Osphena (ospemifene)

No dosing information is available for this tab.

Ospemifene is administered orally with food.

No dosing information is available for this tab.

In vitro studies indicate that ospemifene is principally metabolized by cytochrome P-450 (CYP) isoenzymes 3A4 and 2C9; other isoenzymes (specifically CYP2C19 and 2B6) also are involved in the drug's metabolism. Ospemifene is a weak inhibitor of CYP2B6, 2C9, 2C19, 2C8, 2D6, and 3A4 in vitro. Ospemifene is not a clinically important substrate of the P-glycoprotein (P-gp) transport system in vitro.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Agents Affecting Plasma Cortisol Levels/Cosyntropin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

CLINICAL EFFECTS: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of cosyntropin states accuracy of diagnosis using the cosyntropin diagnostic test may be complicated by concomitant medications affecting plasma cortisol levels.(1) Agents affecting plasma cortisol levels and recommendation to stop prior to cosyntropin diagnostic test include: - Glucocorticoids: May elevate plasma cortisol levels. Stop these drugs on the day of testing. Long-acting glucocorticoids may need to be stopped for a longer period before testing. - Spironolactone: May elevate plasma cortisol levels. Stop spironolactone on the day of testing. - Estrogen: May elevate plasma total cortisol levels. Discontinue estrogen containing drugs 4 to 6 weeks prior to testing to allow cortisol binding globulin levels to return to levels within the reference range. Alternatively, concomitant measurement of cortisol binding globulin at the time of testing can be done; if cortisol binding globulin levels are elevated, plasma total cortisol levels are considered inaccurate.(1)

DISCUSSION: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

Estrogen Receptor Blockers (Erbs)/Fluoroestradiol F-18

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Drugs that bind to the estrogen receptor (ER) may compete with the binding of radioactive diagnostic agent fluoroestradiol F-18.(1)

CLINICAL EFFECTS: Concurrent use of estrogen receptor blockers such as selective estrogen receptor modulators (SERMs) and selective estrogen receptor down-regulators (SERDs) may reduce the detection of ER-positive lesions with fluoroestradiol F-18.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Before administering fluoroestradiol F-18, discontinue drugs that bind to the ER, such as SERMs and SERDs, for at least 5 biological half-lives.(1) The following washout periods apply when discontinuing ERBs, prior to fluoroestradiol F-18 administration: - Bazedoxifene = 7 days - Clomiphene = 25 days - Elacestrant = 11 days - Enclomiphene = 25 days - Fulvestrant = 28 weeks - Imlunestrant = 7 days - Ospemifene = 5 days - Raloxifene = 7 days - Tamoxifen = 8 weeks - Toremifene = 5 weeks

DISCUSSION: The following ERBs are linked to this monograph: SERDs: elacestrant, imlunestrant, and fulvestrant. SERMs: bazedoxifene, clomiphene, enclomiphene, ospemifene, raloxifene, tamoxifen and toremifene.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Ospemifene/Fluconazole; Voriconazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ospemifene is primarily metabolized by CYP3A4, CYP2C9 and CYP2C19.(1) Fluconazole and voriconazole each inhibit all three of these metabolic pathways. Ospemifene is an estrogen agonist/antagonist which has dose-dependent agonist effects on the endometrium.(2)

CLINICAL EFFECTS: Inhibition of major metabolic pathways increases systemic exposure to ospemifene and may increase risk for adverse reactions or toxicity, including increased risk for endometrial hyperplasia which may be a precursor to endometrial cancer.(1)

PREDISPOSING FACTORS: Patients taking progestin therapy or without an intact uterus have a lower or no risk respectively for endometrial cancer.

