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  • CLASSES

    Cytostatic Progestogens
    Progestogen Only Contraceptives
    Progestogens

    BOXED WARNING

    Breast cancer, cervical cancer, endometrial cancer, endometrial hyperplasia, new primary malignancy, ovarian cancer, uterine cancer, vaginal bleeding, vaginal cancer

    Medroxyprogesterone contraceptive injections and oral tablets are contraindicated in patients with pre-existing breast cancer. The oral tablets are contraindicated in any other known or suspected estrogen- or progestin-dependent neoplasia, including cervical cancer, endometrial cancer, uterine cancer, or vaginal cancer. Medroxyprogesterone depot injection suspension for the treatment of endometrial or renal cancer should generally not be used in women with a history of breast cancer, as breast cancer may be hormonally sensitive. Women with a strong family history of breast cancer should be monitored with particular care. Do not use medroxyprogesterone products in patients with undiagnosed abnormal genital or vaginal bleeding. HORMONE REPLACEMENT THERAPY (HRT): The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer (new primary malignancy of the breast) in postmenopausal women receiving HRT. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms, requiring further evaluation. All women taking estrogen with or without a progestin should receive an annual clinical breast examination, perform monthly self-examinations, and have regular mammograms as recommended by their health care professional based on patient age, risk factors, and prior mammogram results. The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of CE (0.625 mg/day) plus MPA (2.5 mg/day).[27530] [27272] After a mean follow-up of 5.6 years, the WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups.[27530] Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. Adding a progestin such as medroxyprogesterone to estrogen therapy has been shown to reduce, but not completely eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen plus progestin therapy is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95% CI, 0.77 to 3.24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association. MEDROXYPROGESTERONE CONTRACEPTIVE INJECTIONS: The relative risk of developing breast cancer in patients receiving depot medroxyprogesterone for contraception has been investigated in a number of trials. Among 5 epidemiologic studies assessing the associated risk, three of the studies suggested a slightly increased risk of breast cancer in the overall population of users. Data from one study (n = 1028) of women 20 to 44 years of age, receiving depo-medroxyprogesterone acetate, showed that recent use (last use within the previous 5 years) for 12 months or longer was associated with a 2.2-fold (95% CI: 1.2 to 4.2) increased risk of invasive breast cancer.

    Acquired immunodeficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection, sexually transmitted disease

    Patients should be counseled that medroxyprogesterone contraceptive injections do not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted disease. Conversely, patients with known HIV infection or acquired immunodeficiency syndrome (AIDS) should be aware that the use of medroxyprogesterone depot-injection will not prevent the transmission of HIV or other diseases to their partner(s).

    Dementia, geriatric

    Estrogen/progestin combination therapy does not prevent mild cognitive impairment (memory loss) and has been found to increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in geriatric women (65 years of age or older), reported similar rates of developing mild cognitive impairment in those receiving active treatment vs. placebo. Also, patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic adult women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory).

    Alcoholism, anorexia nervosa, corticosteroid therapy, osteopenia, osteoporosis

    Medroxyprogesterone contraceptive depot-injections carry a boxed warning regarding bone mineral density reductions (osteopenia) in pre-menopausal women. Women using medroxyprogesterone contraceptive injections may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of these contraceptive injections during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporosis and osteoporotic fracture in later life. Women should not use medroxyprogesterone injections as a long-term birth control method (i.e., longer than 2 years) unless other birth control methods are considered inadequate. Consider alternative methods of contraception in women with osteoporosis risk factors (e.g., metabolic bone disease, chronic alcohol use, alcoholism, anorexia nervosa, strong family history of osteoporosis, tobacco smoking, or chronic use of drugs that can reduce bone mass, such as anticonvulsants or chronic corticosteroid therapy). While there are no studies available which address the usefulness of calcium and vitamin D to lessen BMD loss in women using medroxyprogesterone depot-injections, all patients should have adequate calcium and vitamin D intake. OTHER USES: BMD evaluation may also be appropriate in patients who use higher doses of depot medroxyprogesterone injections for long-term treatment of endometrial or renal cancers, due to a potential risk for loss of bone mineral density.

    DEA CLASS

    Rx

    DESCRIPTION

    Synthetic progestin 15 times more potent than progesterone; used for endocrine disorders; prevents endometrial hyperplasia from HRT with estrogens; acts as a respiratory stimulant in some pulmonary conditions; depot injections are used for contraception or for endometrial or renal cancer.

    COMMON BRAND NAMES

    Amen, Depo-Provera, Depo-subQ Provera 104, Provera

    HOW SUPPLIED

    Amen/Medroxyprogesterone/Medroxyprogesterone Acetate/Provera Oral Tab: 2.5mg, 5mg, 10mg
    Depo-Provera/Medroxyprogesterone/Medroxyprogesterone Acetate Intramuscular Inj Susp: 1mL, 150mg, 400mg
    Depo-subQ Provera 104 Subcutaneous Inj Susp: 0.65mL, 104mg

    DOSAGE & INDICATIONS

    For the treatment of secondary amenorrhea.
    Oral dosage
    Adult and Adolescent females

    5 to 10 mg PO once daily for 5 to 10 days, starting anytime during the cycle; but usually started during the latter half of the cycle (days 16 to 21). If the endometrium has been primed with estrogens, administer 10 mg PO once daily for 10 days starting on the 16th day of the cycle. Progestin withdrawal bleeding usually occurs 3 to 7 days after discontinuation of therapy.

    For the treatment of dysfunctional uterine bleeding due to hormonal imbalance, in the absence of organic pathology such as fibroids or uterine cancer.
    Oral dosage
    Adult and Adolescent females

    5 to 10 mg PO once daily for 5 to 10 days during the latter half of the cycle (days 16 to 21). If the endometrium has been primed with estrogens, administer 10 mg PO once daily for 10 days starting on the 16th day of the cycle. Progestin withdrawal bleeding usually occurs 3 to 7 days after discontinuation of therapy.

