Osphena

Selective Estrogen Receptor Modulators (SERMs)

Hazardous Drugs Classification
NIOSH 2016 List: Group 2
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.

Administer the ospemifene tablets with food, at about the same time each day.

stroke / Early / 0-0.4
thromboembolism / Delayed / 0-0.3
myocardial infarction / Delayed / 0-0.1
thrombosis / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
new primary malignancy / Delayed / Incidence not known
endometrial cancer / Delayed / Incidence not known

hot flashes / Early / 6.5-12.2
vaginal bleeding / Delayed / 1.3-1.3
endometrial hyperplasia / Delayed / 0-0.1

vaginal discharge / Delayed / 3.8-6.0
muscle cramps / Delayed / 3.2-4.5
headache / Early / 2.8-2.8
hyperhidrosis / Delayed / 1.1-2.5
night sweats / Early / 1.2-1.2
urticaria / Rapid / Incidence not known
pruritus / Rapid / Incidence not known
rash / Early / Incidence not known

Ospemifene is contraindicated for use in patients with vaginal bleeding or dysfunctional uterine bleeding of undetermined origin. Use is contraindicated in known or suspected estrogen-dependent neoplasia; therefore, neoplasm (e.g., breast cancer, ovarian cancer, or endometrial cancer) should be ruled out before ospemifene use. Ospemifene is an estrogen agonist/antagonist with tissue selective effects. Routine clinical surveillance is important during ospemifene therapy. 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. Limit the length of therapy to the shortest duration consistent with treatment goals and risks for the individual patient. Monitoring to determine the continued need for treatment is advised. Ospemifene 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. Unopposed estrogen therapy increases the risk of a new primary malignancy of endometrial cancer in women with a uterus; ospemifene has agonistic effects on the endometrium. In ospemifene clinical trials, 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 more was seen in the ospemifene up to 52 weeks treatment groups at a rate of 101.4 per thousand women vs. 20.9 per thousand women for placebo. The incidence of any type of proliferative (weakly plus active plus disordered) endometrium was 26.3 per thousand women in the ospemifene up to 52 weeks treatment groups vs. 0 per thousand women for placebo. Uterine polyps occurred at an incidence of 19.6 per thousand women in the ospemifene up to 52 weeks treatment groups vs. 8.3 per thousand women for placebo. 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 ospemifene therapy was not evaluated in the clinical trials.

Ospemifene is contraindicated in patients with acute thromboembolism or a history of thromboembolic disease, including patients with a history of deep vein thrombosis (DVT), pulmonary embolism, retinal vein thrombosis, other venous thromboembolism (VTE), stroke, or myocardial infarction. Discontinue ospemifene immediately if a thromboembolic event occurs or is suspected, including thromboembolic or hemorrhagic stroke. There is a reported increased risk of stroke, cardiovascular, and thromboembolic events in postmenopausal women (50 to 79 years) who received daily unopposed estrogen therapy over 7.1 years as part of the Women's Health Initiative trial. Ospemifene has estrogenic effects. In the clinical trials for ospemifene therapy (15 months or less), the incidence rates of thromboembolic and hemorrhagic stroke were 1.13 and 3.39 per thousand women, respectively in the ospemifene treatment group (60 mg) and 3.15 and 0 in the placebo group. Ospemifene therapy 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. Finally, because tobacco smoking increases the risk of DVT, myocardial infarction, and other thromboembolic disease, ospemifene treatment should be used cautiously in smokers. Patients should be advised not to smoke. Patients with other risk factors for heart disease, stroke, or thromboembolism [e.g., hypertension, diabetes mellitus, hypercholesterolemia, obesity, personal history or family history of VTE, and systemic lupus erythematosus (SLE)] should be managed appropriately as per standards of care. Overall, limiting the length of therapy to the shortest duration consistent with treatment goals and risks for the individual patient is advised.[53344]

Osphena

Rx

Oral estrogen receptor agonist/antagonist (selective estrogen-receptor modulator, or SERM)
Used to treat moderate to severe vaginal dryness and dyspareunia, which are symptoms of vulvar and vaginal atrophy due to menopause
Boxed warning alerting to estrogen-like activity that may encourage endometrial hyperplasia in women with an intact uterus and a risk for thrombotic events

60 mg PO once daily with food. Ospemifene should be used for the shortest duration consistent with treatment goals and risks for the individual woman. Assess the need for continued treatment periodically. For postmenopausal women with an intact uterus, the addition of progestin should be considered to reduce the risk of endometrial hyperplasia; adding a progestin is not necessary for women without a uterus.[53344] In guidelines, ospemifene is an option and alternative to estrogen therapy for women with exclusive genitourinary symptoms of menopause.[50638]

Mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment: No dosage adjustment needed.
Severe (Child-Pugh Class C) hepatic impairment: Do not use.

