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, pulmonary embolism, stroke, and myocardial infarction 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.
The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.
Estrogen plus progestin therapy should not be used for the prevention of dementia. The WHI 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.
Medroxyprogesterone is not recommended as a long-term (ie, longer than 2 years) birth control method or medical therapy for endometriosis-associated pain unless other options are considered inadequate.
Women who use medroxyprogesterone 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 medroxyprogesterone 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.
In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens and medroxyprogesterone acetate and other combinations and dosage forms of estrogens and 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.
Abnormal uterine bleeding: Adolescents: Oral: 5 to 10 mg for 5 to 10 days starting on day 16 or day 21 of menstrual cycle
Amenorrhea: Adolescents: Oral: 5 to 10 mg/day for 5 to 10 days
Contraception: Adolescents: First dose to be given only during first 5 days of normal menstrual period; only within 5 days postpartum if not breast-feeding, or only at sixth postpartum week if exclusively breast-feeding. When switching from other contraceptive methods, depo-subQ provera 104 should be administered within 7 days after the last day of using the last method (pill, ring, patch).
IM (Depo-Provera): 150 mg every 3 months (every 13 weeks)
SubQ (depo-subQ provera 104): 104 mg every 3 months (every 12 to 14 weeks)
Endometriosis-associated pain: Adolescents: SubQ (depo-subQ provera 104): 104 mg every 3 months; treatment longer than 2 years is not recommended due to impact of long-term use on bone mineral density
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Use is contraindicated with severe impairment. Discontinue with jaundice or if liver function disturbances occur. Consider lower dose or less frequent administration with mild to moderate impairment. Use of the contraceptive injection has not been studied in patients with hepatic impairment; consideration should be given to not readminister if jaundice develops.
(For additional information see "Medroxyprogesterone acetate: Drug information")
Abnormal uterine bleeding: Oral: 5 or 10 mg daily for 5 to 10 days starting on day 16 or 21 of menstrual cycle. A suggested dose of 10 mg daily for 10 days starting on day 16 of the cycle induces optimum secretory transformation of the endometrium when adequately primed with endogenous or exogenous estrogen. Withdrawal bleeding may be expected within 3 to 7 days after discontinuing medroxyprogesterone. Planned menstrual cycling may benefit patients with a history of recurrent episodes of abnormal uterine bleeding.
Abnormal uterine bleeding, acute (off-label): Oral: 20 mg three times a day for 7 days (ACOG 557 2013; Munro 2006)
Amenorrhea, secondary: Oral: 5 or 10 mg daily for 5 to 10 days. Therapy may be started at any time. A dose of 10 mg daily for 10 days induces optimum secretory transformation of the endometrium when adequately primed with endogenous or exogenous estrogen. Withdrawal bleeding may be expected within 3 to 7 days after discontinuing
Contraception: Note: Patients not currently using a hormonal contraceptive may receive the first dose at any time during the menstrual cycle if reasonably sure the patient is not pregnant. If administration is ≤7 days since menstrual bleeding started, no additional contraception is needed. If >7 days since menstrual bleeding started, abstain from sexual intercourse, or use additional contraceptive protection (nonhormonal) for the next 7 days (CDC [Curtis 2016a]). Use is not recommended for long-term (ie, longer than 2 years) birth control unless other options are considered inadequate.