    For routine contraception.
    Intramuscular dosage (e.g., medroxyprogesterone acetate contraceptive Injection 150 mg/mL, Depo-Provera Contraceptive)
    Adult and Adolescent females

    150 mg (using 150 mg/mL depot contraceptive injection suspension) IM every 3 months. Initial dose is given within 5 days postpartum or the onset of menses. A woman who is breast-feeding should optimally wait until 6 weeks postpartum before receiving this product. For subsequent IM doses, if more than 13 weeks have passed, determine the patient is not pregnant before dosing. When considering long term use (i.e., more than 2 years), also consider the impact on peak bone mass in adolescents and bone mineral density (BMD) loss in women of all ages, along with the decrease in BMD that occurs during pregnancy and/or lactation.

    Subcutaneous dosage (e.g., medroxyprogesterone acetate 104 mg/0.65 mL depot injection, Depo-subQ Provera 104 Injection)
    Adult and Adolescent females

    104 mg (using 104 mg/0.65 mL prefilled syringe) subcutaneously into the anterior thigh or abdomen every 3 months. Initial dose is given within 5 days of the onset of menses and during or after the sixth postpartum week in breast-feeding women. For subsequent subcutaneous doses, if more than 14 weeks have passed, determine the patient is not pregnant before dosing. When considering long term use (i.e., more than 2 years), also consider the impact on peak bone mass in adolescents and bone mineral density (BMD) loss in women of all ages, along with the decrease in BMD that occurs during pregnancy and/or lactation.

    For the treatment of endometriosis-associated pain.
    Subcutaneous dosage (e.g., medroxyprogesterone acetate 104 mg/0.65 mL injection, Depo-subQ Provera 104 Injection)
    Adult and Adolescent females

    104 mg (using 104 mg/0.65 mL prefilled syringe) subcutaneously every 3 months. Initial dose is given within 5 days of the onset of menses and during or after the sixth postpartum week in breast-feeding women. For subsequent doses, if more than 14 weeks have passed, determine the patient is not pregnant before dosing. Treatment for longer than 2 years is not recommended, due to the impact on peak bone mass in adolescents and bone mineral density (BMD) in women of all ages. If symptoms of endometriosis recur upon discontinuation, evaluate BMD before considering retreatment. Endometriosis treatment guidelines recommend progestins, including medroxyprogesterone, as options for reducing endometriosis-associated pain.

    Oral dosage†
    Adult and Adolescent females

    10 mg PO once daily for 10 days a month (e.g., from day 16 to 25 of the menstrual cycle) for 3 months. Treatment guidelines recommend progestogens, including medroxyprogesterone, as options for reducing endometriosis-associated pain. Although many oral progestogen regimens have been studied, current practice is to use regimens with a lower dose and for a shorter duration.

    For the treatment of inoperable, recurrent, and metastatic endometrial cancer or renal cell cancer.
    Intramuscular dosage (depot medroxyprogesterone injection suspension 400 mg/mL)
    Adults

    Initially, 400 mg to 1 g IM (using 400 mg/mL depot medroxyprogesterone injection suspension). Repeat at weekly intervals. When improvement or stabilization occurs, it may be possible to reduce dosage to as little as 400 mg/month IM.

    For the prevention of endometrial hyperplasia associated with estrogen replacement therapy in postmenopausal women with an intact uterus.
    Oral dosage
    Adult females with an intact uterus

    5 to 10 mg PO once daily for 10 to 14 or more days each month for females with an intact uterus in whom estrogen is given in a sequential manner (e.g., withdrawal bleeding is expected). Alternatively, if estrogens are administered continuously each day, take 2.5 to 5 mg PO once daily (when withdrawal bleeding not desirable).

    For the treatment of hypoventilation due to obesity-hypoventilation syndrome† (Pickwickian syndrome†).
    Oral dosage
    Adults

    Dosage not established. 20 mg PO 3 times per day is a commonly reported dosage. The results of treatment have been contradictory; some studies have reported improvements in oxygenation and ventilation, others have not. Randomized controlled trials are needed to define efficacy and safety, since medroxyprogesterone can increase the risk for thromboembolism in at-risk patients.

    For the treatment of hot flashes† due to menopause†.
    Oral dosage
    Adult females

    Various doses have been reported; a common dose is 10 mg or 20 mg PO once daily. Several clinical trials have demonstrated the effectiveness of medroxyprogesterone in significantly reducing the number of daily hot flashes in postmenopausal women. The North American Menopause Society (NAMS) Guidelines recommend the short-term use of progestin monotherapy in women who do not want to use or who have contraindications to the use of estrogens and do not have contraindications to progestin therapy and find the potential risks of progestin therapy acceptable. No long term studies have addressed the safety of progestin-only treatment on menopause symptoms.

    Intramuscular dosage (depot suspension injection)
    Adult females

    Various doses have been reported. 150 mg IM once every month reduced hot flashes by 90% compared to baseline compared to 25% with placebo. In another study, a single 400 mg IM injection of medroxyprogesterone was compared to venlafaxine 75 mg/day PO. Hot flash scores were reduced by 79% in the medroxyprogesterone arm compared to 55% in the venlafaxine arm after 6 weeks (p less than 0.0001). In addition, significantly more patients receiving medroxyprogesterone had a decrease in hot flashes by 50% compared to baseline (74% for medroxyprogesterone vs. 46% for venlafaxine, p less than 0.0001). Of note, 61% of the women in this trial had a history of breast cancer. Lower doses (e.g., 150 mg) administered IM once every 3 months have also been shown to be effective. The North American Menopause Society (NAMS) Guidelines recommend the short-term use of progestin monotherapy in women who do not want to use or who have contraindications to the use of estrogens and do not have contraindications to progestin therapy and find the potential risks of progestin therapy acceptable. No long term studies have addressed the safety of progestin-only treatment on menopause symptoms.

    For use to reduce the rate of decline in bone mineral density and to control biochemical indices of mild primary hyperparathyroidism† in postmenopausal women.
    Oral dosage
    Adult females with an intact uterus

    In one study of 42 postmenopausal women with mild primary hyperparathyroidism, conjugated estrogens 0.625 mg with medroxyprogesterone 5 mg PO once daily for 2 years improved bone mineral density and biochemical markers of bone turnover compared to placebo.