PATIENT MANAGEMENT: In women at risk for endometrial cancer, discontinue ospemifene when fluconazole or voriconazole treatment is started. If patient is already receiving fluconazole or voriconazole when ospemifene is prescribed, delay initiation of ospemifene until fluconazole or voriconazole treatment has been completed. The manufacturer of ospemifene states fluconazole should not be used in patients receiving ospemifene.(1) Counsel patients to report genital bleeding to their physician. The Boxed Warning for ospemifene states postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding should be seen for diagnostic testing to rule out endometrial hyperplasia or endometrial cancer.(1)

DISCUSSION: Fluconazole is a moderate CYP3A4/strong CYP2C9/moderate CYP2C19 inhibitor. In a drug interaction study fluconazole 400 mg given on day one followed by 200 mg on days 2 through 8 increased the area-under-curve (AUC) for ospemifene 2.7-fold.(2) Voriconazole, a strong CYP3A4/weak CYP2C9/moderate CYP2C19 inhibitor(3) has not been studied but may have similar effects.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Ospemifene/Selected Cyp2c And Cyp3a4 Inducers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ospemifene is metabolized by CYP3A4, CYP2C9 and CYP2C19.(1) Agents linked to this monograph are strong inducers of CYP3A4, and moderate inducers of CYP2C9 and/or CYP2C19.

CLINICAL EFFECTS: Concurrent or recent use of ospemifene with agents which induce both CYP3A4 and CYP2C enzyme pathways may lead to decreased levels and effectiveness of ospemifene.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Systemic levels of ospemifene are expected to decrease after starting an inducer, then stabilize at a new lower systemic concentration over approximately 2 to 4 weeks depending upon the dose and half-life of the inducing agent. The manufacturer of ospemifene notes that decreased systemic exposure may lead to a decrease in clinical effectiveness, but does not make recommendations for a dosage adjustment.(1) Instruct patient to contact their prescriber for a significant decrease in ospemifene effectiveness. To ensure maximal absorption, counsel patient to take ospemifene with a meal as food increases bioavailability 2-3 fold.(1)

DISCUSSION: An interaction study included 12 postmenopausal women who received rifampin 600 mg daily for 5 days. On the 6th day, ospemifene 60mg was administered with food. Rifampin reduced maximum concentrations (Cmax) and area-under-curve (AUC) of ospemifene by 51% and 58% respectively.(1) Agents linked to this monograph are apalutamide, carbamazepine, dabrafenib, enzalutamide and rifampin.

Ospemifene is contraindicated in women with undiagnosed abnormal genital bleeding and in women with known or suspected estrogen-dependent neoplasia. (See Genitourinary Effects under Warnings/Precautions: Warnings, in Cautions.)

The drug also is contraindicated in women with active deep-vein thrombosis (DVT), pulmonary embolism (PE), active arterial thromboembolic disease (e.g., stroke, myocardial infarction (MI)), or history of these conditions. (See Cardiovascular Effects under Warnings/Precautions: Warnings, in Cautions.)

Ospemifene is contraindicated in women who are or may become pregnant. (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings/Precautions, in Cautions and also see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

• Acute myocardial infarction
• Acute pulmonary thromboembolism
• Carcinoma of breast
• Cerebrovascular accident
• Deep venous thrombosis
• Estrogen-dependent neoplasm
• Pregnancy

• History of venous thromboembolism
• Peripheral vascular disease

There are no moderate contraindications for this drug.

Adverse effects occurring in at least 1% of patients receiving ospemifene and more frequently with the drug than with placebo include hot flush, vaginal discharge, genital discharge, muscle spasms, and hyperhidrosis.

Rare or Very Rare

• Angioedema
• Cerebrovascular accident
• Deep venous thrombosis
• Endometrial carcinoma
• Endometrial hyperplasia
• Hypersensitivity drug reaction
• Pulmonary thromboembolism

More Frequent

• Abnormal vaginal bleeding
• Flushing
• Hyperhidrosis
• Muscle spasm
• Night sweats
• Vaginal discharge

Rare or Very Rare

• Erythema
• Headache disorder
• Pruritus of skin
• Skin rash
• Urticaria

No enhanced messaging available.

Ospemifene is not indicated in pediatric patients and has not been studied in this age group.

Category X. (See Users Guide.) (See Cautions: Contraindications and also see Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

It is not known whether ospemifene is distributed into human milk. Ospemifene is distributed into milk in rats and detected at higher concentrations than in maternal plasma.

No substantial differences in safety and efficacy have been observed in women 65 years of age or older compared with younger women.