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)
a CDC [Curtis 2016a]. b Depo-Provera CI prescribing information. c Depo-SubQ Provera 104 prescribing information. d Also refer to prescribing information for product-specific information. | |
• DMPA may be initiated if it is reasonably sure the patient is not pregnanta • Ensure continuous contraceptive coverage based upon the mechanism of action of both contraception methodsb | |
Current method |
Instructions for switching to DMPA |
Combined oral contraceptivec |
Administer first injection within 7 days of taking the last active tablet |
DMPA- IMc |
When switching from the DMPA-IM to DMPA-SUBQ formulation, the DMPA-SUBQ dose should be administered 12 to 14 weeks after the last DMPA-IM injection |
Implantc |
Administer first injection on day of implant removal |
Intrauterine device (IUD)a,c,d |
If sexual intercourse occurred since the start of the current menstrual cycle and it is >5 days since menstrual bleeding began: • Initiate DMPA and keep the IUD in place for ≥7 days before removing • Alternately, abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to DMPA • Consider use of emergency contraception if either option is not available (refer to guideline for details) |
Transdermal systemc |
Administer first injection on day the next application would be scheduled |
Vaginal insertc |
Administer first injection on the day when the next insertion would be scheduled |
Use after childbirth |
Patients who are breastfeeding: • The first injection may be administered the sixth week after birth (per manufacturer) or anytime <1 month postpartuma,b,c • The first injection may be administered ≥1 month postpartum if it is reasonably certain the patient is not pregnanta Patients who are not breastfeeding: • The first injection may be administered anytime it is reasonably certain the patient is not pregnanta Patients ≥21 days postpartum who have not had a return of menses, or who are not fully or nearly fully breastfeeding should abstain from sexual intercourse or use barrier contraception for the next 7 daysa Patients ≥21 days postpartum who have had a return of menses, but the injection is administered >7 days since menstrual bleeding started should abstain from sexual intercourse or use barrier contraception for the next 7 daysa |
Use after abortion |
The first DMPA injection may be administered within the first 7 days after a spontaneous or induced abortiona DMPA may be administered immediately following a septic abortiond Additional contraceptive protection (nonhormonal) is needed for the next 7 days unless the injection is administered at the time of surgical abortiona |
a CDC [Curtis 2016a]. b Depo-Provera CI prescribing information. c Depo-SubQ Provera 104 prescribing information. d CDC [Curtis 2016b]. |
a CDC [Curtis 2016a]. | |
Early dose |
A repeat dose of DMPA may be administered early when necessary. |
Late dose |
If >2 weeks since dose was due (>15 weeks since last injection) the injection may be administered if is reasonably certain the patient is not pregnant. Additional contraceptive protection (nonhormonal) is needed for the next 7 days. Consider use of emergency contraception if appropriate. |
Endometrial carcinoma, recurrent or metastatic (adjunctive/palliative treatment):
IM (Depo-Provera): Initial: 400 to 1,000 mg/week
Oral: Canadian 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 prevention in postmenopausal persons receiving daily conjugated estrogen (alternative agent): 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 persons, 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. Treatment is indicated for postmenopausal persons with a uterus to decrease the risk of endometrial cancer; persons who have had a hysterectomy generally do not need a progestin. Due to safety considerations, when a progesterone is needed, use of micronized progesterone is preferred over medroxyprogesterone acetate (AACE [Goodman 2011]; AACE/ACE [Cobin 2017]).
Endometrial hyperplasia, treatment (off-label use): Note: The optimal duration of therapy is unknown (ACOG 631 2015; Armstrong 2012; Trimble 2012).
Endometrial hyperplasia with atypia (also known as atypical endometrial hyperplasia or endometrial intraepithelial neoplasia ): Oral: 10 to 20 mg once daily (continuous dosing) or 10 to 20 mg once daily (cyclic dosing) for 12 to 14 days per month (ACOG 631 2015; Trimble 2012).
Endometrial hyperplasia without atypia (also known as nonatypical endometrial hyperplasia or benign endometrial hyperplasia): Oral: 10 mg once daily (continuous dosing) (Orbo 2014) or 10 mg once daily (cyclic dosing) for 10 to 12 days per cycle (Abu Hashim 2015); continuous daily oral dosing was shown to be superior to cyclic oral dosing (Orbo 2014).
Endometriosis (104 mg/0.65 mL injection): SUBQ: 104 mg every 3 months (every 12 to 14 weeks). Note: Use is not recommended for long-term (ie, longer than 2 years) endometriosis-associated pain unless other options are considered inadequate.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Medroxyprogesterone is extensively metabolized in the liver and elimination is significantly reduced in patients with advanced hepatic disease. 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.
Discontinue if jaundice develops or if acute or chronic hepatic function disturbances occur; do not resume until liver function returns to normal. In patients with a history of cholestatic jaundice, discontinue if cholestatic jaundice recurs.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Suspension, Intramuscular, as acetate:
Depo-Provera: 150 mg/mL (1 mL) [contains methylparaben, polyethylene glycol, polysorbate 80, propylparaben]
Depo-Provera: 400 mg/mL (2.5 mL) [contains polyethylene glycol]
Generic: 150 mg/mL (1 mL)
Suspension Prefilled Syringe, Intramuscular, as acetate:
Depo-Provera: 150 mg/mL (1 mL) [contains methylparaben, polyethylene glycol, polysorbate 80, propylparaben]
Generic: 150 mg/mL (1 mL)
Suspension Prefilled Syringe, Subcutaneous, as acetate:
Depo-SubQ Provera 104: 104 mg/0.65 mL (0.65 mL) [contains methylparaben, polyethylene glycol, polysorbate 80, propylparaben]
Tablet, Oral, as acetate:
Provera: 2.5 mg, 5 mg [DSC] [scored]
Provera: 5 mg [contains corn starch, fd&c blue #2 aluminum lake]
Provera: 10 mg [scored]
Generic: 2.5 mg, 5 mg, 10 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, IM, as acetate:
Depo-Provera: 50 mg/mL (1 mL)
Tablet, Oral, as acetate: 100 mg
Provera: 2.5 mg, 5 mg, 10 mg
Oral: Administer with food
Parenteral:
IM: (Depo-Provera Contraceptive): Shake suspension vigorously; administer by deep IM injection in the gluteal or deltoid muscle
SubQ (depo-subQ provera 104): Shake vigorously for at least 1 minute; administer by subQ injection slowly over 5 to 7 seconds in the anterior thigh or abdomen; avoid boney areas and the umbilicus. Do not rub the injection area; not for IM or IV use.
