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MedroxyPROGESTERone

Pronunciation

Pronunciation

(me DROKS ee proe JES te rone)

Index Terms

  • Acetoxymethylprogesterone
  • Medroxyprogesterone Acetate
  • Methylacetoxyprogesterone
  • MPA

Dosage Forms

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

Suspension, Intramuscular, as acetate:

Depo-Provera: 150 mg/mL (1 mL)

Depo-Provera: 150 mg/mL (1 mL) [contains methylparaben, polyethylene glycol, polysorbate 80, propylparaben]

Depo-Provera: 400 mg/mL (2.5 mL)

Generic: 150 mg/mL (1 mL)

Suspension, Subcutaneous, as acetate:

Depo-SubQ Provera 104: 104 mg/0.65 mL (0.65 mL) [contains methylparaben, propylparaben]

Tablet, Oral, as acetate:

Provera: 2.5 mg, 5 mg, 10 mg [scored]

Generic: 2.5 mg, 5 mg, 10 mg

Brand Names: U.S.

  • Depo-Provera
  • Depo-SubQ Provera 104
  • Provera

Pharmacologic Category

  • Contraceptive
  • Progestin

Pharmacology

Medroxyprogesterone acetate (MPA) transforms a proliferative endometrium into a secretory endometrium. When administered with conjugated estrogens, MPA reduces the incidence of endometrial hyperplasia and risk of adenocarcinoma. When used as an injection for contraception (doses of 150 mg IM or 104 mg SubQ), MPA inhibits secretion of pituitary gonadotropins, which prevents follicular maturation and ovulation and causes endometrial thinning. Progestogens, such as medroxyprogesterone when used for endometriosis, lead to atrophy of the endometrial tissue. They may also suppress new growth and implantation. Pain associated with endometriosis is decreased (ASRM, 2014).

Absorption

Oral: Rapid; IM: Slow

Metabolism

Extensively hepatic via hydroxylation and conjugation; forms metabolites

Excretion

Urine

Onset of Action

Time to ovulation (after last injection): 10 months (range: 6 to 12 months)

Time to Peak

Oral: 2 to 4 hours; IM (Depo-Provera Contraceptive): ~3 weeks; SubQ: ~1 week

Half-Life Elimination

Oral: 12 to 17 hours; IM (Depo-Provera Contraceptive): ~50 days; SubQ: ~43 days

Protein Binding

86% to 90% primarily to albumin; does not bind to sex hormone-binding globulin

Use: Labeled Indications

Abnormal uterine bleeding (tablet): Treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer.

Amenorrhea, secondary (tablet): Treatment of secondary amenorrhea due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer.

Contraception (104 mg/0.65 mL and 150 mg/mL injection): Prevention of pregnancy in women of childbearing potential.

Endometrial hyperplasia (tablet): Prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving daily oral conjugated estrogens 0.625 mg.

Endometrial carcinoma (400 mg/mL injection) (100 mg tablet [Canadian product]): Adjunctive therapy and/or palliative treatment of inoperable, recurrent, and/or metastatic endometrial carcinoma.

Endometriosis (104 mg/0.65 mL injection): Management of endometriosis-associated pain.

Use: Unlabeled

Treatment of low-grade endometrial stromal sarcoma; treatment of paraphilia/hypersexuality

Contraindications

Angioedema, anaphylactic reaction, or hypersensitivity to medroxyprogesterone or any component of the formulation

Additional contraindications:

Injection (104 mg/0.65 mL): Active thrombophlebitis; venous thromboembolic disorders or cerebral vascular disease (current or history of); undiagnosed genital bleeding; breast cancer (known, suspected or history of); significant hepatic impairment or disease; pregnancy

Injection (150 mg/mL): Active thrombophlebitis; venous thromboembolic disorders or cerebral vascular disease (current or history of); undiagnosed genital bleeding; breast cancer (known, suspected or history of); significant hepatic impairment or disease; pregnancy; diagnostic test for pregnancy

Injection (400 mg/mL): Active thrombophlebitis; venous thromboembolic disorders or cerebral vascular disease (current or history of)

Tablet: DVT or PE (current or history of); active or history of arterial thromboembolic disease (eg, stroke, MI); estrogen or progesterone dependent tumor (known or suspected) (excludes 100 mg tablet [Canadian product] indicated for endometrial cancer); undiagnosed abnormal genital bleeding; breast cancer (known, suspected or history of); hepatic impairment or disease; pregnancy; undiagnosed abnormal genital bleeding; breast cancer (known, suspected or history of); hepatic impairment or disease; pregnancy

Dosing: Adult

Abnormal uterine bleeding: Oral: 5 or 10 mg daily for 5 to 10 days starting on day 16 or 21 of menstrual cycle. Secretory transformation of the endometrium will occur when adequately primed with endogenous or exogenous estrogen. Withdrawal bleeding may be expected within 3 to 7 days after discontinuing medroxyprogesterone.

