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  • CLASSES

    Appetite Stimulants, Other
    Cytostatic Progestogens

    DEA CLASS

    Rx

    DESCRIPTION

    Synthetic oral progestin with slight glucocorticoid and mineralocorticoid activity, but lack of estrogenic, androgenic, or anabolic effects
    Suspension indicated for anorexia, cachexia, or unexplained, significant weight loss in acquired immunodeficiency syndrome (AIDS)
    Tablets indicated for palliative treatment of advanced breast or endometrial cancer; used off-label for advanced prostate cancer; also used off-label for endometriosis and htreating hot flashes that occur from androgen-deprivation therapy

    COMMON BRAND NAMES

    Megace, Megace ES

    HOW SUPPLIED

    Megace/Megace ES/Megestrol Acetate Oral Susp: 1mL, 5mL, 40mg, 625mg
    Megace/Megestrol Acetate Oral Tab: 20mg, 40mg

    DOSAGE & INDICATIONS

    For the treatment of anorexia, cachexia, or unexplained weight loss in patients with acquired immunodeficiency syndrome (AIDS).
    Oral dosage (megestrol acetate suspension containing 125 mg/mL, e.g., Megace ES suspension 125 mg/mL)
    Adults

    625 mg PO once daily. This oral suspension strength (125 mg/mL) is not substitutable with other strengths (e.g., 40 mg/mL).

    Oral dosage (Megestrol acetate suspension 40 mg/mL)
    Adults

    800 mg PO once daily. At least 2 studies documented the efficacy of megestrol in treating cachexia and reversing weight loss in patients with AIDS. In both studies, 800 mg/day PO, administered as the oral suspension in a single dose was found superior to placebo. Doses of 400 mg/day to 800 mg/day were effective in clinical trials. This oral suspension strength (40 mg/mL) is not substitutable with other strengths (e.g., 125 mg/mL).

    For the palliative treatment of advanced, inoperable, recurrent metastatic breast cancer.
    Oral dosage (tablets)
    Adults

    40 mg PO given 4 times per day. At least 2 months of therapy is considered an adequate period for determining the antineoplastic effectiveness of megestrol.

    For the palliative treatment of advanced, inoperable, recurrent metastatic endometrial cancer.
    Oral dosage (tablets)
    Adults

    40 to 320 mg/day PO, given in divided doses. At least 2 months of therapy is adequate for determining the antineoplastic effectiveness of megestrol.

    For the treatment of advanced hormone-refractory prostate cancer†.
    Oral dosage (tablets)
    Adult males

    Dosage has not been established. In a randomized study that compared low-doses of 160 mg PO once daily to high-doses of 640 mg PO once daily in 149 patients with progressive prostate cancer following androgen ablation and 1 prior hormone therapy, there was no significant difference in response rate (2 partial responses (PR) vs. 1 PR), median overall survival time (11.2 vs. 12.1 months), or progression-free survival time (3.8 vs. 4.3 months) between the 2 treatment arms. Toxicity was similar in both study arms and 7% of patients experienced a pain flare. In another randomized phase II trial of 58 patients, 40 mg PO 4 times daily resulted in an objective response rate of 10% compared with 7% in patients who received dexamethasone 0.75 mg PO twice daily. A separate randomized trial was closed early after enrolling 22% of the planned patient accrual; no complete or PR were observed in 86 patients with HRPC who received 1 of 4 treatments: megestrol 40 mg PO 3 times per day as monotherapy, megestrol 40 mg PO given 3 times per day plus diethylstilbestrol 0.1 mg PO once daily, stilphostrol, or streptozotocin.

    For the for the treatment of metastatic renal cell cancer†.
    Oral dosage (tablets)
    Adults

    Dosage has not been established. In a randomized, 4-arm phase II study in 144 evaluable patients, 1 partial response (PR) was reported in 37 patients who received initial treatment with megestrol acetate 150 mg/m2/day PO in 3 divided doses; additionally, 2 PR were reported in 48 patients who crossed over to the megestrol arm after failing initial therapy with one of the other 3 study treatments (etoposide, cyclophosphamide, or dianhydrogalactitol). In another phase II trial, no complete response or PR was observed in 15 patients who received megestrol 80 mg PO twice daily plus interferon alpha-2b (10 million international units/m2 subcutaneously 5 days/week). Stable disease was achieved in 5 patients; 12 patients discontinued therapy due to fatigue.