IM: Depo-Provera Contraceptive: Administer first dose during the first 5 days of menstrual period, or within the first 5 days postpartum if not breastfeeding, or at the sixth week postpartum if breastfeeding exclusively. Shake vigorously prior to administration. Administer by deep IM injection in the gluteal or deltoid muscle. Rotate administration site with each injection. Injection must be administered by a health care professional only.
SUBQ: Depo-SubQ Provera 104: Administer first dose during the first 5 days of menstrual period, or at the sixth week postpartum if breastfeeding. Shake vigorously for at least 1 minute prior to administration. Administer by SUBQ injection in the upper anterior thigh or abdomen; avoid boney areas and the umbilicus. Administer slowly over 5 to 7 seconds. Do not rub the injection area. Rotate administration site with each injection. Product labeling recommends the SUBQ injection be administered by a health care professional; however, patient administration is also an option (CDC [Curtis 2021]).
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Store at 20°C to 25°C (68°F to 77°F).
Secondary amenorrhea or abnormal uterine bleeding due to hormonal imbalance; prevention of pregnancy; reduction of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving conjugated estrogens; endometrial carcinoma; management of endometriosis-associated pain (FDA approved in adults)
Depo-Provera may be confused with DEPO-Medrol, depo-subQ provera 104
MedroxyPROGESTERone may be confused with HYDROXYprogesterone caproate, methylPREDNISolone, methylTESTOSTERone
Provera may be confused with Covera, Femara, Parlodel, Premarin, Proscar, PROzac
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
The injectable dosage form is available in different formulations. Carefully review prescriptions to assure the correct formulation and route of administration.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse effects as reported with any dosage form.
>10%:
Endocrine & metabolic: Amenorrhea (6% to 68%), change in menstrual flow (18%; including irregular, increase or decrease flow, and spotting), hot flash (≤36%), menstrual disease (IM: 57% at 12 months; 32% at 24 months), weight gain (7% to 38%), weight loss (≤12%)
Gastrointestinal: Abdominal pain (4% to 11%)
Nervous system: Headache (9% to 17%), nervousness (11%)
1% to 10%:
Cardiovascular: Edema (2%)
Dermatologic: Acne vulgaris (1% to 4%), alopecia (1%), skin rash (1%)
Endocrine & metabolic: Decreased libido (3% to 6%)
Gastrointestinal: Abdominal distension (1% to <5%), bloating (2%), diarrhea (1% to <5%), nausea (1% to <5%)
Genitourinary: Bacterial vaginosis (≤5%), breast tenderness (≤2%), dysmenorrhea (≤2%), leukorrhea (3%), mastalgia (≤3%), urinary tract infection (4%), vaginitis (≤5%), vulvovaginal candidiasis (≤5%)
Local: Atrophy at injection site (≤1%), induration at injection site (≤1%), injection site reaction (5% to 6%)
Nervous system: Anxiety (1%), depression (2% to 3%), dizziness (1% to 6%), fatigue (≤4%), insomnia (1%), irritability (1%)
Neuromuscular & skeletal: Arthralgia (2%), asthenia (≤4%), back pain (2% to 3%), lower limb cramp (4%)
<1%:
Cardiovascular: Chest pain, syncope, tachycardia
Dermatologic: Pruritus, urticaria
Endocrine & metabolic: Fluid retention, galactorrhea not associated with childbirth
Gastrointestinal: Abdominal distension, diarrhea
Genitourinary: Dyspareunia, lump in breast
Hematologic & oncologic: Anemia
Hypersensitivity: Hypersensitivity reaction
Nervous system: Drowsiness, facial nerve paralysis, paresthesia
Respiratory: Asthma, dyspnea
Frequency not defined:
Cardiovascular: Acute myocardial infarction, cerebrovascular accident, retinal thrombosis
Dermatologic: Skin discoloration at injection site
Endocrine & metabolic: Decreased glucose tolerance, drug-induced Cushing’s syndrome, hypercalcemia, lipodystrophy, spotty menstruation
Genitourinary: Change in cervical erosion, change in cervical secretions, nipple discharge
Hepatic: Cholestatic jaundice
Local: Injection site nodule, tenderness at injection site
Nervous system: Euphoria, malaise
Ophthalmic: Optic neuritis
Postmarketing:
Cardiovascular: Deep vein thrombosis, pulmonary embolism, thrombophlebitis, varicose veins
Dermatologic: Chloasma, diaphoresis, skin discoloration (melasma)
Endocrine & metabolic: Breast changes, hirsutism, increased libido, increased thirst
Gastrointestinal: Change in appetite
Genitourinary: Anovulation (prolonged), delayed return to fertility, genitourinary infection, lactation insufficiency, malignant neoplasm of cervix, nipple bleeding, uterine hyperplasia, vaginal cyst
Hematologic & oncologic: Malignant neoplasm of breast, rectal hemorrhage
Hepatic: Jaundice
