15 months duration: thromboembolic stroke 1.13/1,000 women years (placebo 3.15/1,000 women years); hemorrhagic stroke 3.39/1,000 women years (placebo 0/1,000 women years); DVT 2.26/1,000 women years (placebo 3.15/1,000 women years). Risk factors for cardiovascular disorders, arterial vascular disorders, and/or venous thromboembolism (VTE) should be managed appropriately. Risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of VTE. Discontinue immediately if a VTE, thromboembolic, or hemorrhagic stroke occur or are suspected. Use is contraindicated in women with active DVT, PE, or a history of these conditions and in women with active or recent arterial thromboembolic disease (stroke and MI) or a history of these conditions.
• Hepatic dysfunction: Has not been studied in patients with severe hepatic impairment; use is not recommended.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Surgical patients: Whenever possible, discontinue at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.

Other warnings/precautions:

• Risks vs benefits: [US Boxed Warning]: Ospemifene should be used for the shortest duration possible consistent with treatment goals and risks for the individual woman. With appropriate clinical monitoring, use may continue as long as bothersome symptoms are present (NAMS 2013).

Monitoring Parameters

Evaluate baseline risk for breast cancer and CVD prior to therapy. Efficacy and side effects beginning 1 to 3 months after starting therapy, then every 6 to 12 months as appropriate; age appropriate breast and pelvic exams; blood pressure; unscheduled bleeding lasting >6 months for endometrial pathology (sooner in patients who are obese, diabetic, or have a history of endometrial cancer). Duration of treatment should be evaluated at least annually (ES [Stuenkel 2015]).

Pregnancy

Pregnancy Considerations

Use is contraindicated in women who are or may become pregnant.

Ospemifene is only approved for use in postmenopausal women.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience hot flashes, vaginal pain, itching, and discharge, muscle spasms, night sweats, or sweating a lot. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood), severe loss of strength and energy, severe headache, lump in breast, breast soreness, or vaginal bleeding (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.