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Ospemifene

Pronunciation

(os PEM i feen)

Index Terms

  • FC1271a

Dosage Forms

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

Tablet, Oral:

Osphena: 60 mg

Brand Names: U.S.

  • Osphena

Pharmacologic Category

  • Selective Estrogen Receptor Modulator (SERM)

Pharmacology

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).

Distribution

Vd: 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

Treatment of moderate-to-severe dyspareunia due to vulvar and vaginal atrophy (VVA) of menopause

Contraindications

Hypersensitivity (eg, angioedema, urticaria, rash, pruritus) to ospemifene or any component of the formulation; undiagnosed abnormal vaginal 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

Dosing: Adult

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): No dosage adjustment provided in manufacturer's labeling (has not been studied). Use is not recommended.

Administration

Administer with food. Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

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

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Strong): May increase the serum concentration of Ospemifene. Monitor therapy

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

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. 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. 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. 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. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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. 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

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

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

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. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Adverse Reactions

1% to 10%:

Dermatologic: Hyperhidrosis (2%)

Endocrine & metabolic: Hot flash (8%)

Genitourinary: Proliferative endometrium (9%), endometrial hyperplasia (without atypia, 6%), vaginal discharge (4%), genital discharge (1%)

Neuromuscular & skeletal: Muscle spasm (3%)

<1% (Limited to important or life-threatening: Deep vein thrombosis, endometrial polyps, hemorrhagic stroke, hypersensitivity, thrombotic stroke

ALERT: U.S. Boxed Warning

Endometrial cancer:

Ospemifene is an estrogen agonist/antagonist with tissue selective effects. In the endometrium, ospemifene 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. 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.

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 (0.625 mg)–alone therapy over 7.1 years as part of the Women's Health Initiative (WHI).

In the clinical trials for ospemifene (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 ospemifene 60 mg treatment group and 1.04 and 0 in placebo. The incidence of DVT was 1.45 per thousand women in ospemifene 60 mg treatment group and 1.04 per thousand women in placebo.

Risks vs benefits:

Ospemifene should be prescribed for the shortest duration consistent with treatment goals and risk for the individual woman.

Warnings/Precautions

Concerns related to adverse effects:

• Breast cancer: Ospemifene was not 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: [U.S. Boxed Warning]: The use of unopposed estrogen in women with an intact uterus is associated with an increased risk of endometrial cancer. The addition of a progestin to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Adequate diagnostic measures, including endometrial sampling if indicated, should be performed to rule out malignancy in postmenopausal women with undiagnosed abnormal vaginal bleeding. Ospemifene is an estrogen agonist/antagonist with agonistic effects on the endometrium. 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.

Disease-related concerns:

• Cardiovascular disease: [U.S. Boxed Warning]: Using data from the Women’s Health Initiative (WHI) studies, an increased risk of deep vein thrombosis (DVT) and stroke has been reported with oral conjugated estrogens. The following were reported with ospemifene in clinical trials lasting ≤15 months duration: thromboembolic stroke 0.72/1000 women (placebo 1.04/1000 women); hemorrhagic stroke 1.45/1000 women (placebo 0/1000 women); DVT 1.45/1000 women (placebo 1.04/1000 women). 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.

• 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 4-6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Other warnings/precautions:

• Risks vs benefits: [U.S. Boxed Warning]: Ospemifene should be used for the shortest duration possible consistent with treatment goals and risks for the individual woman.

Monitoring Parameters

Monitor for signs of endometrial cancer in female patients with uterus. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding. Assess need for therapy at regular intervals. Monitor for signs/symptoms of stroke and VTE.

Pregnancy Risk Factor

X

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Use is contraindicated in women who are or may become pregnant. Ospemifene is currently approved only for the treatment of moderate-to-severe dyspareunia due to vulvar and vaginal atrophy (VVA) of menopause.

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, vaginitis, muscle spasms, 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, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, shortness of breath, loss of strength and energy, severe headache, or severe vaginal hemorrhaging (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 healthcare 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.

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