No dosage adjustment is needed.

Adagrasib: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with adagrasib is necessary. Ospemifene is a CYP2C9 and CYP3A substrate and adagrasib is a dual moderate CYP2C9 and strong CYP3A inhibitor. Coadministration of another dual CYP2C9/CYP3A inhibitor increased ospemifene systemic exposure by 2.7-fold.
Amiodarone: (Major) Avoid the use of ospemifene in a patient taking amiodarone, if possible. Amiodarone inhibits CYP2C9 and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by these two CYP450 enzymes, including ospemifene. The increase in serum concentration may increase the risk of ospemifene-related adverse reactions, including hot flashes, changes in vaginal bleeding, and a risk for thromboembolism or stroke. Consider an alternative to ospemifene therapy.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Coadministration of clarithromycin and ospemifene may increase ospemifene systemic concentrations and increase the risk of ospemifene-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor, and ospemifene is a CYP3A4 substrate. Strong CYP3A4 inhibitors increase the systemic exposure of ospemifene by approximately1.4-fold.
Apalutamide: (Moderate) Monitor for decreased efficacy of ospemifene if coadministration with apalutamide is necessary. Ospemifene is a CYP2C9, CYP2C19, and CYP3A4 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer as well as a weak inducer of CYP2C9. Coadministration with a strong CYP3A4/moderate CYP2C9 and CYP2C19 inducer decreased ospemifene exposure by 58%.
Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with ospemifene as there is a potential for elevated concentrations of ospemifene. Clinical monitoring for ospemifene-related adverse effects is recommended during coadministration. Atazanavir is an inhibitor of CYP3A4 and ospemifene is a substrate for CYP3A4.
Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with ospemifene as there is a potential for elevated concentrations of ospemifene. Clinical monitoring for ospemifene-related adverse effects is recommended during coadministration. Atazanavir is an inhibitor of CYP3A4 and ospemifene is a substrate for CYP3A4. (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with cobicistat is necessary. Ospemifene is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Carbamazepine: (Moderate) Coadministration of carbamazepine and ospemifene may decrease the systemic exposure of ospemifene, which may decrease the clinical effect of ospemifene. Ospemifene is a substrate of CYP3A4, CYP2C9, and CYP2C19, and carbamazepine is an inducer of CYP2C9 and a strong inducer of CYP3A4. Similar enzyme inducers decreased the systemic exposure of ospemifene by 58%.
Ceritinib: (Major) Monitor for an increase in ospemifene-related adverse reactions if coadministration with ceritinib is necessary. Ospemifene is a CYP3A4 and CYP2C9 substrate. Ceritinib is a strong CYP3A4 inhibitor and a weak CYP2C9 inhibitor. Coadministration of another strong inhibitor increased ospemifene systemic exposure by 1.4-fold. Coadministration with drugs known to inhibit both CYP3A4 and CYP2C9 may increase the risk of ospemifene-related adverse reactions.
Clarithromycin: (Moderate) Coadministration of clarithromycin and ospemifene may increase ospemifene systemic concentrations and increase the risk of ospemifene-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor, and ospemifene is a CYP3A4 substrate. Strong CYP3A4 inhibitors increase the systemic exposure of ospemifene by approximately1.4-fold.
Cobicistat: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with cobicistat is necessary. Ospemifene is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Conjugated Estrogens: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Conjugated Estrogens; Bazedoxifene: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Conjugated Estrogens; Medroxyprogesterone: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Dabrafenib: (Moderate) The concomitant use of dabrafenib, a CYP2C9 inducer, and ospemifene, a CYP2C9 substrate, may result in decreased levels of ospemiphene, which may decrease the clinical effect. Monitor patients for reduced ospemiphene efficacy.
Darunavir: (Moderate) Caution is warranted when darunavir is administered with ospemifene as there is a potential for elevated concentrations of ospemifene. Clinical monitoring for ospemifene adverse effects is recommended. Darunavir is an inhibitor of CYP3A4.
Darunavir; Cobicistat: (Moderate) Caution is warranted when darunavir is administered with ospemifene as there is a potential for elevated concentrations of ospemifene. Clinical monitoring for ospemifene adverse effects is recommended. Darunavir is an inhibitor of CYP3A4. (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with cobicistat is necessary. Ospemifene is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when darunavir is administered with ospemifene as there is a potential for elevated concentrations of ospemifene. Clinical monitoring for ospemifene adverse effects is recommended. Darunavir is an inhibitor of CYP3A4. (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with cobicistat is necessary. Ospemifene is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Delavirdine: (Major) Administration of delavirdine with ospemifene may increase the risk of ospemifene-related adverse reactions Delavirdine is a strong CYP3A4 inhibitor and also an inhibitor of CYP2C9 and of CYP2C19 whereas ospemifene is a CYP3A4, CYP2C9, and CYP2C19 substrate. A moderate CYP3A/strong CYP2C9 inhibitor increased the systemic exposure of ospemifene by 2.7-fold.