    For the treatment of endometriosis†-associated pain†.
    Oral dosage (tablets)
    Adult females

    40 mg PO once daily for 3 to 6 months has been described in a restrospective case study of patients (n = 29) treated for up to 2 years. Disease-related symptoms (dysmenorrhea, noncyclic pelvic pain, and dyspareunia) were relieved in 86% of the subjects treated with an adequate course of therapy. Eight women discontinued treatment within 2 months and 2 others stopped the drug by 4 months, but side effects were typically well tolerated. Treatment guidelines recommend an oral progestogen as a treatment option for reducing endometriosis-associated pain; however, other progestins have more data supporting their use.

    For the treatment of hot flashes† in women with a history of breast cancer or in men with prostate cancer who have undergone androgen-deprivation therapy.
    Oral dosage (tablets)
    Adults

    Dosage not established. A double-blind, cross over study of 4 weeks of megestrol 20 mg PO twice daily compared to placebo was studied in 97 females with breast cancer and 66 males with prostate cancer who had hot flashes. During the first 4 weeks, 74% of the megestrol group vs. 20% of the placebo group had a 50% decrease in hot flashes compared to baseline. In general, 2 to 3 weeks of therapy was needed to achieve optimal effect. Cross over data demonstrated a carry-over effect of the megestrol and therefore this data was not included in the data analysis.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Specific maximum dose information is not available for oncologic treatments; see indications. 800 mg/day PO (of the 40 mg/ml suspension) or 625 mg/day PO (of the 125 mg/ml suspension) for anorexia/cachexia due to HIV infection.

    Elderly

    Specific maximum dose information is not available for oncologic treatments; see indications. 800 mg/day PO (of the 40 mg/ml suspension) or 625 mg/day PO (of the 125 mg/ml suspension) for anorexia/cachexia due to HIV infection.

    Adolescents

    Specific maximum dose information is not available for oncologic treatments; see indications. 800 mg/day PO (of the 40 mg/ml suspension) or 625 mg/day PO (of the 125 mg/ml suspension) for anorexia/cachexia due to HIV infection.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Hepatic impairment can affect megestrol plasma concentrations; however, specific guidelines for dosage adjustments in hepatic impairment are not available.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. However, megestrol is substantially excreted by the kidney and the risk of toxic reactions may be greater in patients with impaired renal function.
     
    Intermittent hemodialysis
    Megestrol acetate has not been tested for dialyzability; however, due to its low solubility it is postulated that hemodialysis is not an effective means of drug removal. No supplemental dosages are needed.

    ADMINISTRATION

    NOTE: The correct dose of megestrol for the treatment of neoplastic disease will vary from protocol to protocol. Clinicians should consult the appropriate references to verify the dose.
     
    For storage information see specific product information, within the How Supplied section.

    Oral Administration

    Administer orally. The bioavailability of the regular strength oral suspension (40 mg/ml) is significantly higher when administered in the fed state compared to a fasting state with Cmax 729% higher and AUC 208% higher. The bioavailability of the concentrated oral suspension (125 mg/ml) is also higher in the fed state with the AUC 136% higher and Cmax 148% higher. Whether the tablets are affected by food has not been established. Recommendations on the administration of the 40 mg/ml suspension with food have NOT been made; however, safety differences following administration of the 125 mg/ml suspension in the fed or fasting state are not apparent. The concentrated 125 mg/ml suspension can be taken without regard to meals.

    Oral Liquid Formulations

    Suspension: Shake well prior to administration. Measure dosage with calibrated cup, spoon, or oral syringe. NOTE: Megace suspension (40 mg/ml) and Megace ES suspension (125 mg/ml) are available in different strengths and the dosage for the treatment of cachexia and anorexia in AIDS patients is different for these 2 formulations (see Dosage). It is imperative that health care providers inform patients of these differences to prevent errors in dosage.