    For the management of paraphilia† (atypical or extreme compulsive sexual behaviors†) in men.
    Intramuscular dosage
    Adult males†

    Dosage is not established. The evidence for effective dosing is lacking due to the lack of controlled trials and need for individualization of dose to response. Secondary outcomes are often reported in the small trials available, such as reduction in sexual fantasy or other compulsive behavior, rather than reduction in sexual offending. Initial doses are usually given once weekly. Maintenance doses range from 200 to 600 mg IM weekly, biweekly, or monthly and are usually adjusted based on patient sexual response, tolerance, and/or plasma testosterone levels. In one open-label study, male patients with long-standing histories of deviant sexual behavior (n = 48) received weekly medroxyprogesterone acetate IM (dose individualized) along with therapy for up to 12 months. Forty subjects responded positively, all within 3 weeks, with diminished frequency of sexual fantasies and arousal, decreased desire for deviant sexual behavior, increased control over sexual urges, and improvement in psychosocial functioning.

    For the treatment of hot flashes† due to prostate cancer† and associated induced androgen deficiency† ("andropause†") in men who have had surgical or medication induced castration.
    Intramuscular dosage
    Adult males

    Dosage is not established. 150 mg or 400 mg IM as needed (once monthly or for a longer duration between doses) based on patient-reported symptoms has been used. In a retrospective review, 91% of 48 patients that received either 150 mg IM or 400 mg IM reported an improvement in hot flashes, with 46% reporting elimination of hot flashes. Patients received additional injections based on symptoms; in general, patients received a median of 4 injections over a 43 month period. Statistical differences between the 2 dosages were not noted; however, the power for detecting a difference between the 2 groups was small because only 8 patients received the 150 mg dose. Only those patients receiving 400 mg IM reported a complete response.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Dependent on product used and indication for therapy.

    Elderly

    Dependent on product used and indication for therapy.

    Adolescents

    Dependent on product used and indication for therapy.

    Children

    Not indicated in prepubescent children.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Elimination of medroxyprogesterone is reduced in patients with alcoholic cirrhosis; the oral dose may need to be lowered in patients with significant hepatic impairment. No guidelines are available for the injectable formulations. In general, progestins such as medroxyprogesterone should be avoided in patients with hepatic dysfunction.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Oral Administration
    Oral Solid Formulations

    Medroxyprogesterone tablets may be administered without regard to meals.
    When needed, tablets may be administered sublingually†; absorption is adequate by this route.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intramuscular Administration

    Depo-Provera Contraceptive injection suspension:
    For IM administration only, NEVER administer intravenously (IV).
    Instruct patient on risks and warnings associated with hormonal contraceptives (see Patient Information).
    The possibility of pregnancy should be excluded prior to giving the first dose of medroxyprogesterone or whenever more than 14 weeks has passed since the last dose.
    Do not dilute.
    Shake vigorously immediately before administration.
    Inject deeply into the gluteal or deltoid muscle.
     
    Depo-Provera Sterile Aqueous Suspension, preserved:
    For IM administration only, NEVER administer intravenously (IV).
    Instruct patient on risks and warnings associated with progestin use (see Patient Information).
    Shake vigorously immediately before administration.
    When multi-dose vials are used, special care to prevent contamination of the contents is essential.
    Inject medroxyprogesterone deeply into the gluteal or deltoid muscle.

    Subcutaneous Administration

    Depo-subQ provera 104 Contraceptive injection suspension ONLY:
    For subcutaneous (SC) administration only, NEVER administer intramuscularly (IM) or intravenously (IV).
    Instruct patient on risks and warnings associated with hormonal contraceptives (see Patient Information).
    Shake vigorously for at least 1 minute immediately before administration.
    Inject the entire contents of the prefilled medroxyprogesterone syringe SC into the anterior thigh or abdomen, avoiding boney areas and the umbilicus. Gently grasp and squeeze a large areas of skin in the chosen injection area ensuring that the skin is pulled away from the body. Insert the needle at a 45 degree angle. Inject the medication until the syringe is empty; this usually requires 5—7 seconds. Following administration, press lightly on the injection site with a clean cotton pad for a few seconds; do not rub the area.

    STORAGE

    Amen:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Depo-Provera:
    - Discard unused portion. Do not store for later use.
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store upright
    Depo-subQ Provera 104:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Provera:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    History of angioedema

    Medroxyprogesterone acetate products are contraindicated in patients with a known hypersensitivity to medroxyprogesterone acetate or any of the product ingredients, including history of anaphylaxis or history of angioedema to medroxyprogesterone acetate. Cases of both anaphylactic reactions and angioedema have been reported in patients receiving medroxyprogesterone acetate.

    Intravenous administration

    Medroxyprogesterone acetate depot injections are suspensions that are either administered intramuscularly or subcutaneously depending on the formulation. Never administer via intravenous administration; intravenous administration may result in serious adverse reactions.

    Breast cancer, cervical cancer, endometrial cancer, endometrial hyperplasia, new primary malignancy, ovarian cancer, uterine cancer, vaginal bleeding, vaginal cancer

    Medroxyprogesterone contraceptive injections and oral tablets are contraindicated in patients with pre-existing breast cancer. The oral tablets are contraindicated in any other known or suspected estrogen- or progestin-dependent neoplasia, including cervical cancer, endometrial cancer, uterine cancer, or vaginal cancer. Medroxyprogesterone depot injection suspension for the treatment of endometrial or renal cancer should generally not be used in women with a history of breast cancer, as breast cancer may be hormonally sensitive. Women with a strong family history of breast cancer should be monitored with particular care. Do not use medroxyprogesterone products in patients with undiagnosed abnormal genital or vaginal bleeding. HORMONE REPLACEMENT THERAPY (HRT): The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer (new primary malignancy of the breast) in postmenopausal women receiving HRT. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms, requiring further evaluation. All women taking estrogen with or without a progestin should receive an annual clinical breast examination, perform monthly self-examinations, and have regular mammograms as recommended by their health care professional based on patient age, risk factors, and prior mammogram results. The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of CE (0.625 mg/day) plus MPA (2.5 mg/day).[27530] [27272] After a mean follow-up of 5.6 years, the WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups.[27530] Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. Adding a progestin such as medroxyprogesterone to estrogen therapy has been shown to reduce, but not completely eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen plus progestin therapy is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95% CI, 0.77 to 3.24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association. MEDROXYPROGESTERONE CONTRACEPTIVE INJECTIONS: The relative risk of developing breast cancer in patients receiving depot medroxyprogesterone for contraception has been investigated in a number of trials. Among 5 epidemiologic studies assessing the associated risk, three of the studies suggested a slightly increased risk of breast cancer in the overall population of users. Data from one study (n = 1028) of women 20 to 44 years of age, receiving depo-medroxyprogesterone acetate, showed that recent use (last use within the previous 5 years) for 12 months or longer was associated with a 2.2-fold (95% CI: 1.2 to 4.2) increased risk of invasive breast cancer.