Desogestrel; Ethinyl Estradiol: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Dienogest; Estradiol valerate: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Diethylstilbestrol, DES: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Drospirenone; Estetrol: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Drospirenone; Estradiol: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Drospirenone; Ethinyl Estradiol: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Elagolix; Estradiol; Norethindrone acetate: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with cobicistat is necessary. Ospemifene is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with cobicistat is necessary. Ospemifene is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Enzalutamide: (Moderate) Monitor for decreased efficacy of ospemifene if coadministration with enzalutamide is necessary. Ospemifene is a CYP2C9, CYP2C19, and CYP3A4 substrate. Enzalutamide is a strong CYP3A4 inducer as well as a moderate inducer of CYP2C9 and CYP2C19. Coadministration with another strong CYP3A4/moderate CYP2C9 and CYP2C19 inducer decreased ospemifene exposure by 58%.
Esterified Estrogens: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Esterified Estrogens; Methyltestosterone: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Estradiol: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Estradiol; Levonorgestrel: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Estradiol; Norethindrone: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Estradiol; Norgestimate: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Estradiol; Progesterone: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Estrogens: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Estropipate: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Ethinyl Estradiol; Norelgestromin: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Ethinyl Estradiol; Norgestrel: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Etonogestrel; Ethinyl Estradiol: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Fluconazole: (Major) Do not use fluconazole concomitantly with ospemifene. Fluconazole (a CYP3A4, CYP2C9, and CYP2C19 inhibitor) increases the systemic exposure of ospemifene by 2.7-fold and may increase the risk of ospemifene-related adverse reactions.
Fosamprenavir: (Moderate) Coadministration of fosamprenavir and ospemifene may increase ospemifene systemic concentrations and increase the risk of ospemifene-related adverse reactions. Fosamprenavir is a prodrug for amprenavir. Amprenavir is a strong CYP3A4 inhibitor, and ospemifene is a CYP3A4 substrate. Strong CYP3A4 inhibitors increase the systemic exposure of ospemifene by approximately 1.4-fold.
Fosphenytoin: (Moderate) Fosphenytoin is expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect. Fosphenytoin is a prodrug of phenytoin. Phenytoin is a potent inducer of hepatic cytochrome P450 microsomal enzymes including CYP3A4, CYP2C9, and CYP2C19, the same enzymes that are responsible for the metabolism of ospemifene. In drug interaction studies, the use of another strong combined CYP inducer decreased the systemic exposure of ospemifene by 58%. Also, ospemifene is more than 99% bound to serum proteins and might affect the protein binding of other highly protein bound drugs; this action may lead to an increase in free phenytoin concentrations as phenytoin is a highly-protein bound narrow therapeutic index medication.
Glyburide: (Moderate) Administer glyburide with ospemifene with considerable caution. Ospemifene is more than 99% bound to serum proteins and might affect the protein binding of other highly protein bound drugs, such as glyburide. This might increase the risk for low blood sugar from glyburide. The patient should closely monitor their blood sugar when these drugs are used together.
Glyburide; Metformin: (Moderate) Administer glyburide with ospemifene with considerable caution. Ospemifene is more than 99% bound to serum proteins and might affect the protein binding of other highly protein bound drugs, such as glyburide. This might increase the risk for low blood sugar from glyburide. The patient should closely monitor their blood sugar when these drugs are used together.
Indinavir: (Moderate) Coadministration of indinavir and ospemifene may increase ospemifene systemic concentrations and increase the risk of ospemifene-related adverse reactions. Indinavir is a strong CYP3A4 inhibitor, and ospemifene is a CYP3A4 substrate. Strong CYP3A4 inhibitors increase the systemic exposure of ospemifene by approximately1.4-fold.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the use of rifampin with ospemifene if possible. Rifampin, a strong CYP3A4 / moderate CYP2C9 / moderate CYP2C19 inducer, decreases the systemic exposure of ospemifene by 58%. Therefore, coadministration of ospemifene with rifampin would be expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect.