    STORAGE

    Megace:
    - Avoid excessive heat (above 104 degrees F)
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Megace ES:
    - Protect from extreme heat
    - Store between 59 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Megestrol is contraindicated in those patients with a history of hypersensitivity to megestrol acetate or any component of the formulation.
     
    Megestrol acetate is not intended for prophylactic use to avoid weight loss. Therapy with megestrol acetate oral suspension for weight loss should only be instituted after treatable causes of weight loss are sought and addressed. These treatable causes include possible malignancies, systemic infections, gastrointestinal disorders affecting absorption, endocrine disease, renal disease, or psychiatric disease.

    Dysfunctional uterine bleeding, females, vaginal bleeding

    Megestrol acetate has been used extensively in women for the treatment of breast and endometrial cancer, its use in HIV-infected females has been limited. In establishing the indication for the treatment of anorexia and cachexia secondary to human immunodeficiency virus (HIV), all ten females in the clinical trial reported the side effect of menstrual irregularity (breakthrough bleeding). Vaginal bleeding can occur with megestrol, however, vaginal bleeding can also be a sign of a serious gynecological problem. Prior to starting megestrol, females with undiagnosed abnormal vaginal bleeding or dysfunctional uterine bleeding should be evaluated.

    Breast cancer, neoplastic disease

    Breast cancer in which estrogen and/or progesterone receptors are positive are more likely to respond to megestrol. The use of megestrol in other types of neoplastic disease is not recommended. Close surveillance is indicated for any patient treated for recurrent or metastatic cancer. Administration of megestrol acetate to female dogs for up to 7 years is associated with an increased incidence of both benign and malignant tumors of the breast. Comparable studies in rats and studies in monkeys are not associated with an increased incidence of tumors. Pituitary tumors were observed in female rats treated with 3.9 or 10 mg/kg/day of megestrol acetate for 2 years. The relationship of the dog tumors to humans is unknown but should be considered in assessing the benefit-to-risk ratio when prescribing megestrol and in surveillance of patients on therapy.

    Adrenal insufficiency, Cushing's syndrome, diabetes mellitus, hyperglycemia, hypotension, hypothalamic-pituitary-adrenal (HPA) suppression, infection, surgery, vomiting

    The glucocorticoid activity of megestrol has not been fully evaluated, clinical cases of new onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia, and overt Cushing's syndrome have been reported in association with the chronic use of megestrol. In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic megestrol therapy in the stressed and non-stressed state. Furthermore, adrenocorticotropin (ACTH) stimulation testing has revealed the frequent occurrence of asymptomatic pituitary-adrenal suppression in patients treated with chronic megestrol therapy. The possibility of adrenal suppression should be considered in any patient taking or withdrawing from chronic megestrol therapy who presents with symptoms of adrenal insufficiency (e.g., hypotension, nausea, vomiting, dizziness, or weakness). Laboratory evaluation for adrenal insufficiency and replacement stress doses of a rapidly acting glucocorticoid may be indicated for such patients. Failure to recognize hypothalamic-pituitary-adrenal (HPA) suppression may result in death. Finally, in patients who are receiving or being withdrawn from chronic megestrol therapy, consideration should be given to the use of empiric therapy with stress doses or a rapidly acting glucocorticoid in conditions of stress or serious intercurrent illness (e.g., surgery, infection).

    Thromboembolic disease, thrombophlebitis

    Use megestrol cautiously in patients with a history of thromboembolic disease. Thromboembolism (including deep vein thrombosis and pulmonary embolism) and thrombophlebitis have been associated with megestrol therapy.

    Hepatic disease

    Hepatic impairment can affect the inactivation of megestrol and, thus, plasma concentrations, patients with severe hepatic disease should be monitored for adverse effects. Specific guidelines for dosage adjustments in these patients are not available.

    Pregnancy

    Megestrol is classified as FDA pregnancy risk category X (oral suspension) and category D (tablets); the different pregnancy risk ratings is based upon the need for the drug and patient risk: benefit ratios. In general, megestrol is contraindicated during known or suspected pregnancy. Genital abnormalities in male and female fetuses have been reported in women who had received progestational agents during the first trimester. In male fetuses, the risk of developing hypospadias is about doubled when fetuses are exposed to progestational agents; feminization may occur. The reproductive capability was impaired in rat or dog male offspring exposed to megestrol acetate in utero. In female fetuses, there is a risk of mild virilization of the external genitalia, however, there is insufficient data to quantify the risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Females of childbearing potential should be advised to avoid becoming pregnant while receiving megestrol treatment.