Hypersensitivity: Anaphylaxis, angioedema, nonimmune anaphylaxis
Local: Residual mass at injection site, sterile abscess at injection site
Nervous system: Chills
Neuromuscular & skeletal: Axillary swelling, decreased bone mineral density, osteoporosis, pathological fracture due to osteoporosis, systemic sclerosis
Miscellaneous: Fever
Injection (104 mg/0.65 mL): Hypersensitivity to medroxyprogesterone or any component of the formulation; active thrombophlebitis; thromboembolic disorders (current or history of); cerebral vascular disease; undiagnosed vaginal bleeding; breast cancer (known, suspected, or history of); significant hepatic disease.
Injection (150 mg/mL): Hypersensitivity to medroxyprogesterone or any component of the formulation; active thrombophlebitis; thromboembolic disorders (current or history of) or cerebral vascular disease; undiagnosed vaginal bleeding; breast cancer (known, suspected, or history of); significant hepatic disease; pregnancy; diagnostic test for pregnancy.
Injection (400 mg/mL): Hypersensitivity to medroxyprogesterone or any component of the formulation; active thrombophlebitis; thromboembolic disorders (current or history of); cerebral vascular disease.
Tablet: Anaphylactic reaction or angioedema to medroxyprogesterone; 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 Canadian product indicated for endometrial cancer); undiagnosed abnormal genital bleeding; breast cancer (known, suspected, or history of); hepatic impairment or disease; pregnancy.
Canadian labeling: Additional contraindications (not in the US labeling):
Injection (50 mg/mL, 150 mg/mL): History of or current benign or malignant liver tumors; current or history of migraine with focal aura; any ocular lesion arising from ophthalmic vascular disease, such as partial or complete loss of vision or defect in visual fields; undiagnosed breast pathology; known or suspected progestin-dependent neoplasia; MI or coronary artery disease (current or history of); urinary tract bleeding; presence of severe or multiple risk factors for arterial or venous thrombosis including the following: severe hypertension (persistent bp ≥160/100 mm Hg); hereditary or acquired predisposition for venous or arterial thrombosis (eg, Factor V leiden and Prothrombin G20210 A mutation, activated protein C (APC) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinanemia and antiphospholipid-antibodies (anticardiolipin antibodies, lupus anticoagulant); severe dyslipoproteinemia; heavy smoking (>15 cigarettes per day) and older than 35 years of age; diabetes mellitus with vascular involvement.
Tablet: Partial or complete loss of vision due to ophthalmic vascular disease.
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.
• Bleeding irregularities: Amenorrhea, bleeding or spotting that is irregular or unpredictable, prolonged spotting or bleeding, or heavy bleeding may occur with use of medroxyprogesterone contraceptive injection. Breakthrough vaginal bleeding may also occur when used for other indications. Evaluate abnormal bleeding that persists or is severe.
• Bone mineral density loss: Prolonged use of medroxyprogesterone injection may result in a loss of bone mineral density. 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 or alternative medical therapy for endometriosis-associated pain 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 antiseizure medications or corticosteroids). All patients should have adequate calcium and vitamin D intake.
• Breast cancer: Based on data from the Women's Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in postmenopausal women using oral conjugated estrogens (CE) in combination with oral medroxyprogesterone acetate (MPA). The risk of breast cancer in postmenopausal patients on hormone therapy may depend upon type of estrogen and/or progestin, dose, timing of therapy initiation, duration of therapy, route of administration, and individual patient characteristics (AACE/ACE [Cobin 2017]; NAMS 2017). Hormone therapy may be associated with increased breast density (NAMS 2017); an increase in abnormal mammogram findings requiring further evaluation has been reported with estrogen alone or in combination with progestin therapy. Most studies do not see an increased risk of breast cancer following medroxyprogesterone use for contraception (Chelmow 2020). However, breast cancer is a hormonal sensitive tumor and the prognosis for patients with a current or recent history of breast cancer may be worse with progestin-only contraceptive use (CDC [Curtis 2016b]). Use of medroxyprogesterone for the treatment of endometrial carcinoma is not recommended in patients with known or suspected breast cancer and patients with a strong family history of breast cancer should be carefully monitored.