Amenorrhea, secondary: Oral: 5 or 10 mg daily for 5 to 10 days. Therapy may be started at any time. Secretory transformation of the endometrium will occur when adequately primed with endogenous or exogenous estrogen. Withdrawal bleeding may be expected within 3 to 7 days after discontinuing medroxyprogesterone.

Contraception:

Depo-Provera Contraceptive: IM: 150 mg every 3 months (every 13 weeks)

depo-subQ provera 104: SubQ: 104 mg every 3 months (every 12 to 14 weeks)

Endometrial carcinoma, recurrent or metastatic (adjunctive/palliative treatment):

IM (Depo-Provera): Initial: 400 to 1,000 mg/week

Oral (100 mg tablet [Canadian product]): Manufacturer’s labeling: Usual dose: 200 to 400 mg daily. Doses >200 mg daily may not confer additional benefit (Thigpen 1999). If improvement or disease stabilization occurs, 200 mg daily may be sufficient for maintenance. Discontinue use if no improvement within 2 to 3 months.

Endometrial hyperplasia reduction: Oral: 5 or 10 mg daily for 12 to 14 consecutive days each month, starting on day 1 or day 16 of the cycle. When treating postmenopausal women, use for the shortest duration possible at the lowest effective dose consistent with treatment goals. Reevaluate patients as clinically appropriate to determine if treatment is still necessary. Consider use of an estrogen with a progestin in postmenopausal women with a uterus. Women who have had a hysterectomy generally do not need a progestin. Adjust dose based on patient response. Attempt to taper or discontinue at 3- to 6-month intervals.

Endometriosis (depo-subQ provera 104): SubQ: 104 mg every 3 months (every 12 to 14 weeks)

Paraphilia/hypersexuality (off-label use) (Reilly 2000): Males (Note: Avoid use if active pituitary pathology, hepatic failure, or thromboembolic disease):

IM (Depo-Provera): 100 to 600 mg weekly

Oral: 100 to 500 mg daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Adolescents:

Abnormal uterine bleeding: Refer to adult dosing.

Amenorrhea, secondary: Refer to adult dosing.

Contraception: Refer to adult dosing.

Endometriosis: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Medroxyprogesterone is extensively metabolized in the liver. Most products are contraindicated in patients with hepatic impairment. If needed for the palliative treatment metastatic endometrial carcinoma, monitor closely; withhold or discontinue treatment if liver dysfunction develops and do not resume until hepatic function has returned to normal.

Administration

IM: Depo-Provera Contraceptive: Administer first dose during the first 5 days of menstrual period, or within the first 5 days postpartum if not breast-feeding, or at the sixth week postpartum if breast-feeding exclusively. Shake vigorously prior to administration. Administer by deep IM injection in the gluteal or deltoid muscle.

When switching from combined hormonal contraceptives (estrogen plus progestin), the first injection should be on the day after the last active tablet or (at the latest) the day after the final inactive tablet. When switching from other contraceptive methods, ensure continuous contraceptive coverage.

SubQ: depo-subQ provera 104: Administer first dose during the first 5 days of menstrual period, or at the sixth week postpartum if breast-feeding. Shake vigorously for at least 1 minute prior to administration. Administer by SubQ injection in the anterior thigh or abdomen; avoid boney areas and the umbilicus. Administer slowly over 5 to 7 seconds. Do not rub the injection area.

When switching from combined hormonal contraceptives (estrogen plus progestin), the first injection should be within 7 days after the last active pill, or removal of patch or ring. If switching from the IM to SubQ formulation, the next dose should be given within the prescribed dosing period for the IM injection to ensure continuous coverage.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Dietary Considerations

Ensure adequate calcium and vitamin D intake

Storage

Store at 20°C to 25°C (68°F to 77°F).