    Breast-feeding

    Megestrol is known to be excreted in breast milk; amounts potentially reaching an infant per day are estimated to be 0.1% of the maternal daily ingested dose based on available data. Megestrol should not be used during breast-feeding since its effect to the neonate or nursing infant is not known. Alternate forms of feeding are recommended if megestrol therapy is essential to the mother.

    Children

    Safety and effectiveness of megestrol in children have not been established.

    Renal failure, renal impairment

    Megestrol acetate is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with renal impairment or renal failure. Care should be taken in dose selection, and it may be useful to monitor renal function in patients with impaired renal function, especially in elderly adults.

    Geriatric

    Clinical studies of megestrol acetate oral suspension in the treatment of cachexia, anorexia, or an unexplained weight loss in patients with AIDS did not include sufficient numbers of patients aged 65 years of age or older to determine if they respond differently than younger adults. Other reported clinical experience has not identified differences in responses between younger and geriatric patients. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. According to the Beers Criteria, megestrol is considered a potentially inappropriate medication (PIM) for use in geriatric patients as a treatment for cachexia/poor appetite and should be avoided due to a minimal effect on weight and an increased risk of thrombotic events and possibly death in older adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of medications in residents of long-term care facilities. According to the OBRA guidelines, use of appetite stimulants should be reserved for situations where assessment and management of underlying correctable causes of anorexia and weight loss are not feasible or successful, and after evaluating the potential benefits versus risks. Appetite and weight should be monitored at least monthly and the appetite stimulant should be discontinued if there is no improvement. Possible adverse effects of megestrol acetate include fluid retention, adrenal suppression, and symptoms of adrenal insufficiency.

    ADVERSE REACTIONS

    Severe

    cardiomyopathy / Delayed / 1.0-3.0
    seizures / Delayed / 1.0-3.0
    heart failure / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known

    Moderate

    impotence (erectile dysfunction) / Delayed / 4.0-14.0
    hypertension / Early / 0-8.0
    hyperglycemia / Delayed / 0-6.0
    anemia / Delayed / 3.0-5.0
    candidiasis / Delayed / 1.0-3.0
    hepatomegaly / Delayed / 1.0-3.0
    constipation / Delayed / 1.0-3.0
    chest pain (unspecified) / Early / 1.0-3.0
    peripheral edema / Delayed / 1.0-3.0
    palpitations / Early / 1.0-3.0
    edema / Delayed / 1.0-3.0
    dyspnea / Early / 1.0-3.0
    confusion / Early / 1.0-3.0
    depression / Delayed / 1.0-3.0
    impaired cognition / Early / 1.0-3.0
    peripheral neuropathy / Delayed / 1.0-3.0
    leukopenia / Delayed / 1.0-3.0
    urinary incontinence / Early / 1.0-3.0
    amblyopia / Delayed / 1.0-3.0
    hot flashes / Early / Incidence not known
    phlebitis / Rapid / Incidence not known
    Cushing's syndrome / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    hypothalamic-pituitary-adrenal (HPA) suppression / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    hypercalcemia / Delayed / Incidence not known