    Diabetes mellitus

    Medroxyprogesterone should be used cautiously in patients with diabetes mellitus. Although the effects appear to be minimal during therapy with progestins, altered glucose tolerance secondary to decreased insulin sensitivity has been reported during hormonal contraception and during hormonal replacement therapy (HRT). Monitor blood glucose routinely, and manage risk factors for heart disease to help reduce cardiovascular risks in patients with diabetes receiving hormonal therapy.

    Cerebrovascular disease, coronary artery disease, hypercholesterolemia, hypertension, myocardial infarction, obesity, stroke, thromboembolic disease, thromboembolism, thrombophlebitis, tobacco smoking, visual disturbance

    Medroxyprogesterone injections are contraindicated in patients with active or a history of thrombophlebitis. Medroxyprogesterone oral and injectable dose forms are contraindicated in patients with active arterial or venous thromboembolic disease (e.g., thromboembolism, deep venous thrombosis, pulmonary embolism, myocardial infarction (MI), cerebrovascular disease and stroke) or a history of these conditions. Patients with risk factors for heart disease, arterial vascular disease, thromboembolism, and stroke (e.g., hypertension, diabetes mellitus, tobacco smoking, hypercholesterolemia, obesity, etc.) should be monitored closely and managed appropriately. During use of medroxyprogesterone in patients without a history of thrombosis, the provider should be alert to the earliest manifestations of thrombotic disorder (thrombophlebitis, heart attack, cerebrovascular disorder such as stroke or focal headache with symptoms consistent with cerebral ischemia, pulmonary embolism, or unexplained visual disturbance with ocular pain, which might indicate retinal thrombosis). Should any of these occur or be suspected, medroxyprogesterone therapy should be discontinued immediately; with depot-injections, the effects of the hormone may persist for some time after discontinuation. HORMONAL REPLACEMENT THERAPY: Medroxyprogesterone, when used with estrogen therapy for postmenopausal hormone replacement, is associated with cardiovascular and thromboembolic risks. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen (conjugated estrogens) plus progestin (medroxyprogesterone) HRT compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. Estrogens with or without a progestin such as medroxyprogesterone should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease) in postmenopausal women. In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. Studies have also shown no cardiovascular benefit to the use of estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD. In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke. MEDROXYPROGESTERONE CONTRACEPTIVE INJECTIONS: Despite the contraindication against use of medroxyprogesterone injection in patients with known active or history of thrombotic disease, progestin-only contraceptives are generally the hormonal contraceptives of choice in patients with a potential risk for thrombosis when reliable contraception must be ensured and the risks of hormonal therapy are acceptable; advantages of these methods usually outweigh proven or theoretical risks. When multiple thrombosis risk factors exist, the risk of thromboembolic disease may increase; determine risk vs. benefit for use of the progestin-only contraceptive. The increase in the risk of thrombosis from newer progestin-only contraceptives (e.g., etonorgestrel implants) is still substantially less than with combined oral contraceptives containing both estrogen and progestin. For women who are at an increased risk of thromboembolism and have multiple-risk factors for thrombosis, consider an IUD or other estrogen-free contraceptive if appropriate. Use with caution in patients with pre-existing hypertension. A woman who is taking a hormonal contraceptive should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

    Hyperlipidemia

    Medroxyprogesterone should be used cautiously in patients with hyperlipidemia. Although hyperlipidemia is associated with estrogen-progestin combinations, the effects of progestin-only oral contraceptives on serum lipids have not been studied. Serum lipoproteins (HDL and LDL) should be monitored during therapy with medroxyprogesterone.

    Ectopic pregnancy, infertility, pregnancy

    Medroxyprogesterone is contraindicated for use during known pregnancy or suspected pregnancy. Although the drug should not be used during pregnancy, there appears to be little or no increased risk of birth defects in women who have inadvertently been exposed to medroxyprogesterone acetate contraceptive injections in early pregnancy. Newborns exposed to medroxyprogesterone acetate in-utero and followed to adolescence showed no evidence of any adverse effects on their health including their physical, intellectual, sexual or social development. There may be an increased risk of minor birth defects in pediatric patients whose mothers are exposed to medroxyprogesterone tablets during the first 4 months of pregnancy, such as hypospadias, clitoral enlargement and labial fusion; however a clear association between these conditions and the use of the drug has not been established. It is not known whether other forms of medroxyprogesterone acetate (such as the injection dose used for cancer) can cause fetal harm when administered to a pregnant woman; use this cancer treatment during pregnancy only if clearly needed and the benefits to the mother outweigh potential fetal risks. Be alert to the possibility of an ectopic pregnancy among women using medroxyprogesterone contraceptive injections who complain of severe abdominal pain or become pregnant during use. Medroxyprogesterone contraceptive injections should not be used if there is a history of ectopic pregnancy or in diagnostic tests for pregnancy. When used in high doses, medroxyprogesterone acetate depot suspension injection is an anti-fertility drug in females, inducing temporary infertility, and a return to ovulation and baseline fertility may be delayed after stopping treatment. Available surveillance data suggest that the median time to conception for those who do conceive is 10 months following the last medroxyprogesterone contraceptive injection with a range of 4 to 31 months, and is unrelated to the duration of use.

    Incomplete abortion, menstrual irregularity

    Medroxyprogesterone tablets are contraindicated in incomplete abortion. Medroxyprogesterone contraceptive injections can cause irregular menstrual bleeding in most women. In general, these irregularities diminish with continuing use. Women should be counseled regarding menstrual irregularity.