• Dementia: Estrogens with or without progestin should not be used to prevent dementia. Hormone therapy is not recommended at any age to prevent or treat cognitive decline or dementia (AACE [Goodman 2011]; NAMS 2017).
• Ectopic pregnancy: When used for contraception, the possibility of ectopic pregnancy should be considered in patients with severe abdominal pain.
• Endometrial hyperplasia: MPA is used to reduce the risk of endometrial hyperplasia in nonhysterectomized postmenopausal patients receiving conjugated estrogens. MPA is not the preferred progesterone for this indication (AACE [Goodman 2011]; AACE/ACE [Cobin 2017]). The use of unopposed estrogen in patients 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 patients with undiagnosed abnormal vaginal bleeding. The use of a progestin is not generally required when low doses of estrogen are used locally for vaginal atrophy, although long-term data (>1 year) supporting this recommendation are lacking (NAMS 2017; NAMS 2020).
• Hypertriglyceridemia: In patients using estrogen plus progesterone therapy, triglycerides may be increased in patients with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs.
• Ovarian cancer: Available information related to the use of menopausal estrogen or estrogen/progestin therapy and risk of ovarian cancer is inconsistent. If an association is present, the absolute risk is likely rare and may be influenced by duration of therapy (AACE [Goodman 2011]; ES [Stuenkel 2015]; NAMS 2017).
• Retinal 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.
Disease-related concerns:
• Asthma: Use with caution in patients with asthma; may exacerbate disease.
• Cardiovascular disease: Using data from the Women’s Health Initiative (WHI) studies, an increased risk of deep vein thrombosis (DVT), pulmonary emboli (PE), and stroke has been reported with oral estrogen plus progestin therapy 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 immediately if adverse cardiovascular events occur or are suspected. When used for contraception, use caution in patients with risk factors for cardiovascular disease (CDC [Curtis 2016b]). If thrombosis develops with contraceptive treatment, discontinue treatment (unless no other acceptable contraceptive alternative).
• Depression: Monitor patients with a history of depression; consider discontinuing if depression recurs.
• Diabetes: Medroxyprogesterone therapy may have adverse effects on glucose tolerance; monitor patients with diabetes mellitus.
• Diseases exacerbated by fluid retention: Use with caution in patients with diseases that may be exacerbated by fluid retention, including cardiac or renal dysfunction.
• Epilepsy: Use with caution in patients with epilepsy; may exacerbate disease.
• Hepatic dysfunction: Use caution in patients with a history of cholestatic jaundice associated with prior estrogen use or pregnancy.
• Hepatic hemangiomas: Use estrogen plus progestin therapy with caution in patients with hepatic hemangiomas; may exacerbate disease.
• Hypoparathyroidism: Use estrogen plus progestin therapy with caution in patients with hypoparathyroidism; estrogen-induced hypocalcemia may occur.
• 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.
Special populations:
• Body weight: Contraceptive therapy with medroxyprogesterone commonly results in an average weight gain of ~3.5 kg after 2 years of treatment. Dose adjustment of depo-medroxyprogesterone 150 mg/mL IM or 104 mg/0.65 mL SUBQ contraceptive injections is not required based on body weight.
• 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.
Other warnings/precautions:
• Abnormal uterine bleeding: When considering specific treatment for acute or chronic abnormal uterine bleeding due to ovulatory dysfunction (not structural causes), consideration should be given to medical contraindications to available therapies as well as if simultaneous contraception is needed or pregnancy is desired (ACOG 136 2013; ACOG 557 2013).
• Endometrial carcinoma: When used for endometrial carcinoma, the effects of long-term use on adrenal, hepatic, ovarian, pituitary, and uterine function is not known. Use for endometrial carcinoma may mask the onset of menopause.
• HIV infection protection: Injectable contraceptives do not protect against HIV infection or other sexually transmitted diseases.