    Mild

    diarrhea / Early / 6.0-15.0
    rash (unspecified) / Early / 2.0-12.0
    flatulence / Early / 1.0-10.0
    vomiting / Early / 0-6.0
    insomnia / Early / 0-6.0
    asthenia / Delayed / 3.0-6.0
    nausea / Early / 0-5.0
    libido decrease / Delayed / 0-5.0
    fever / Early / 2.0-5.0
    dyspepsia / Early / 3.0-4.0
    infection / Delayed / 1.0-3.0
    hypersalivation / Early / 1.0-3.0
    abdominal pain / Early / 1.0-3.0
    xerostomia / Early / 1.0-3.0
    diaphoresis / Early / 1.0-3.0
    alopecia / Delayed / 1.0-3.0
    vesicular rash / Delayed / 1.0-3.0
    pruritus / Rapid / 1.0-3.0
    pharyngitis / Delayed / 1.0-3.0
    cough / Delayed / 1.0-3.0
    headache / Early / 1.0-3.0
    paresthesias / Delayed / 1.0-3.0
    hypoesthesia / Delayed / 1.0-3.0
    gynecomastia / Delayed / 1.0-3.0
    increased urinary frequency / Early / 1.0-2.0
    weight gain / Delayed / 10.0
    appetite stimulation / Delayed / Incidence not known
    menstrual irregularity / Delayed / Incidence not known
    breakthrough bleeding / Delayed / Incidence not known
    weakness / Early / Incidence not known
    insulin resistance / Delayed / Incidence not known
    dizziness / Early / Incidence not known
    carpal tunnel syndrome / Delayed / Incidence not known
    malaise / Early / Incidence not known
    lethargy / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Acetaminophen; Butalbital; Caffeine: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Acetaminophen; Butalbital; Caffeine; Codeine: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Acetohexamide: Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Alogliptin: Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Alogliptin; Metformin: Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Alogliptin; Pioglitazone: Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Alpha-glucosidase Inhibitors: Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Amobarbital: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Amprenavir: Progestins may decrease the serum concentrations of amprenavir, which could lead to loss of virologic response and possible viral resistance. Oral contraceptives and non-oral combination contraceptives should not be administered with amprenavir. Alternative methods of non-hormonal contraception are recommended if amprenavir is prescribed. Additionally, data on the effects that other protease inhibitors have on the serum concentrations of estrogens and progestins are complex; some protease inhibitors increase and others decrease the metabolism of hormonal contraceptives. It is not known if amprenavir alters the metabolism of hormonal contraceptives or other estrogen or progestin products. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms.
    Aprepitant, Fosaprepitant: If aprepitant, fosaprepitant is coadministered with hormonal contraceptives, including hormonal contraceptive devices (skin patches, implants, and hormonal IUDs), use an alternative or back-up non-hormonal method of contraception (e.g., condoms, spermicides) during treatment and for at least 1 month following the last dose of aprepitant, fosaprepitant. The efficacy of progestins may be reduced when coadministered with aprepitant, fosaprepitant and for 28 days after the last dose. The exact mechanism for this interaction has not been described. Progestins are CYP3A4 substrates and aprepitant, fosaprepitant is a CYP3A4 inducer; however, aprepitant, fosaprepitant is also a dose-dependent weak-to-moderate CYP3A4 inhibitor. When administered as an oral 3-day regimen (125mg/80mg/80mg) in combination with ondansetron and dexamethasone, aprepitant decreased trough concentrations of ethinyl estradiol and norethindrone by up to 64% for 3 weeks post-treatment. When ethinyl estradiol and norgestimate were administered on days 1 to 21 and aprepitant (40mg) give as a single dose on day 8, the AUC of ethinyl estradiol decreased by 4% on day 8 and by 29% on day 12; the AUC of norelgestromin increased by 18% on day 8, and decreased by 10% on day 12. Trough concentrations of both ethinyl estradiol and norelgestromin were generally lower after coadministration of aprepitant (40mg) on day 8 compared to administration without aprepitant. Specific studies have not been done with other hormonal contraceptives (e.g., progestins, non-oral combination contraceptives), an alternative or additional non-hormonal method of birth control during treatment and for 28 days after treatment is prudent to avoid potential for contraceptive failure. The clinical significance of this is not known since aprepitant, fosaprepitant is only used intermittently.
    Armodafinil: Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estrogens and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Aspirin, ASA; Butalbital; Caffeine: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Atazanavir; Cobicistat: Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progestins. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. There is a potential for altered efficacy for combined hormonal contraceptives. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Barbiturates: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Bexarotene: Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Bosentan: Bosentan is a significant inducer of CYP3A hepatic enzymes. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. In addition, bosentan is teratogenic and is contraindicated during pregnancy. An interaction study has demonstrated that coadministration of bosentan and an oral contraceptive product (ethinyl estradiol; norethindrone) produced average decreases in norethindrone and ethinyl estradiol serum concentrations of 14% and 31%, respectively; however, decreases in drug exposure were are as high as 56% and 66%, respectively, in individual subjects. Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. Effective contraception through additional forms of contraception must be practiced. The manufacturer recommends that follow-up pregnancy tests be obtained monthly for women of childbearing potential taking bosentan. Additionally, estrogens and progestins used for hormone replacement therapy may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