Isoniazid, INH; Rifampin: (Major) Avoid the use of rifampin with ospemifene if possible. Rifampin, a strong CYP3A4 / moderate CYP2C9 / moderate CYP2C19 inducer, decreases the systemic exposure of ospemifene by 58%. Therefore, coadministration of ospemifene with rifampin would be expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect.
Itraconazole: (Moderate) Coadministration of itraconazole and ospemifene may increase ospemifene systemic concentrations and increase the risk of ospemifene-related adverse reactions. Itraconazole is a strong CYP3A4 inhibitor, and ospemifene is a CYP3A4 substrate. Another azole antifungal that is a strong CYP3A4 inhibitor increased the systemic exposure of ospemifene by 1.4-fold.
Ketoconazole: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with ketoconazole is necessary. Ospemifene is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased ospemifene systemic exposure by 1.4-fold.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Coadministration of clarithromycin and ospemifene may increase ospemifene systemic concentrations and increase the risk of ospemifene-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor, and ospemifene is a CYP3A4 substrate. Strong CYP3A4 inhibitors increase the systemic exposure of ospemifene by approximately1.4-fold.
Letermovir: (Moderate) Plasma concentrations of ospemifene could be increased when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for ospemifene-related adverse events. Ospemifene is primarily metabolized by CYP3A4. Letermovir is a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased ospemifene systemic exposure (AUC) by 1.4-fold.
Levoketoconazole: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with ketoconazole is necessary. Ospemifene is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased ospemifene systemic exposure by 1.4-fold.
Levonorgestrel; Ethinyl Estradiol: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Lonafarnib: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with lonafarnib is necessary. Ospemifene is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong inhibitor increased ospemifene systemic exposure by 1.4-fold.
Lopinavir; Ritonavir: (Major) Use caution when administering ospemifene to a patient taking ritonavir, as concurrent use may increase ospemifene systemic exposure and increase the risk of ospemifene-related adverse reactions. Consider if alternative therapy is appropriate. Ritonavir is a strong CYP3A4 inhibitor and a CYP2C9 inhibitor, and ospemifene is a CYP3A4 and CYP2C9 substrate. Co-administration of ospemifene with a drug known to inhibit CYP3A4 and CYP2C9 isoenzymes increased the ospemifene exposure 2.7-fold.
Mitotane: (Moderate) Use caution if mitotane and ospemifene are used concomitantly, and monitor for decreased efficacy of ospemifene. Mitotane is a strong CYP3A4 inducer and ospemifene is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ospemifene and a resultant decrease in clinical effect.
Nirmatrelvir; Ritonavir: (Major) Use caution when administering ospemifene to a patient taking ritonavir, as concurrent use may increase ospemifene systemic exposure and increase the risk of ospemifene-related adverse reactions. Consider if alternative therapy is appropriate. Ritonavir is a strong CYP3A4 inhibitor and a CYP2C9 inhibitor, and ospemifene is a CYP3A4 and CYP2C9 substrate. Co-administration of ospemifene with a drug known to inhibit CYP3A4 and CYP2C9 isoenzymes increased the ospemifene exposure 2.7-fold.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Norethindrone; Ethinyl Estradiol: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Norgestimate; Ethinyl Estradiol: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Phenobarbital: (Moderate) Phenobarbital is expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect. Phenobarbital induces CYP450 enzymes including CYP3A4, CYP2C9, and CYP2C19, the same enzymes that are responsible for the metabolism of ospemifene. In drug interaction studies, the use of another strong combined CYP inducer decreased the systemic exposure of ospemifene by 58%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Phenobarbital is expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect. Phenobarbital induces CYP450 enzymes including CYP3A4, CYP2C9, and CYP2C19, the same enzymes that are responsible for the metabolism of ospemifene. In drug interaction studies, the use of another strong combined CYP inducer decreased the systemic exposure of ospemifene by 58%.
Phenytoin: (Moderate) Phenytoin is expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect. Phenytoin is a potent inducer of hepatic cytochrome P450 microsomal enzymes including CYP3A4, CYP2C9, and CYP2C19, the same enzymes that are responsible for the metabolism of ospemifene. In drug interaction studies, the use of another strong combined CYP inducer decreased the systemic exposure of ospemifene by 58%. Also, ospemifene is more than 99% bound to serum proteins and might affect the protein binding of other highly protein bound drugs; this action may lead to an increase in free phenytoin concentrations as phenytoin is a highly-protein bound narrow therapeutic index medication.