Drug Interactions

Acitretin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Given the potential for progestin-only preparations to fail to prevent pregnancy during acitretin therapy, such products should not be relied upon. Alternative, nonhormonal forms of contraception must be employed during acitretin therapy. Consider therapy modification

Anticoagulants: Progestins may diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Aprepitant: May decrease the serum concentration of Contraceptives (Progestins). Management: Alternative or additional methods of contraception should be used both during treatment with aprepitant or fosaprepitant and for at least one month following the last aprepitant/fosaprepitant dose. Consider therapy modification

Artemether: May decrease the serum concentration of Contraceptives (Progestins). Management: Consider the use of an alternative (i.e., non-hormonal) means of contraception in all women of childbearing potential who are using artemether. Consider therapy modification

Atazanavir: May increase the serum concentration of Contraceptives (Progestins). However, atazanavir may lead to decreased ethinyl estradiol concentrations and decreased effectiveness of oral contraceptive products. Management: Consider an alternative or additional method of contraception, particularly with combined estrogen/progestin products. Depot medroxyprogesterone acetate may be used without a need for additional contraception. Consider therapy modification

Barbiturates: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Consider therapy modification

Bexarotene (Systemic): May decrease the serum concentration of Contraceptives (Progestins). Management: Women of childbearing potential receiving bexarotene should use two reliable forms of contraception (including at least one nonhormonal form). Consider therapy modification

Bile Acid Sequestrants: May decrease the serum concentration of Contraceptives (Progestins). Management: Administer oral progestin-containing contraceptives at least 1-4 hours prior to or 4-6 hours after administration of a bile acid sequestrant. Consider therapy modification

Boceprevir: May increase the serum concentration of Contraceptives (Progestins). This has been seen specifically with norethindrone. Boceprevir may increase the serum concentration of Contraceptives (Progestins). This has been seen specifically with drospirenone. Management: Patients receiving boceprevir, ribavirin, and peginterferon alfa should use two reliable forms of contraception. Norethindrone/ethinyl estradiol may be used for one of these when norethindrone dose is at least 1 mg/day. Avoid drospirenone. Consider therapy modification

Bosentan: May decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative (i.e., non-hormonal) means of contraception for all women of childbearing potential who are using bosentan, and do not rely on hormonal contraceptives alone. Consider therapy modification

C1 inhibitors: Progestins may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy

CarBAMazepine: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Consider therapy modification

Carfilzomib: May enhance the thrombogenic effect of Contraceptives (Progestins). Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib. Consider therapy modification

Choline C 11: Antiandrogens may diminish the therapeutic effect of Choline C 11. Monitor therapy

CloBAZam: May decrease the serum concentration of Contraceptives (Progestins). Consider therapy modification

Cobicistat: May increase the serum concentration of Contraceptives (Progestins). Management: Consider an alternative, non-hormone-based contraceptive in patients receiving cobicistat-containing products. Consider therapy modification

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

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of MedroxyPROGESTERone. Exceptions: Atazanavir; Boceprevir; Cobicistat; Darunavir; Lopinavir; Nelfinavir; Saquinavir; Telaprevir. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dabrafenib: May decrease the serum concentration of Contraceptives (Progestins). Management: Females of reproductive potential should use an alternative, highly effective, non-hormonal means of contraception during and at least 2 weeks (dabrafenib alone) or 4 months (dabrafenib + trametinib) after discontinuation of dabrafenib treatment. Consider therapy modification

Darunavir: May decrease the serum concentration of Contraceptives (Progestins). Management: Consider using an alternative or additional means of contraception. Injected depot medroxyprogesterone acetate may be used without a need for additional contraception. Consider therapy modification

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

Efavirenz: May decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Eslicarbazepine: May decrease the serum concentration of Contraceptives (Progestins). Management: Alternative, non-hormonal means of birth control should be considered for women of child-bearing potential. Consider therapy modification

Felbamate: May decrease the serum concentration of Contraceptives (Progestins). Management: Contraceptive failure is possible. Use of an alternative, nonhormonal method of contraception is recommended. Consider therapy modification

Flibanserin: Contraceptives (Progestins) may increase the serum concentration of Flibanserin. Monitor therapy