• Menopause: When used for the relief of menopausal symptoms, the benefit-risk of combination hormone therapy is most favorable if started in patients who have no contraindications to therapy, are <60 years of age, within 10 years of menopause onset, have a favorable lipid profile, and do not have the factor V Leiden genotype or metabolic syndrome. Risk factors for cardiovascular disease should also be considered when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2017). 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 patient.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Aprepitant: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration with aprepitant, and to continue back-up contraception for 28 days after discontinuing aprepitant to ensure contraceptive reliability. Risk D: Consider therapy modification
Asunaprevir: May decrease the serum concentration of Hormonal Contraceptives. Management: Use of a high-dose oral contraceptive (at least 30 mcg of ethinyl estradiol combined with norethindrone) is recommended when combined with asunaprevir. Consider an additional barrier method when other forms of contraception are used with asunaprevir. Risk D: Consider therapy modification
Atazanavir: May decrease the serum concentration of Hormonal Contraceptives. Specifically, atazanavir/ritonavir may decrease concentrations of estrogens. Atazanavir may increase the serum concentration of Hormonal Contraceptives. Specifically, atazanavir alone may increase concentrations of estrogens and atazanavir alone or boosted may increase concentrations of progestins. Management: Dose adjustment of hormonal contraceptives or use of alternative or additional nonhormonal contraceptive may be needed when combined with atazanavir. See full interact monograph for details. Atazanavir/cobicistat with drospirenone is contraindicated. Risk D: Consider therapy modification
Brigatinib: May decrease the serum concentration of Hormonal Contraceptives. Management: Use a non-hormonal contraceptive during brigatinib use and for at least 4 months after the last brigatinib dose. Males with partners of reproductive potential should use contraception during treatment with brigatinib and for 3 months after brigatinib use. Risk D: Consider therapy modification
Carfilzomib: Hormonal Contraceptives may enhance the thrombogenic effect of Carfilzomib. Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib, especially patients using carfilzomib in combination with dexamethasone, lenalidomide plus dexamethasone, or daratumumab plus dexamethasone. Risk D: Consider therapy modification
Choline C 11: Antiandrogens may diminish the therapeutic effect of Choline C 11. Risk C: Monitor therapy
Cladribine: May diminish the therapeutic effect of Hormonal Contraceptives. Management: In females of reproductive potential using systemically acting hormonal contraceptives, add a barrier method during cladribine dosing and for at least 4 weeks after the last dose in each treatment course Risk D: Consider therapy modification
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Cobicistat: May decrease the serum concentration of Hormonal Contraceptives. Specifically, cobicistat may decrease serum concentrations of estrogens. Cobicistat may increase the serum concentration of Hormonal Contraceptives. Specifically, cobicistat may increase serum concentrations of progestins. Management: Use alternative or additional nonhormonal forms of contraception when estrogen-containing hormonal contraceptives are combined with cobicistat. Progestin-only contraceptives can be used without back up, but monitor for progestin toxicities. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a moderate CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a strong CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification
CYP3A4 Inducers (Weak): May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a weak CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Hormonal Contraceptives. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Efavirenz: May decrease the serum concentration of Hormonal Contraceptives. Management: Use a back-up method during coadministration, and to continue back-up contraception for 12 weeks after stopping efavirenz to ensure contraceptive reliability. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Risk D: Consider therapy modification
Elagolix: Hormonal Contraceptives may diminish the therapeutic effect of Elagolix. Specifically, estrogen-containing hormonal contraceptives may diminish the therapeutic effects of elagolix. Elagolix may increase the serum concentration of Hormonal Contraceptives. Specifically, concentrations of ethinyl estradiol may be increased with elagolix therapy. Elagolix may decrease the serum concentration of Hormonal Contraceptives. Specifically, concentrations of progestins may be decreased with elagolix therapy. Management: Use an alternative, nonhormonal contraceptive during treatment with elagolix and for at least 28 days following discontinuation of elagolix treatment. Use of elagolix 200 mg twice daily with an estrogen-containing hormonal contraceptive is not recommended Risk D: Consider therapy modification
Elexacaftor, Tezacaftor, and Ivacaftor: Hormonal Contraceptives may enhance the adverse/toxic effect of Elexacaftor, Tezacaftor, and Ivacaftor. Specifically, the risk for rash may be increased. Risk C: Monitor therapy
Encorafenib: May decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Etravirine: May decrease the serum concentration of Hormonal Contraceptives. Specifically, progestin concentrations may decrease. Etravirine may increase the serum concentration of Hormonal Contraceptives. Specifically, estrogen concentrations may increase. Risk C: Monitor therapy