    Bromocriptine: Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women. Progestins can cause amenorrhea and, therefore, counteract the desired effects of bromocriptine. Concurrent use is not recommended; an alternate form of contraception is recommended during bromocriptine therapy.
    Butabarbital: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Canagliflozin; Metformin: Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Carbamazepine: Concomitant use of carbamazepine with hormonal products may render the hormonal product less effective. The plasma concentrations of the hormones may be decreased because carbamazepine induces the activity of hepatic metabolic enzymes. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs, or higher-dose hormonal regimens may be indicated where acceptable or applicable as pregnancy has been reported in patients taking the hepatic enzyme inducing drug phenytoin concurrently with hormonal contraceptives. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Patients taking progestins for other indications may need to be monitored for reductions in clinical effect of the progestin.
    Chlorpropamide: Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Clobazam: The addition of non-hormonal forms of contraception are recommended during concurrent use of clobazam and hormonal contraceptives. Concurrent administration of clobazam, a weak CYP3A4 inducer, with progestins may increase the elimination of these hormones. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for indications other than contraception may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
    Cobicistat: Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progestins. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. There is a potential for altered efficacy for combined hormonal contraceptives. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progestins. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. There is a potential for altered efficacy for combined hormonal contraceptives. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progestins. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. There is a potential for altered efficacy for combined hormonal contraceptives. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Dapagliflozin: Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Dapagliflozin; Metformin: Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Darunavir; Cobicistat: Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progestins. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. There is a potential for altered efficacy for combined hormonal contraceptives. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Dofetilide: All inhibitors of renal cationic secretion, including megestrol, are contraindicated with dofetilide. In a population pharmacokinetic analysis of plasma dofetilide concentrations, the mean clearance of dofetilide was 15% lower in patients receiving inhibitors of tubular organic cation transport.
    Empagliflozin: Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Empagliflozin; Linagliptin: Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Empagliflozin; Metformin: Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Entecavir: Entecavir and megestrol are eliminated by active tubular secretion. In theory, coadministration of these drugs may increase the serum concentrations of either drug due to competition for the drug elimination pathway.
    Felbamate: Based on very limited data, it appears felbamate can accelerate the clearance of the estrogen component of some oral contraceptives. Patients who experience breakthrough bleeding while receiving these drugs together should notify their prescribers. An alternate or additional form of contraception should be used during concomitant treatment. Additionally, patients taking non-oral combination contraceptives or estrogens or progestins for hormone replacement therapy may also experience reduced clinical efficacy; dosage adjustments may be necessary.
    Fosamprenavir: Clinically significant hepatic transaminase elevations may occur with concomitant use of fosamprenavir, boosted with ritonavir, and oral contraceptives; fosamprenavir should not be coadministered with oral contraceptives. Additionally, hormonal contraceptives, estrogens, and progestins may decrease the serum concentrations of fosamprenavir's active metabolite, amprenavir, which could lead to loss of virologic response and possible viral resistance. Oral contraceptives and non-oral combination contraceptives should not be administered with fosamprenavir. Alternative methods of non-hormonal contraception are recommended. Additionally, data on the effects that other protease inhibitors have on the serum concentrations of estrogens and progestins are complex; some protease inhibitors increase and others decrease the metabolism of hormonal contraceptives. Coadministration of medroxyprogesterone, a CYP3A substrate with fosamprenavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro. It is not known if fosamprenavir alters the metabolism of other hormonal contraceptives or other estrogen or progestin products. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms. In women receiving oral contraceptives containing drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors, such as atazanavir, long-term and concomitantly. Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium.
    Glimepiride: Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glimepiride; Pioglitazone: Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glimepiride; Rosiglitazone: Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glipizide: Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glipizide; Metformin: Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glyburide: Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glyburide; Metformin: Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Griseofulvin: The concurrent use of griseofulvin and oral contraceptives can reduce contraceptive efficacy and result in an unintended pregnancy and/or breakthrough bleeding. This risk is particularly serious because griseofulvin is contraindicated during pregnancy due to the risk of teratogenic and abortifacient effects. An alternate or additional form of contraception should be used during concomitant treatment and continued for 1 month after griseofulvin discontinuation. If these drugs are used together, counsel the patient about the risk of pregnancy and teratogenic effects, and instruct the patient to notify the prescriber if they experience breakthrough bleeding while receiving these drugs together. Additionally, patients taking non-oral combination contraceptives or progestins for hormone replacement therapy may also experience reduced clinical efficacy.