Fosamprenavir: Contraceptives (Progestins) may decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Fosamprenavir may decrease the serum concentration of Contraceptives (Progestins). Management: Consider using an alternative or additional means of contraception. Injected depot medroxyprogesterone acetate may be used without a need for additional contraception. Consider therapy modification

Fosaprepitant: May decrease the serum concentration of Contraceptives (Progestins). The active metabolite aprepitant is likely responsible for this effect. Management: Alternative or additional methods of contraception should be used both during treatment with aprepitant or fosaprepitant and for at least one month following the last aprepitant/fosaprepitant dose. Consider therapy modification

Fosphenytoin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Consider therapy modification

Griseofulvin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Avoid combination

Herbs (Progestogenic Properties) (eg, Bloodroot, Yucca): May enhance the adverse/toxic effect of Progestins. Monitor therapy

Indium 111 Capromab Pendetide: Antiandrogens may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination

LamoTRIgine: May decrease the serum concentration of Contraceptives (Progestins). Management: Women using progestin-only “minipill” products may be at risk for contraceptive failure; it is unclear if other progestin-containing products would be significantly impacted. Alternative, non-hormonal, means of contraception are recommended. Consider therapy modification

Lesinurad: May decrease the serum concentration of Contraceptives (Progestins). Management: Use of an additional, nonhormonal contraceptive is recommended in patients being treated with lesinurad who desire effective contraception. Consider therapy modification

Lixisenatide: May decrease the serum concentration of Contraceptives (Progestins). Management: Administer oral contraceptives 1 hour before or at least 11 hours after administration of lixisenatide. Consider therapy modification

Lopinavir: May decrease the serum concentration of Contraceptives (Progestins). Lopinavir may increase the serum concentration of Contraceptives (Progestins). Management: Consider using an alternative or additional means of contraception. Injected depot medroxyprogesterone acetate and etonogestrel implants may be used without a need for additional contraception. Consider therapy modification

Lumacaftor: May decrease the serum concentration of Contraceptives (Progestins). Management: Do not rely on hormone-based contraceptives with concurrent use of lumacaftor/ivacaftor; an alternative, non-hormonal, method of contraception should be used if this combination is required. Consider therapy modification

Metreleptin: May decrease the serum concentration of Contraceptives (Progestins). Metreleptin may increase the serum concentration of Contraceptives (Progestins). Monitor therapy

MiFEPRIStone: May diminish the therapeutic effect of Contraceptives (Progestins). MiFEPRIStone may increase the serum concentration of Contraceptives (Progestins). Management: Women of childbearing potential should use an effective, nonhormonal means of contraception during and 4 weeks following mifepristone treatment. Consider therapy modification

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

Mycophenolate: May decrease the serum concentration of Contraceptives (Progestins). Management: Use of an additional or alternative (nonhormonal) method of contraception should be considered. Consider therapy modification

Nalmefene: MedroxyPROGESTERone may increase the serum concentration of Nalmefene. Monitor therapy

Nelfinavir: May decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification

Nevirapine: May decrease the serum concentration of Contraceptives (Progestins). Management: Instruct patients receiving nevirapine to use an alternative or additional nonhormonal contraceptive. Nevirapine product labeling however suggests that depo-medroxyprogesterone acetate may be used as a sole method of contraception. Consider therapy modification

OXcarbazepine: May decrease the serum concentration of Contraceptives (Progestins). Management: Contraceptive failure is possible. Use of an additional or alternative, nonhormonal method of contraception is recommended. Consider therapy modification

Perampanel: May decrease the serum concentration of Contraceptives (Progestins). Management: Patients should use an alternative, non-hormonal based form of contraception for the duration of concurrent perampanel. Both oral and non-oral progestin-based contraceptives are likely to be impacted by this interaction. Consider therapy modification

Phenytoin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Consider therapy modification

Pomalidomide: Progestins may enhance the thrombogenic effect of Pomalidomide. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification

Primidone: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Consider therapy modification

Prucalopride: May decrease the serum concentration of Contraceptives (Progestins). Consider therapy modification

Retinoic Acid Derivatives: May diminish the therapeutic effect of Contraceptives (Progestins). Retinoic Acid Derivatives may decrease the serum concentration of Contraceptives (Progestins). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Particularly, microdosed progesterone-only preparations may be inadequately effective. Exceptions: Adapalene; Bexarotene (Topical); Tretinoin (Topical). Consider therapy modification