    Cholestasis, hepatic disease, jaundice

    Combination estrogen-progestin oral contraceptives are classified as carcinogenic to humans in the development of hepatic cancer by the World Health Organization, International Agency for Research on Cancer (WHO IARC). Because of this association, medroxyprogesterone is contraindicated in patients with hepatic dysfunction or hepatic disease; specifically, the injectable medroxyprogesterone acetate (Depot-Provera) for contraception, is contraindicated for use in patients with severe hepatic disease. Medroxyprogesterone for palliative care should not be used by women with significant liver disease and should be discontinued if jaundice or disturbances of liver function occur. Use medroxyprogesterone with caution in patients with a past history of cholestasis and jaundice associated with past estrogen use or with pregnancy. If hepatic adverse events recur following medroxyprogesterone administration, consider discontinuation. 

    Breast-feeding

    Medroxyprogesterone contraceptive injections may be used safely during breast-feeding. Detectable amounts of drug have been identified in the milk of mothers receiving contraceptive injections of medroxyprogesterone. However, in nursing mothers, milk composition, quality, and amount are not adversely affected. Neonates and infants exposed to medroxyprogesterone from breast milk have been studied for developmental and behavioral effects through puberty. No adverse effects have been identified. Alternatives include other progestin-only contraceptives, such as norethindrone oral contraceptive pills. Other dosage forms, such as the medroxyprogesterone suspension injection for cancer treatment, or medroxyprogesterone tablets, are recommended to be avoided during lactation.

    Asthma, renal disease

    Medroxyprogesterone should be prescribed cautiously in patients with asthma, congestive heart failure, nephrotic syndrome or other renal disease, or cardiac disease. Hormonal contraceptives can cause fluid retention and may exacerbate any of the above conditions.

    Depression, migraine, seizure disorder

    Medroxyprogesterone should be used cautiously in patients with a history of major depression, migraine, or seizure disorder. Progestins may exacerbate these conditions in some patients. If a patient receiving medroxyprogesterone develops changes in migraine patterns, or a focal migraine with symptoms consistent with cerebral ischemia, or a severe headache pattern that may indicate a cerebrovascular disorder, consider discontinuation of the drug.

    Acquired immunodeficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection, sexually transmitted disease

    Patients should be counseled that medroxyprogesterone contraceptive injections do not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted disease. Conversely, patients with known HIV infection or acquired immunodeficiency syndrome (AIDS) should be aware that the use of medroxyprogesterone depot-injection will not prevent the transmission of HIV or other diseases to their partner(s).

    Dementia, geriatric

    Estrogen/progestin combination therapy does not prevent mild cognitive impairment (memory loss) and has been found to increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in geriatric women (65 years of age or older), reported similar rates of developing mild cognitive impairment in those receiving active treatment vs. placebo. Also, patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic adult women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory).

    Hypocalcemia, porphyria, systemic lupus erythematosus (SLE)

    Estrogen plus progestin therapy should be used with caution in individuals with severe hypocalcemia. In addition, combination hormonal therapy may cause an exacerbation of porphyria and systemic lupus erythematosus (SLE) and should be used with caution in women with these conditions.

    Alcoholism, anorexia nervosa, corticosteroid therapy, osteopenia, osteoporosis

    Medroxyprogesterone contraceptive depot-injections carry a boxed warning regarding bone mineral density reductions (osteopenia) in pre-menopausal women. Women using medroxyprogesterone contraceptive injections may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of these contraceptive injections during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporosis and osteoporotic fracture in later life. Women should not use medroxyprogesterone injections as a long-term birth control method (i.e., longer than 2 years) unless other birth control methods are considered inadequate. Consider alternative methods of contraception in women with osteoporosis risk factors (e.g., metabolic bone disease, chronic alcohol use, alcoholism, anorexia nervosa, strong family history of osteoporosis, tobacco smoking, or chronic use of drugs that can reduce bone mass, such as anticonvulsants or chronic corticosteroid therapy). While there are no studies available which address the usefulness of calcium and vitamin D to lessen BMD loss in women using medroxyprogesterone depot-injections, all patients should have adequate calcium and vitamin D intake. OTHER USES: BMD evaluation may also be appropriate in patients who use higher doses of depot medroxyprogesterone injections for long-term treatment of endometrial or renal cancers, due to a potential risk for loss of bone mineral density.

    Children, infants, neonates

    The safety and efficacy of medroxyprogesterone in children below age 12 years have not been established; there is no known use of the hormone in infants or neonates. The safety and efficacy of hormonal contraceptive products have only been established in females of reproductive age. Safety and efficacy of hormonal birth control is expected to be the same for postpubertal children under the age of 16 and for users 16 years of age and older; medroxyprogesterone depot-contraceptive injection and other depot-injections are associated with a significant loss of bone mineral density, which is of particular concern during the critical period of bone accretion: adolescence and early adulthood. It is unknown if use of medroxyprogesterone depot-injections by young menarchal women will reduce peak bone mass and increase the risk of osteoporotic fractures in later life. Use of hormonal contraceptive products in female children before menarche is not indicated.

    ADVERSE REACTIONS

    Severe

    skin atrophy / Delayed / 1.0-1.0
    anaphylactic shock / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    seizures / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    retinal thrombosis / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    stroke / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known
    porphyria / Delayed / Incidence not known
    dementia / Delayed / Incidence not known
    ovarian cancer / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    endometrial cancer / Delayed / Incidence not known
    breast cancer / Delayed / Incidence not known

    Moderate

    hot flashes / Early / 1.0-5.0
    depression / Delayed / 1.0-5.0
    edema / Delayed / 2.2-2.2
    fluid retention / Delayed / 2.2-2.2
    vaginitis / Delayed / 1.2-1.2
    cystitis / Delayed / Incidence not known
    postmenopausal bleeding / Delayed / Incidence not known
    cervical dysplasia / Delayed / Incidence not known
    anovulation / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    dyspareunia / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known
    migraine / Early / Incidence not known
    euphoria / Early / Incidence not known
    cholestasis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    lipodystrophy / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    osteopenia / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hypercalcemia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    impaired cognition / Early / Incidence not known
    vaginal bleeding / Delayed / Incidence not known
    endometrial hyperplasia / Delayed / Incidence not known