Primidone: (Moderate) Primidone is metabolized to phenobarbital in the body and is expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect. Phenobarbital induces CYP450 enzymes including CYP3A4, CYP2C9, and CYP2C19, the same enzymes that are responsible for the metabolism of ospemifene. In drug interaction studies, the use of another strong combined CYP inducer decreased the systemic exposure of ospemifene by 58%.
Raloxifene: (Major) Ospemifene should not be used concomitantly with estrogen agonists/antagonists such as raloxifene. The safety of concomitant use of ospemifene with estrogen agonists/antagonists has not been studied.
Relugolix; Estradiol; Norethindrone acetate: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
Ribociclib: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with ribociclib is necessary. Ospemifene is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
Ribociclib; Letrozole: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with ribociclib is necessary. Ospemifene is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor.
Rifampin: (Major) Avoid the use of rifampin with ospemifene if possible. Rifampin, a strong CYP3A4 / moderate CYP2C9 / moderate CYP2C19 inducer, decreases the systemic exposure of ospemifene by 58%. Therefore, coadministration of ospemifene with rifampin would be expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect.
Rifapentine: (Moderate) Monitor for decreased efficacy of ospemifene if coadministration with rifapentine is necessary. Ospemifene is a CYP3A4 and CYP2C9 substrate; rifapentine is a strong CYP3A4 inducer as well as a moderate inducer of CYP2C9. Coadministration of another dual CYP2C9/CYP3A inhibitor increased ospemifene systemic exposure by 2.7-fold.
Ritonavir: (Major) Use caution when administering ospemifene to a patient taking ritonavir, as concurrent use may increase ospemifene systemic exposure and increase the risk of ospemifene-related adverse reactions. Consider if alternative therapy is appropriate. Ritonavir is a strong CYP3A4 inhibitor and a CYP2C9 inhibitor, and ospemifene is a CYP3A4 and CYP2C9 substrate. Co-administration of ospemifene with a drug known to inhibit CYP3A4 and CYP2C9 isoenzymes increased the ospemifene exposure 2.7-fold.
Rucaparib: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with rucaparib is necessary. Ospemifene is a substrate of CYP2C9, CYP2C19, and CYP3A4, while rucaparib is a weak inhibitor of these 3 isoenzymes. Concomitant use may increase ospemifene plasma concentrations.
Segesterone Acetate; Ethinyl Estradiol: (Major) Ospemifene should not be used concomitantly with estrogens. The safety of concomitant use of ospemifene with estrogens or estrogen agonists/antagonists has not been studied.
St. John's Wort, Hypericum perforatum: (Moderate) Coadministration of St. John's Wort, Hypericum perforatum and ospemifene may decrease the systemic exposure of ospemifene, which may decrease the clinical effect. If possible, the patient should avoid St John's Wort while taking ospemifene. Ospemifene is a substrate of CYP3A4, CYP2C9, and CYP2C19, and St. John's Wort is a strong inducer of CYP3A4 and an inducer of CYP2C19. Administration of another mixed CYP inducer with ospemifene decreased the systemic exposure of ospemifene by 58%.
Tamoxifen: (Major) Ospemifene should not be used concomitantly with estrogen agonists/antagonists such as tamoxifen. The safety of concomitant use of ospemifene with estrogen agonists/antagonists has not been studied.
Toremifene: (Major) Ospemifene should not be used concomitantly with estrogen agonists/antagonists such as toremifene. The safety of concomitant use of ospemifene with estrogen agonists/antagonists has not been studied.
Tucatinib: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with tucatinib is necessary. Ospemifene is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration of another strong inhibitor increased ospemifene systemic exposure by 1.4-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Coadministration of clarithromycin and ospemifene may increase ospemifene systemic concentrations and increase the risk of ospemifene-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor, and ospemifene is a CYP3A4 substrate. Strong CYP3A4 inhibitors increase the systemic exposure of ospemifene by approximately1.4-fold.
Voriconazole: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with voriconazole is necessary. Ospemifene is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration of another strong inhibitor increased ospemifene systemic exposure by 1.4-fold.
Warfarin: (Moderate) Administer warfarin with ospemifene with considerable caution. The effect of ospemifene on clotting time such as the International Normalized Ratio (INR) or prothrombin time (PT) has not been studied. Repeated administration of ospemifene had no effect on the pharmacokinetics of a single 10 mg dose of warfarin. However, no study was conducted with multiple doses of warfarin.