Rifamycin Derivatives: May decrease the serum concentration of Contraceptives (Progestins). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Consider therapy modification

Saquinavir: May decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification

Selegiline: Contraceptives (Progestins) may increase the serum concentration of Selegiline. Monitor therapy

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

St John's Wort: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Consider using a product other than St John's wort. Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Consider therapy modification

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

Sugammadex: May decrease the serum concentration of Contraceptives (Progestins). Management: Patients receiving any hormonal contraceptive (oral or non-oral) should use an additional, nonhormonal contraceptive method during and for 7 days following sugammadex treatment. Consider therapy modification

Telaprevir: May decrease the serum concentration of Contraceptives (Progestins). Management: Two different nonhormonal forms of contraception are required for women of childbearing potential taking telaprevir. Hormonal contraceptives may be less effective during concurrent telaprevir and for up to 2 weeks after telaprevir discontinuation. Consider therapy modification

Thalidomide: Contraceptives (Progestins) may enhance the thrombogenic effect of Thalidomide. Monitor therapy

Tipranavir: May increase the serum concentration of Contraceptives (Progestins). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification

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

Topiramate: May decrease the serum concentration of Contraceptives (Progestins). Management: Caution patients that this combination may be associated with reduced contraceptive effectiveness. Consider adding an additional (non-hormonal) contraceptive method. Consider therapy modification

Tranexamic Acid: Contraceptives (Progestins) may enhance the thrombogenic effect of Tranexamic Acid. Avoid combination

Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Management: Ulipristal for uterine fibroids (Canadian indication): avoid progestins within 12 days of stopping ulipristal; as emergency contraceptive (U.S. indication): avoid progestins within 5 days of stopping ulipristal. Avoid combination

Vitamin K Antagonists (eg, warfarin): Contraceptives (Progestins) may diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Management: When possible, concomitant hormonal contraceptives and coumarin derivatives should be avoided in order to eliminate the risk of thromboembolic disorders. Consider using an alternative, nonhormonal contraceptive. Consider therapy modification

Voriconazole: May increase the serum concentration of Contraceptives (Progestins). Contraceptives (Progestins) may increase the serum concentration of Voriconazole. Monitor therapy

Adverse Reactions

Adverse effects as reported with any dosage form.

>10%:

Central nervous system: Headache (9% to 17%), nervousness (11%)

Endocrine & metabolic: Amenorrhea (IM: 55% at 12 months; 68% at 24 months; SubQ: 6%), weight gain (IM: >10 lbs at 24 months: 38%; SubQ: 6%), menstrual disease (IM: 57% at 12 months; 32% at 24 months; SubQ: 1% to 7%)

Gastrointestinal: Abdominal pain (1% to 11%)

1% to 10%:

Cardiovascular: Edema (2%)

Central nervous system: Dizziness (1% to 6%), anxiety (1% to <5%), depression (1% to <5%), insomnia (1% to <5%), irritability (1% to <5%), fatigue (<5%)

Dermatologic: Acne vulgaris (1% to <5%), alopecia (1%), skin rash (1%)

Endocrine & metabolic: Decreased libido (1% to 6%), change in menstrual flow (menometrorrhagia; 1% to <5%), hypermenorrhea (1% to <5%), hot flash (1% to <5%)

Gastrointestinal: Abdominal distension (1% to <5%), diarrhea (1% to <5%), nausea (1% to <5%), bloating (2%)

Genitourinary: Abnormal Pap smear (1% to <5%), bacterial vaginosis (1% to <5%), breast tenderness (1% to <5%), dysmenorrhea (1% to <5%), mastalgia (1% to <5%), urinary tract infection (1% to <5%), uterine hemorrhage (1% to <5%), vaginal hemorrhage (1% to <5%), vaginitis (1% to <5%), vulvovaginal candidiasis (1% to <5%), leukorrhea (3%)

Infection: Influenza (1% to <5%)

Local: Pain at injection site (SubQ: 1% to <5%), atrophy at injection site (SubQ: ≤1%), induration at injection site (SubQ: ≤1%)

Neuromuscular & skeletal: Arthralgia (1% to <5%), back pain (1% to <5%), limb pain (1% to <5%), leg cramps (4%), weakness (≤4%)