    Mild

    headache / Early / 9.0-16.5
    abdominal pain / Early / 1.0-11.2
    emotional lability / Early / 1.0-10.0
    dizziness / Early / 0-5.6
    libido decrease / Delayed / 5.5-5.5
    menorrhagia / Delayed / 1.0-5.0
    dysmenorrhea / Delayed / 1.0-5.0
    acne vulgaris / Delayed / 1.0-5.0
    insomnia / Early / 1.0-5.0
    irritability / Delayed / 1.0-5.0
    anxiety / Delayed / 1.0-5.0
    diarrhea / Early / 1.0-5.0
    nausea / Early / 1.0-5.0
    injection site reaction / Rapid / 0-5.0
    back pain / Delayed / 1.0-5.0
    asthenia / Delayed / 1.0-5.0
    fatigue / Early / 4.2-4.2
    muscle cramps / Delayed / 3.7-3.7
    leukorrhea / Delayed / 2.9-2.9
    mastalgia / Delayed / 2.8-2.8
    alopecia / Delayed / 1.1-1.1
    arthralgia / Delayed / 1.0-1.0
    breakthrough bleeding / Delayed / 10.0
    amenorrhea / Delayed / 10.0
    menstrual irregularity / Delayed / 10.0
    weight gain / Delayed / 10.0
    oligomenorrhea / Delayed / Incidence not known
    pelvic pain / Delayed / Incidence not known
    breast discharge / Delayed / Incidence not known
    breast enlargement / Delayed / Incidence not known
    libido increase / Delayed / Incidence not known
    rash / Early / Incidence not known
    hirsutism / Delayed / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    melasma / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    drowsiness / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    polydipsia / Early / Incidence not known
    appetite stimulation / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known
    syncope / Early / Incidence not known
    skin discoloration / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    fever / Early / Incidence not known
    malaise / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Major) 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: (Major) 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: (Major) 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: (Minor) 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.
    Acitretin: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations). It is not known if acitretin also interacts with other progestational contraceptives, such as medroxyprogesterone injectables, or if this method is an adequate method of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Alogliptin: (Minor) 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: (Minor) 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. (Minor) 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: (Minor) 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: (Minor) 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: (Major) 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: (Major) Oral contraceptives and non-oral combination contraceptives should not be administered with amprenavir. Alternative methods of non-hormonal contraception are recommended. Clinically significant hepatic enzyme (transaminase) elevations may occur with concomitant use. Additionally, hormonal contraceptives, estrogens, and progestins may decrease the serum concentrations of amprenavir, which could lead to loss of virologic response and possible viral resistance. 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 amprenavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. It is not known if amprenavir 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 the progestin drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors concomitantly.
    Apalutamide: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers.
    Aprepitant, Fosaprepitant: (Major) 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: (Major) 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.
    Artemether; Lumefantrine: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e. medroxyprogesterone). This may be due to a CYP3A4 interaction. Additional use of a non-hormonal method of birth control is recommended.
    Aspirin, ASA; Butalbital; Caffeine: (Major) 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: (Major) 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: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with atazanavir, 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.
    Atazanavir; Cobicistat: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with atazanavir, 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. (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with medroxyprogesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. 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: (Major) 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: (Major) 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: (Major) 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: (Major) 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: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. 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 and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) 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.
    Brigatinib: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with medroxyprogesterone and brigatinib, and for at least 4 months after the final dose of brigatinib. Medroxyprogesterone is a CYP3A4 substrate. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Coadministration with brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Bromocriptine: (Minor) 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: (Major) 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: (Minor) 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: (Major) 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.
    Ceritinib: (Moderate) Use caution if coadministration of ceritinib with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Ceritinib is a strong CYP3A4 inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4.
    Chlorpropamide: (Minor) 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: (Major) 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: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with medroxyprogesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. 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: (Minor) 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: (Minor) 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. (Minor) 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.
    Dapagliflozin; Saxagliptin: (Minor) 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. (Minor) 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.
    Darunavir; Cobicistat: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with medroxyprogesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. 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.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with medroxyprogesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. 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.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with ritonavir, 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.
    Elbasvir; Grazoprevir: (Moderate) Administering medroxyprogesterone with elbasvir; grazoprevir may result in elevated medroxyprogesterone plasma concentrations. Medroxyprogesterone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with medroxyprogesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. 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.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with medroxyprogesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. 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.
    Empagliflozin: (Minor) 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: (Minor) 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. (Minor) 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: (Minor) 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. (Minor) 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.
    Enzalutamide: (Major) Avoid coadministration of enzalutamide with progestins if used for contraception; consider an alternate or additional form of contraception. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Higher-dose hormonal regimens may be indicated where acceptable or applicable. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers. Progestins are substrates of CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations.
    Ertugliflozin; Metformin: (Minor) 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.
    Ertugliflozin; Sitagliptin: (Minor) 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.
    Felbamate: (Major) 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.
    Fluvoxamine: (Moderate) Coadministration of medroxyprogesterone, a CYP3A substrate, with fluvoxamine, a moderate CYP3A inhibitor, may result in an increase in concentrations of medroxyprogesterone. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via CYP3A4 in vitro.
    Fosamprenavir: (Major) Oral contraceptives and non-oral combination contraceptives should not be administered with fosamprenavir. Alternative methods of non-hormonal contraception are recommended. Fosamprenavir should not be coadministered with oral contraceptives as clinically significant hepatic enzyme (transaminase) elevations may occur with concomitant use. 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. 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. 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 the progestin drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors concomitantly.
    Glimepiride: (Minor) 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: (Minor) 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: (Minor) 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: (Minor) 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: (Minor) 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. (Minor) 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: (Minor) 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: (Minor) 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. (Minor) 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.
    Grapefruit juice: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with grapefruit juice, 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.
    Griseofulvin: (Major) 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: (Major) 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.
    Idelalisib: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with idelalisib, 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.
    Incretin Mimetics: (Moderate) 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: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with indinavir, 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. Indinavir also decreases the metabolism of oral contraceptives and non-oral combination contraceptives; the AUC for ethinyl estradiol and norethindrone increased by 24+/-17% and 26+/-14%, respectively, when coadministered with indinavir. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as indinavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives with PIs should use an additional barrier method of contraception such as condoms.
    Insulins: (Minor) 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.
    Isotretinoin: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.
    Itraconazole: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with itraconazole, 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.
    Ivosidenib: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
    Ketoconazole: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with ketoconazole, 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.
    Lesinurad: (Major) Hormonal contraceptives, including combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins. This includes injectable, transdermal, and implantable forms. Hormonal contraceptives may not be reliable when coadministered with lesinurad. Females should use additional, non-hormonal methods of contraception and not rely solely on hormonal contraceptive methods when taking lesinurad.
    Lesinurad; Allopurinol: (Major) Hormonal contraceptives, including combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins. This includes injectable, transdermal, and implantable forms. Hormonal contraceptives may not be reliable when coadministered with lesinurad. Females should use additional, non-hormonal methods of contraception and not rely solely on hormonal contraceptive methods when taking lesinurad.