Exenatide: Hormonal Contraceptives may diminish the therapeutic effect of Exenatide. Exenatide may decrease the serum concentration of Hormonal Contraceptives. Management: Administer oral hormonal contraceptives at least one hour prior to exenatide. Monitor blood glucose more frequently when patients treated with exenatide initiate therapy with a hormonal contraceptive. Increases in exenatide doses may be needed. Risk D: Consider therapy modification
Felbamate: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing felbamate to ensure contraceptive reliability. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Flibanserin: Hormonal Contraceptives may increase the serum concentration of Flibanserin. Risk C: Monitor therapy
Fosaprepitant: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration with fosaprepitant, and to continue back-up contraception for 28 days after discontinuing fosaprepitant to ensure contraceptive reliability. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Gallium Ga 68 PSMA-11: Antiandrogens may diminish the therapeutic effect of Gallium Ga 68 PSMA-11. Management: Therapies targeting the androgen pathway may result in changes in the uptake of gallium Ga 68 PSMA-11 in prostate cancer. The impact of these therapies on the performance of gallium Ga 68 PSMA-11 is unknown; consider use of alternative agents. Risk D: Consider therapy modification
Griseofulvin: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing griseofulvin to ensure contraceptive reliability. Risk D: Consider therapy modification
Indium 111 Capromab Pendetide: Antiandrogens may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination
Interleukin-6 (IL-6) Inhibiting Therapies: May decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Ivosidenib: May decrease the serum concentration of Hormonal Contraceptives. Management: Consider alternative methods of contraception (ie, non-hormonal) in patients receiving ivosidenib. Risk D: Consider therapy modification
Ixazomib: May decrease the serum concentration of Hormonal Contraceptives. More specifically, use of ixazomib with dexamethasone may decrease the serum concentrations of hormonal contraceptives. Management: Patients of reproductive potential should use a non-hormonal contraceptive method during treatment with ixazomib and for at least 90 days after the last ixazomib dose. Risk D: Consider therapy modification
LamoTRIgine: May decrease the serum concentration of Progestins (Contraceptive). Risk C: Monitor therapy
Lixisenatide: Hormonal Contraceptives may diminish the therapeutic effect of Lixisenatide. Lixisenatide may decrease the serum concentration of Hormonal Contraceptives. Management: Administer oral hormonal contraceptives 1 hour before or at least 11 hours after administration of lixisenatide. Additionally, monitor blood glucose more frequently when patients treated with lixisenatide initiate therapy with a hormonal contraceptive. Risk D: Consider therapy modification
MiFEPRIStone: May diminish the therapeutic effect of Hormonal Contraceptives. Management: Nonhormonal contraception should be used during, and for 4 weeks following, mifepristone treatment for hyperglycemia due to Cushing syndrome. If used for pregnancy termination, hormonal contraceptives can be used after pregnancy expulsion is confirmed. Risk D: Consider therapy modification
Mobocertinib: May decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination
Mycophenolate: May decrease the serum concentration of Hormonal Contraceptives. Management: Patients of childbearing potential who are taking hormonal contraceptives should use an additional form of barrier contraception during treatment with mycophenolate and for 6 weeks after mycophenolate discontinuation. Risk D: Consider therapy modification
Octreotide: May decrease the serum concentration of Hormonal Contraceptives. Management: Women should use an alternative non-hormonal method of contraception or a back-up method when octreotide is combined with hormonal contraceptives. Risk D: Consider therapy modification
OXcarbazepine: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing oxcarbazepine to ensure contraceptive reliability. Risk D: Consider therapy modification
Pegloticase: May diminish the therapeutic effect of PEGylated Drug Products. Risk C: Monitor therapy
Pegvaliase: MedroxyPROGESTERone may enhance the adverse/toxic effect of Pegvaliase. Specifically, the risk of anaphylaxis or hypersensitivity reactions may be increased. Risk C: Monitor therapy
Perampanel: May decrease the serum concentration of Hormonal Contraceptives. Management: Patients should use an alternative, nonhormonal-based form of contraception during the concurrent use of perampanel and for 1 month after discontinuing perampanel. Risk D: Consider therapy modification
Pexidartinib: May decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination
Piflufolastat F18: Antiandrogens may diminish the diagnostic effect of Piflufolastat F18. Management: Therapies targeting the androgen pathway may result in changes in the uptake of piflufolastat F18 in prostate cancer. The impact of these therapies on the performance of piflufolastat F18 is unknown; consider use of alternative agents. Risk D: Consider therapy modification
Pitolisant: May decrease the serum concentration of Hormonal Contraceptives. Management: Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with pitolisant and for at least 21 days after discontinuation of pitolisant treatment. Risk D: Consider therapy modification