    Hydantoins: Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy.
    Incretin Mimetics: Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Indinavir: In one pharmacokinetic study of healthy male subjects, co-administration of megestrol acetate (675 mg/day for 14 days) and indinavir (a single dose 800 mg) resulted in a 32% decrease in the Cmax of indinavir and a 21% decrease in the AUC of indinavir. A higher dose of indinavir should be considered during concurrent use of megestrol acetate, although no specific dosing recommendations are available.
    Insulins: Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Linagliptin: Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Linagliptin; Metformin: Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Meglitinides: Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Mephobarbital: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Metformin: Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Metformin; Pioglitazone: Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Metformin; Repaglinide: Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Metformin; Rosiglitazone: Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Metformin; Saxagliptin: Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Metformin; Sitagliptin: Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Methohexital: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Modafinil: Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary.
    Nevirapine: Nevirapine may decrease plasma concentrations of oral contraceptives and non-oral combination contraceptives (i.e., ethinyl estradiol and norethindrone). However despite lower exposures, literature suggests that use of nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. Thus, the manufacturer states that no dose adjustments are needed when these drugs are used for contraception in combination with nevirapine. When these oral contraceptives are used for hormone replacement and given with nevirapine, the therapeutic effect of the hormonal therapy should be monitored.
    Oxcarbazepine: Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as oxcarbazepine. Concurrent administration of oxcarbazepine progestins may increase the hormone's elimination. A high percentage of breakthrough bleeding has been reported in the literature from the combined use of oxcarbazepine and oral contraceptives; the results of one study demonstrated that the mean AUC of ethinyl estradiol/levonorgestrel was decreased by 52% when coadministered with oxcarbazepine. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs, or higher-dose hormonal regimens may be indicated where acceptable or applicable as pregnancy has been reported in patients taking the hepatic enzyme inducing drug phenytoin concurrently with hormonal contraceptives. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on oxcarbazepine, with dose adjustments made based on clinical efficacy.
    Pentobarbital: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Phenobarbital: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Phentermine; Topiramate: Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Pioglitazone: Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    Pramlintide: Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): Either additive or antagonistic effects could potentially occur if prasterone is combined with progestins.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): Either additive or antagonistic effects could potentially occur if prasterone is combined with progestins.
    Primidone: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Rifamycins: Hepatic microsomal enzyme inducers, such as rifampin, rifabutin, or rifapentine can increase the rate of metabolism of the progestins. Since megestrol is a progestin-type hormone, it is possible that rifamycins could attenuate megestrol's effects. The effects of rifabutin on the pharmacokinetics of megestrol acetate were not studied by the manufacturer; however, megestrol did not alter rifabutin's pharmacokinetics.
    Rosiglitazone: Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Saxagliptin: Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Secobarbital: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Simvastatin; Sitagliptin: Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Sitagliptin: Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    St. John's Wort, Hypericum perforatum: It is possible that, as with other CYP3A4 inducers, St. John's Wort could reduce the therapeutic efficacy of progestin-only contraceptives. Women should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's Wort concurrently with their hormones. Avoidance of these combinations is recommended.
    Sulfonylureas: Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Thiopental: Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Tolazamide: Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Tolbutamide: Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Topiramate: Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Trospium: Both trospium and megestrol are eliminated by active renal tubular secretion; coadministration has the potential to increase serum concentrations of trospium or megestrol due to competition for the drug elimination pathway. Careful patient monitoring and dosage adjustment of trospium and/or megestrol is recommended.
    Warfarin: At high doses, megestrol may be associated alterations in warfarin pharmacokinetics. In one study, a small change in the rate of warfarin clearance was see with concomitant administration of high doses of megestrol; a minor decrease observed in warfarin clearance may be of clinical importance. Additionally, a 71% increase in warfarin's half-life was seen. Lower doses of warfarin may be necessary when megestrol is given.