    Letermovir: (Moderate) An increase in the plasma concentration of medroxyprogesterone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Avoid coadministration of medroxyprogesterone in patient receiving both letermovir and cyclosporine as this may increase the risk for adverse reactions. Medroxyprogesterone is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Linagliptin: (Minor) 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: (Minor) 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. (Minor) 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.
    Lopinavir; Ritonavir: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with ritonavir, 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.
    Lorlatinib: (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. 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. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of medroxyprogesterone and lumacaftor; ivacaftor, unless the benefits outweigh the risks. Lumacaftor; ivacaftor may decrease medroxyprogesterone, reducing efficacy. When coadministered with lumacaftor; ivacaftor, hormonal contraceptives are not a reliable method of effective contraception; instruct patients on alternative and/or additional methods of birth control. In addition, concomitant use of hormonal contraceptives and lumacaftor; ivacaftor may increase the incidence of menstruation-associated adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia). Patients taking medroxyprogesterone for other indications should be monitored for clinical efficacy of the progestin. Medroxyprogesterone is primarily metabolized in vitro via CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Meglitinides: (Minor) 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: (Major) 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: (Minor) 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: (Minor) 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: (Minor) 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: (Minor) 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; Saxagliptin: (Minor) 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. (Minor) 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: (Minor) 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. (Minor) 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: (Major) 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.
    Mitotane: (Major) Use caution if mitotane and medroxyprogesterone are used concomitantly, and monitor for decreased medroxyprogesterone efficacy. Since the dosage of medroxyprogesterone injections for contraception cannot be modified, an alternate or additional form of contraception should be considered in patients requiring therapy with mitotane. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of mitotane. Mitotane is a strong CYP3A4 inducer and medroxyprogesterone is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of medroxyprogesterone. Pregnancies have been reported during therapy with progestin contraceptives in patients receiving other strong CYP3A inducers.
    Modafinil: (Major) 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.
    Nefazodone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with nefazodone, 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.
    Nelfinavir: (Major) Nelfinavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration with ethinyl estradiol; norethindrone results in a 47% decrease in ethinyl estradiol plasma concentrations and an 18% decrease in norethindrone plasma concentrations. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as nelfinavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. In addition, coadministration of medroxyprogesterone, a CYP3A substrate with nelfinavir, 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.
    Nevirapine: (Moderate) 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.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with ritonavir, 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.
    Oxcarbazepine: (Major) 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.
    Pegvaliase: (Major) The use of medroxyprogesterone acetate suspension injection (a formulation containing PEG 3350) may increase the risk for serious hypersensitivity reactions and anaphylaxis when given with pegvaliase. Make sure any patient receiving pegvaliase has an emergency supply of epinephrine and knows how to use it in the case of a serious allergic reaction or anaphylaxis. In a single dose study of pegvaliase in adult patients with PKU, 2 patients receiving medroxyprogesterone acetate suspension injection (a formulation containing PEG 3350) experienced hypersensitivity reactions. One of the 2 patients experienced a hypersensitivity reaction on day 15 after a single pegvaliase dose of 0.67 mg within 15 minutes following medroxyprogesterone acetate injectable suspension, and subsequently experienced anaphylaxis on day 89 within 30 minutes after the next dose of medroxyprogesterone acetate injectable suspension. The other patient experienced a hypersensitivity reaction on day 40 after a single pegvaliase dosage of 0.08 mg within 10 minutes following medroxyprogesterone acetate injectable suspension. Both patients had high anti-PEG IgG antibody titers at or around the time of the hypersensitivity reactions. Most pegvaliase-treated patients developed anti-PEG IgM and IgG antibodies after treatment with the drug. The clinical effects of concomitant treatment with different PEGylated products is unknown. Monitor patients treated with pegvaliase and concomitantly with other PEGylated products for hypersensitivity reactions including anaphylaxis.
    Pentobarbital: (Major) 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: (Major) 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: (Major) 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.
    Posaconazole: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with posaconazole, 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.
    Pramlintide: (Minor) 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): (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with progestins.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with progestins.
    Primidone: (Major) 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.
    Ribociclib: (Major) Avoid coadministration of medroxyprogesterone with ribociclib due to increased plasma concentrations of medroxyprogesterone. Medroxyprogesterone is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Though no formal drug interaction trials have been conducted, concomitant administration of strong CYP3A4 inhibitors is expected to increase medroxyprogesterone exposure.
    Ribociclib; Letrozole: (Major) Avoid coadministration of medroxyprogesterone with ribociclib due to increased plasma concentrations of medroxyprogesterone. Medroxyprogesterone is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Though no formal drug interaction trials have been conducted, concomitant administration of strong CYP3A4 inhibitors is expected to increase medroxyprogesterone exposure.
    Rifamycins: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with rifamycins, strong CYP3A inducers should be avoided since it is expected to decrease concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro. Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs such as rifampin, rifabutin, or rifapentine. Concurrent administration of these drugs with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins may increase the hormone's elimination. In addition, free estrogen-hormone concentrations are decreased because rifampin increases estrogenic protein binding ability. Additionally, like other anti-infectives, rifampin indirectly inhibits the enterohepatic recirculation of estrogen through disruption of GI flora growth. Women taking both hormones and any of these drugs should report breakthrough bleeding to their prescribers; it is estimated that 70% of women taking oral contraceptives and rifampin experience menstrual abnormalities, and 6% become pregnant. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifampin, rifabutin, or rifapentine. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. In one review, the authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under recognized or under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or newer combined contraceptive deliveries (e.g., patches, rings) are not available. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifampin, rifabutin, or rifapentine, with dose adjustments made based on clinical efficacy.
    Ritonavir: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with ritonavir, 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.
    Saquinavir: (Minor) Coadministration of medroxyprogesterone, a CYP3A substrate with saquinavir, 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.
    Saxagliptin: (Minor) 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: (Major) 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: (Minor) 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: (Minor) 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: (Major) 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.
    Sugammadex: (Major) If an oral contraceptive is taken the same day sugammadex is administered, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception for the next 7 days. Sugammadex may bind to progestogen, resulting in a decrease in progestogen exposure. The administration of a bolus dose of sugammadex results in actions that are essentially equivalent to missing one or more doses of contraceptives containing estrogen or progestogen, including combination oral contraceptives, non-oral combination contraceptives, or progestins.
    Sulfonylureas: (Minor) 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.
    Tamoxifen: (Minor) Medroxyprogesterone reduces plasma concentrations of N-dimethyltamoxifen, the metabolite of tamoxifen, but not tamoxifen.
    Telaprevir: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with telaprevir, 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.
    Telithromycin: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with telithromycin, 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.
    Telotristat Ethyl: (Major) Use caution if coadministration of telotristat ethyl and medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of medroxyprogesterone; consider increasing the dose of medroxyprogesterone if necessary. If medroxyprogesterone is used for contraception, an alternate or additional form of contraception should be considered in patients prescribed telotristat ethyl. Formal drug interaction studies have not been completed; however, medroxyprogesterone is a CYP3A4 substrate in vitro. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Thiopental: (Major) 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.
    Tipranavir: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. In addition, coadministration of medroxyprogesterone, a CYP3A substrate with tipranavir, 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.
    Tolazamide: (Minor) 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: (Minor) 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: (Major) 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.
    Ulipristal: (Major) Avoid concurrent use of ulipristal and progestin-containing hormonal contraceptives or other progestins. Such contraceptives may be started or resumed no sooner than 5 days after ulipristal treatment. A reliable barrier method of contraception should be used during the same menstrual cycle in which ulipristal was administered (until the next menstrual period). Ulipristal may may reduce the effectiveness of progestin-containing hormonal contraceptives by competitively binding at the progesterone receptor. The concurrent use of emergency contraceptives containing levonorgestrel is not recommended, for similar reason. The effectiveness of other progestins may also be impaired.
    Voriconazole: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with voriconazole, 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.