Ospemifene/Osphena Oral Tab: 60mg

60 mg/day PO.

60 mg/day PO.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Not indicated.

Ospemifene is an estrogen agonist/antagonist with tissue selective effects, commonly referred to as a selective estrogen receptor modulator (SERM). Its biological actions are mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). The actions of ospemifine provide specific estrogen-like effects in vaginal tissue; the drug helps reduce vaginal atrophy by increasing superficial cells, decreasing parabasal cells, and reducing vaginal pH and these actions help improve dyspareunia.

Ospemifene is administered orally. It is highly (more than 99%) bound to serum proteins with an apparent volume of distribution of 448 L. Ospemifene is primarily metabolized in the liver by CYP3A4 and CYP2C9. CYP2C19 and other pathways also contribute to ospemifene metabolism. Following an oral administration, approximately 75% and 7% of the dose was excreted in feces and urine, respectively. Less than 0.2% of the dose was excreted unchanged in urine. The apparent terminal half-life in postmenopausal women is approximately 26 hours.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C9
Ospemifene is primarily metabolized by CYP3A4 and CYP2C9. CYP2C19 and other pathways contribute to the its metabolism. Coadministration of ospemifene with a drug known to inhibit both CYP3A4 and CYP2C9 isoenzymes may increase the risk of ospemifene-related adverse reactions; some drugs with combined moderate/strong inhibition of both these enzymes (e.g., fluconazole) should not be used with ospemfene. Combined inducers of CYP3A4 and CYP2C9 (e.g., rifampin) are expected to reduce ospemifene efficacy. In order of decreasing potency, ospemifene was suggested to be a weak inhibitor for CYP2B6, CYP2C9, CYP2C19, CYP2C8, CYP2D6 and CYP3A4 in in vitro studies; clinically significant drug interactions based on these activities have not been demonstrated. Ospemifene is not a significant P-glycoprotein substrate in vitro; no in vivo transporter study was conducted.

Following a single oral administration of ospemifene (60 mg) in postmenopausal women under fasted condition, peak median serum concentrations (Cmax) were achieved at approximately 2 hours (range: 1 to 8 hours). The mean Cmax and AUC were 533 ng/mL and 4,165 ng x hour/mL, respectively. Under fed (high fat/high calorie meal) conditions, peak median serum concentrations were achieved at approximately 2.5 hours (range: 1 to 6 hours). The mean Cmax was 1,198 ng/mL and the mean AUC was 7,521 ng x hour/mL. In general, food increased the bioavailability of ospemifene tablets by approximately 2 to 3 fold; the elimination half-life and time to maximum concentration (Tmax) were essentially unchanged in the presence of food. Ospemifene should be taken with food. The absolute bioavailability of ospemifene has not been evaluated. Accumulation of ospemifene with respect to AUC was approximately 2 after 12 weeks of daily administration. Steady-state was reached after 9 days of oral administration.

Do not use ospemifene in women who are breast-feeding; there are no data on the effects of ospemifene on the breastfed child or milk production. It is not known whether ospemifene is excreted in human breast milk. In an animal study, ospemifene was excreted in rat milk and detected at concentrations higher than that in maternal plasma.[53344]