    PREGNANCY AND LACTATION

    Pregnancy

    Megestrol is classified as FDA pregnancy risk category X (oral suspension) and category D (tablets); the different pregnancy risk ratings is based upon the need for the drug and patient risk: benefit ratios. In general, megestrol is contraindicated during known or suspected pregnancy. Genital abnormalities in male and female fetuses have been reported in women who had received progestational agents during the first trimester. In male fetuses, the risk of developing hypospadias is about doubled when fetuses are exposed to progestational agents; feminization may occur. The reproductive capability was impaired in rat or dog male offspring exposed to megestrol acetate in utero. In female fetuses, there is a risk of mild virilization of the external genitalia, however, there is insufficient data to quantify the risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Females of childbearing potential should be advised to avoid becoming pregnant while receiving megestrol treatment.

    Megestrol is known to be excreted in breast milk; amounts potentially reaching an infant per day are estimated to be 0.1% of the maternal daily ingested dose based on available data. Megestrol should not be used during breast-feeding since its effect to the neonate or nursing infant is not known. Alternate forms of feeding are recommended if megestrol therapy is essential to the mother.

    MECHANISM OF ACTION

    Mechanism of Action: Megestrol shares the properties of the progestins. The drug induces endometrial secretory changes, increases basal body temperature, inhibits pituitary function, and precipitates bleeding when estrogen is present. The mechanism of its antineoplastic activity is not known, but it has been suggested that megestrol-induced suppression of luteinizing hormone release from the pituitary may have a negative effect on cancerous tissues of the breast and endometrial lining. Megestrol enhances estrogen metabolism, which suppresses estrogen-dependent tumors by lowering plasma estrogen concentrations. Megestrol also may change the actively growing cancer cell stroma into decidua. Because megestrol promotes the differentiation and maintenance of endometrial tissue, it is effective in the therapy of endometriosis and endometrial cancer.The reported weight gain associated with megestrol therapy is believed to be due to the drug's metabolic and appetite-stimulatory effects rather than to its glucocorticoid activity. Megestrol, or its metabolites, may interfere with cachexin, the hormone that inhibits adipocyte lipogenic enzymes and leads to the wasting syndrome of AIDS or cancer. Weight gain occurs within 3 weeks in most patients who receive megestrol for this purpose.

    PHARMACOKINETICS

    Megestrol is administered orally. The drug is highly bound to plasma proteins, chiefly transcortin. Megestrol tends to concentrate in adipose tissue. Megestrol is inactivated by the liver; however, metabolites account for only 5% to 8% of the administered dose and are considered negligible. The major route of drug elimination in humans is the urine with a minor portion excreted in the feces; the urinary excretion within 10 days after administration ranges from 56.5% to 78.4% and fecal excretion ranges from 7.7% to 30.3%. Respiratory excretion and fat storage of metabolites may account for at least part of the radioactivity not found in urine and feces. During a pharmacokinetic evaluation of megestrol in healthy subjects, the mean elimination half-life ranged from 20 to 50 hours.

    Oral Route

    The relative bioavailability of the oral tablets to the oral suspension has not been determined. When both are administered under fed conditions, 625 mg (5 ml) of concentrated megestrol acetate suspension (125 mg/ml) is equivalent to 800 mg (20 ml) of regular megestrol acetate suspension (40 mg/ml). The bioavailability of the oral suspension (40 mg/ml) is higher when administered in the fed state (high fat meal) compared to the fasting state, with Cmax being 7-fold higher and the AUC being 2-fold higher. The bioavailability of the concentrated suspension (125 mg/ml) is also higher in the fed state (high fat meal), with AUC 36% higher and Cmax 48% higher. Whether the tablets are affected by food has not been established. Megestrol appears to be rapidly absorbed across the GI tract, with a bioavailability of > 90%, although this varies significantly among individual patients. Peak concentrations after administration of the suspension are reached in approximately 3—5 hours; peak concentrations for the tablets are reached in 1—3 hours.