    PREGNANCY AND LACTATION

    Pregnancy

    Medroxyprogesterone contraceptive injections may be used safely during breast-feeding. Detectable amounts of drug have been identified in the milk of mothers receiving contraceptive injections of medroxyprogesterone. However, in nursing mothers, milk composition, quality, and amount are not adversely affected. Neonates and infants exposed to medroxyprogesterone from breast milk have been studied for developmental and behavioral effects through puberty. No adverse effects have been identified. Alternatives include other progestin-only contraceptives, such as norethindrone oral contraceptive pills. Other dosage forms, such as the medroxyprogesterone suspension injection for cancer treatment, or medroxyprogesterone tablets, are recommended to be avoided during lactation.

    MECHANISM OF ACTION

    The primary contraceptive effect of progestins involves the inhibition of gonadotropin secretion (suppression of the midcycle surge of luteinizing hormone, or LH), which prevents follicular maturation and ovulation. The exact mechanism of action, however, is unknown. At the cellular level, progestins diffuse freely into target cells and bind to the progesterone receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the progesterone receptor, progestins slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH surge, thereby preventing follicular maturation and ovulation. Additional mechanisms may be involved. Other contraceptive actions of progestins include alterations in the endometrium that can impair implantation and an increase in cervical mucus viscosity which inhibits sperm migration into the uterus. In five clinical contraception studies, the 12-month failure rate for the group of women treated with medroxyprogesterone-contraceptive depot injection was zero (no pregnancies reported) to 0.7 by Life-Table method.
     
    Medroxyprogesterone converts a proliferative endometrium into a secretory one in women with adequate endogenous estrogen. Restoring adequate progesterone can help pre-menopausal women with secondary amenorrhea or dysfunctional uterine bleeding to re-establish normal menstrual patterns. The drug reduces endometrial growth in menopausal and postmenopausal women with an intact uterus who are receiving estrogen therapy, thus adding a protective effect against endometrial hyperplasia. Medroxyprogesterone decreases endometriosis related pain by suppressing serum estradiol concentrations and possibly by having a direct action on the lesions of endometriosis. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. The route and dosage of the drug determine pharmacologic effects. While parenterally administered medroxyprogesterone inhibits gonadotropin production and thus prevents follicular maturation and ovulation, available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. The mode of action of medroxyprogesterone as palliative therapy against certain cancers has not been determined.
     
    Progestins are mild, direct stimulants of the respiratory center. During pregnancy and the luteal phase of the menstrual cycle, women can hyperventilate and become hypocapnic due to elevated concentrations of endogenous progestins. Therapeutically, medroxyprogesterone has been used successfully in patients with COPD and hypercapnia, in patients with Pickwickian syndrome, and in patients with sleep apnea.

    PHARMACOKINETICS

    Medroxyprogesterone is administered orally or injected intramuscularly or subcutaneously as a depot injection. Greater than 90% of the absorbed drug is protein bound. Medroxyprogesterone acetate is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine. Most metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4
    CYP3A4 is the principal enzyme responsible for the overall metabolism of medroxyprogesterone.

    Oral Route

    Peak serum concentrations after oral administration of medroxyprogesterone occur within 2 to 4 hours. The half-life following oral administration of 10 mg for 7 days is variable, but is approximately 16.6 hours to 30 hours. Administration with food increases bioavailability. A 10 mg dose, taken immediately before or after a meal, increased maximum concentration (50 to 70%) and AUC (18 to 33%). The half-life of medroxyprogesterone acetate was not changed with food.

    Intramuscular Route

    Peak serum concentrations of medroxyprogesterone occur within 3 weeks after a single IM depot suspension dose. Once peak concentrations are achieved with the IM injection, serum concentrations then begin to decrease exponentially to undetectable levels at 120 to 200 days following the injection. The half-life is roughly 50 days following IM depot administration.

    Subcutaneous Route

    Peak serum concentrations of medroxyprogesterone are reached within approximately 1 week after a single subcutaneous depot dose. Following subcutaneous administration, serum concentrations at 12 to 14 weeks are generally below 0.5 ng/mL. The half-life is roughly 40 days following subcutaneous depot administration.