Respiratory: Bronchitis (1% to <5%), nasopharyngitis (1% to <5%), pharyngitis (1% to <5%), sinusitis (1% to <5%), upper respiratory tract infection (1% to <5%)

<1% (Limited to important or life-threatening): Anaphylaxis, anaphylactoid reaction, angioedema, asthma, Bell's palsy, breast changes, cervical cancer, chest pain, chloasma, cholestatic jaundice, decreased bone mineral density, decreased glucose tolerance, decreased lactation, deep vein thrombosis, delayed return to fertility, diaphoresis, dyspnea, galactorrhea, hematologic abnormality, hirsutism, hoarseness, jaundice, malignant neoplasm of breast, nipple bleeding, optic neuritis, osteoporosis, paralysis, paresthesia, pathological fracture due to osteoporosis,pulmonary embolus, rectal hemorrhage, residual mass at injection site (aqueous suspension), retinal thrombosis, scleroderma, seizure, skin discoloration at injection site (aqueous suspension), sterile abscess at injection site (aqueous suspension), syncope, tachycardia, thrombophlebitis, weight loss

ALERT: U.S. Boxed Warning

Cardiovascular disorders (tablet):

Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported increased risks 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 (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo.

Breast cancer (tablet):

The Women's Health Initiative (WHI) estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.

Dementia (tablet):

Estrogen plus progestin therapy should not be used for the prevention of dementia. The Women's Health Initiative Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years or older during 4 years of treatment with daily conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

Long-term use (injection):

Medroxyprogesterone contraceptive should not be used as a long-term birth control method (ie, longer than 2 years) unless other birth control methods are considered inadequate.

Loss of bone mineral density (injection):

Women who use medroxyprogesterone contraceptive may lose significant bone mineral density (BMD). Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of medroxyprogesterone contraceptive during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life.

Patient education (subcutaneous injection):

Patients should be counseled that medroxyprogesterone contraceptive does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Risk vs benefits (tablet):

In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens (with or without medroxyprogesterone acetate) and other dosage forms of estrogens (with or without progestins). Estrogens with progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal suppression: May cause suppression of hypothalamic-pituitary-adrenal (HPA) axis, resulting in decreased plasma cortisol concentrations, decreased cortisol secretion, and low plasma ACTH concentrations. Cushingoid symptoms may occur.

• Anaphylaxis/hypersensitivity reactions: Anaphylaxis or anaphylactoid reactions have been reported with use of the injection; medication for the treatment of hypersensitivity reactions should be available for immediate use.

• Bone mineral density loss: [US Boxed Warning]: Prolonged use of medroxyprogesterone contraceptive injection may result in a loss of bone mineral density (BMD). It is not known if use during adolescence or early adulthood will decrease peak bone mass accretion or increase the risk for osteoporotic fractures later in life. Loss is related to the duration of use, may not be completely reversible on discontinuation of the drug, and incidence is not significantly different between the SubQ and IM dosage forms. The impact on peak bone mass in adolescents should be weighed against the potential for unintended pregnancies in treatment decision. Consider alternative contraceptive methods in patients at risk for osteoporosis (eg, metabolic bone disease, chronic alcohol and/or tobacco use, anorexia nervosa, strong family history of osteoporosis, chronic use of medications associated with osteoporosis such as anticonvulsants or corticosteroids). All patients should have adequate calcium and Vitamin D intake. Consider evaluating bone mineral density in patients receiving high doses of medroxyprogesterone for long term endometrial cancer.

• Breast cancer: [US Boxed Warning]: Based on data from the Women’s Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in postmenopausal women using conjugated estrogens (CE) in combination with medroxyprogesterone acetate (MPA). This risk may be associated with duration of use and declines once combined therapy is discontinued (Chlebowski, 2009). The risk of invasive breast cancer was decreased in postmenopausal women with a hysterectomy using CE only, regardless of weight. However, the risk was not significantly decreased in women at high risk for breast cancer (family history of breast cancer, personal history of benign breast disease) (Anderson, 2012). Women who used depo-medroxyprogesterone within the previous 5 years and for a duration of 12 months or longer were found to have an increased risk of breast cancer. An increase in abnormal mammogram findings has also been reported with estrogen alone or in combination with progestin therapy. Most products are contraindicated in patients with known or suspected breast cancer. Use of medroxyprogesterone for the treatment of endometrial carcinoma is not recommended in women with known or suspected breast cancer and women with a strong family history of breast cancer should be carefully monitored.

• Dementia: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent dementia. In the Women's Health Initiative Memory Study (WHIMS), an increased incidence of probable dementia was observed in women ≥65 years of age taking CE alone or in combination with MPA.

• Ectopic pregnancy: When used for contraception, the possibility of ectopic pregnancy should be considered in patients with severe abdominal pain.

• Endometrial cancer: MPA is used to reduce the risk of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving conjugated estrogens. The use of unopposed estrogen in women with a uterus is associated with an increased risk of endometrial cancer. The addition of a progestin to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Adequate diagnostic measures, including endometrial sampling if indicated, should be performed to rule out malignancy in postmenopausal women with undiagnosed abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. The risk of endometrial cancer is dose and duration dependent; risk appears to be greatest with use ≥5 years and may persist following discontinuation of therapy.

• Hypertriglyceridemia: In women using estrogen plus progesterone therapy, triglycerides may be increased in women with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs.

• Ovarian cancer: Postmenopausal estrogen therapy and combined estrogen/progesterone therapy may increase the risk of ovarian cancer; however, the absolute risk to an individual woman is small. Although results from various studies are not consistent, risk does not appear to be significantly associated with the duration, route, or dose of therapy. In one study, the risk decreased after 2 years following discontinuation of therapy (Mørch, 2009). Although the risk of ovarian cancer is rare, women who are at an increased risk (eg, family history) should be counseled about the association (NAMS, 2012).

• Retinal vascular thrombosis: Discontinue pending examination in cases of sudden partial or complete vision loss, sudden onset of proptosis, diplopia, or migraine; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.

• Vaginal bleeding: Unscheduled bleeding/spotting may occur. Presentation of irregular, unresolving vaginal bleeding following previously regular cycles warrants further evaluation including endometrial sampling, if indicated, to rule out malignancy.

• Weight gain: Contraceptive therapy with medroxyprogesterone commonly results in an average weight gain of ~3.7 kg after 2 years of treatment.

Disease-related concerns:

• Asthma: Use estrogen plus progestin therapy with caution in patients with asthma; may exacerbate disease.

• Carbohydrate intolerance: Estrogen plus progestin therapy may have adverse effects on glucose tolerance; use caution in women with diabetes.

• Cardiovascular disease: [US Boxed Warning]: Estrogens with progestin should not be used to prevent cardiovascular disease. Using data from the Women’s Health Initiative (WHI) studies, an increased risk of deep vein thrombosis (DVT), and stroke, has been reported with CE and an increased risk of DVT, stroke, pulmonary emboli (PE) and myocardial infarction (MI) has been reported with CE with MPA in postmenopausal women 50 to 79 years of age. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Risk factors should be managed appropriately; discontinue use if adverse cardiovascular events occur or are suspected. Use is contraindicated in women with active DVT, PE, active arterial thromboembolic disease or a history of these conditions. If thrombosis develops with contraceptive treatment, discontinue treatment (unless no other acceptable contraceptive alternative).

• Depression: Use with caution in patients with a history of depression.

• Diseases exacerbated by fluid retention: Use with caution in patients with diseases which may be exacerbated by fluid retention, including cardiac or renal dysfunction.

• Epilepsy: Use estrogen plus progestin therapy with caution in patients with epilepsy; may exacerbate disease.

• Hepatic dysfunction: Estrogens plus progestins are poorly metabolized in patients with hepatic dysfunction. Use caution with a history of cholestatic jaundice associated with prior estrogen use or pregnancy. Discontinue if jaundice develops or if acute or chronic hepatic disturbances occur. Most products are contraindicated with hepatic impairment or disease. Use of medroxyprogesterone for the treatment of endometrial carcinoma is not recommended in women with significant hepatic dysfunction and should be discontinued if liver dysfunction occurs.

• Hepatic hemangiomas: Use estrogen plus progestin therapy with caution in patients with hepatic hemangiomas; may exacerbate disease.

• Hepatic hemangiomas: Use estrogen plus progestin therapy with caution in patients with hepatic hemangiomas; may exacerbate disease.

• Migraine: Use caution in patients with migraine; may exacerbate disease.

• Porphyria: Use estrogen plus progestin therapy with caution in patients with porphyria; may exacerbate disease.

• Systemic lupus erythematosus: Use estrogen plus progestin therapy with caution in patients with systemic lupus erythematosus (SLE); may exacerbate disease.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Menopause: Use may mask the onset of menopause in women treated for endometrial cancer.

• Pediatric: Not for use prior to menarche.

• Surgical patients: Whenever possible, progestins in combination with estrogens should be discontinued at least 4 to 6 weeks prior to surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Other warnings/precautions:

• Laboratory changes: The use of estrogens and/or progestins may change the results of some laboratory tests (eg, coagulation factors, lipids, glucose tolerance, binding proteins). The dose, route, and the specific estrogen/progestin influences these changes. In addition, personal risk factors (eg, cardiovascular disease, smoking, diabetes, age) also contribute to adverse events; use of specific products may be contraindicated in women with certain risk factors.

• Long-term use: [US Boxed Warning]: Long-term use (ie, >2 years) should be limited to situations where other birth control methods are inadequate. When used for endometrial carcinoma, the effects of long term use on adrenal, hepatic, ovarian, pituitary, and uterine function is not known.

• Patient education: [US Boxed Warning]: Inform patients that injectable contraceptives do not protect against HIV infection or other sexually-transmitted diseases.

• Risks vs benefits: [US Boxed Warning]: Estrogens with progestin should be used for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual woman. Patients should be reevaluated as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from Women’s Health Initiative (WHI) studies, which evaluated oral CE 0.625 mg with or without MPA 2.5 mg relative to placebo in postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied. Outcomes reported from clinical trials using CE with or without MPA should be assumed to be similar for other doses and other dosage forms of estrogens and progestins until comparable data becomes available. Women who are early in menopause, who are in good cardiovascular health, and who are at low risk for adverse cardiovascular events can be considered candidates for estrogen with or without progestin therapy for the relief of menopausal symptoms (ACOG 565 2013).

Monitoring Parameters

Monitor patient closely for loss of vision; sudden onset of proptosis, diplopia, or migraine; signs and symptoms of thromboembolic disorders; signs or symptoms of depression; glucose in patients with diabetes; or blood pressure. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding. Monitor blood pressure at regular intervals with estrogen plus progestin therapy.

Contraception: Assessment of pregnancy status (prior to therapy); weight (optional; BMI at baseline may be helpful to monitor changes during therapy); assess potential health status changes at routine visits (CDC, 2013). BMD with long-term use (per manufacturer).

Endometrial cancer: Consider BMD with long term use; breast cancer (in women with a strong family history of breast cancer).

Treatment of paraphilia/hypersexuality (Guay, 2009; Reilly, 2000): Hepatic function test (baseline and during treatment if suspected hepatotoxicity); CBC (baseline); serum testosterone (baseline then monthly for 4 months then every 6 months); serum LH and prolactin (baseline and every 6 months); FSH (baseline); glucose; bone scan (baseline then annually) if serum testosterone significantly suppressed; gallbladder function; blood pressure; weight gain

Pregnancy Risk Factor

X (tablet)

Pregnancy Considerations

Most products are contraindicated in women who are pregnant, suspected to be pregnant or as a diagnostic test for pregnancy. In general, there is not an increased risk of birth defects following inadvertent use of the injectable medroxyprogesterone acetate (MPA) contraceptives early in pregnancy. Hypospadias has been reported in male babies and clitoral enlargement and labial fusion have been reported in female babies exposed to MPA during the first trimester of pregnancy. High doses impair fertility. Ectopic pregnancies have been reported with use of the MPA contraceptive injection. Median time to conception/return to ovulation following discontinuation of MPA contraceptive injection is 10 months following the last injection and is unrelated to the duration of use.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience weight gain, cramps, bloating, decreased libido, acne, insomnia, loss of strength and energy, enlarged breasts, dark patches on face, or menstrual irregularities. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, shortness of breath, coughing up blood, severe headache, severe nausea, vomiting, severe abdominal pain, severe dizziness, passing out, bulging eyes, vision changes, contact lens discomfort, breast soreness or pain, lump in breast, nipple discharge, vaginitis, vaginal bleeding, depression, mood changes, memory impairment, swelling of arms or legs, seizures, sexual dysfunction, or severe injection site irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating, and advising patients.

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