Protease Inhibitors: May decrease the serum concentration of Hormonal Contraceptives. Specifically, protease inhibitors may decrease concentrations of estrogens. Protease Inhibitors may increase the serum concentration of Hormonal Contraceptives. Specifically, protease inhibitors may increase concentrations of progestins. Management: Use alternative or additional nonhormonal forms of contraception when estrogen-containing hormonal contraceptives are combined with protease inhibitors. Progestin-only contraceptives can be used without back up, but monitor for progestin toxicities. Risk D: Consider therapy modification
Sugammadex: May diminish the therapeutic effect of Hormonal Contraceptives. 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. Risk D: Consider therapy modification
Tazemetostat: May decrease the serum concentration of Hormonal Contraceptives. Management: Individuals of childbearing potential should use a non-hormonal contraceptive method during treatment with tazemetostat and for 6 months after. Males with partners of childbearing potential should use contraception during treatment and for 3 months after. Risk D: Consider therapy modification
Tetrahydrocannabinol and Cannabidiol: May decrease the serum concentration of Hormonal Contraceptives. Management: Patients taking hormonal contraceptives should use an additional, non-hormonal contraceptive or reliable barrier method during treatment with tetrahydrocannabinol and cannabidiol buccal spray. Risk D: Consider therapy modification
Thalidomide: Hormonal Contraceptives may enhance the thrombogenic effect of Thalidomide. Risk C: Monitor therapy
Topiramate: May decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing topiramate to ensure contraceptive reliability. Risk D: Consider therapy modification
Tranexamic Acid: Hormonal Contraceptives may enhance the thrombogenic effect of Tranexamic Acid. Risk X: Avoid combination
Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Risk X: Avoid combination
Vitamin K Antagonists (eg, warfarin): Hormonal Contraceptives may increase the serum concentration of Vitamin K Antagonists. Hormonal Contraceptives may decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy
Voriconazole: Hormonal Contraceptives may increase the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Hormonal Contraceptives. Risk C: Monitor therapy
Bioavailability of the oral tablet is increased when taken with food; half-life is unchanged. Management: Administer without regard to food.
Ensure adequate calcium and vitamin D intake
Depo-medroxyprogesterone 104 mg/0.65 mL and 150 mg/mL injections are used for contraception. Use is not recommended as a long-term (ie, longer than 2 years) birth control method unless other options are considered inadequate.
All available forms of contraception, including depo-medroxyprogesterone acetate (DMPA) injection, can be considered for patients on gender-affirming testosterone therapy after evaluating patient preferences and medical conditions (Bonnington 2020; Krempasky 2020). DMPA may help induce amenorrhea more rapidly than other progestin-only methods when testosterone is initiated. DMPA may cause weight gain; other forms of contraception may be preferred for patients already experiencing weight gain with testosterone therapy (Bonnington 2020).
Median time to conception/return to ovulation following discontinuation of DMPA contraceptive injection is 10 months following the last injection and is unrelated to the duration of use.
High doses of medroxyprogesterone used for indications other than contraception would be expected to impair fertility.
In general, there is not an increased risk of birth defects following inadvertent use of the injectable depo-medroxyprogesterone acetate (DMPA) 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 medroxyprogesterone during the first trimester of pregnancy. When used for contraception, the possibility of ectopic pregnancy should be considered in patients with severe abdominal pain; ectopic pregnancies have been reported with use of the DMPA contraceptive injection.
Before starting therapy, a physical exam with reference to the breasts and pelvis are recommended, including a Papanicolaou smear. Exam may be deferred if appropriate prior to administration of MPA contraceptive injection; pregnancy should be ruled out prior to use. Monitor patient closely for loss of vision; sudden onset of proptosis, diplopia, or migraine; signs and symptoms of thromboembolic disorders; signs and symptoms of depression; glucose in patients with diabetes; or blood pressure. BMD with long-term use.
Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding.
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).
Onset of action: Time to ovulation (after last injection): 10 months (range: 6 to 12 months)
Absorption: Oral: Rapid; IM: Slow
Protein binding: 86% to 90% primarily to albumin; does not bind to sex hormone-binding globulin
Metabolism: Extensively hepatic via hydroxylation and conjugation; forms metabolites
Bioavailability: 0.6% to 10%
Half-life elimination: Oral: 12 to 17 hours; IM (Depo-Provera Contraceptive): ~50 days; SubQ: ~43 days
Time to peak: Oral: 2 to 4 hours; IM (Depo-Provera Contraceptive): ~3 weeks; SubQ: ~1 week
Excretion: Urine
Suspension (Depo-Provera Intramuscular)
150 mg/mL (per mL): $63.16
Suspension (medroxyPROGESTERone Acetate Intramuscular)
150 mg/mL (per mL): $41.27 - $97.85
Suspension Prefilled Syringe (Depo-Provera Intramuscular)
150 mg/mL (per mL): $65.94
Suspension Prefilled Syringe (Depo-SubQ Provera 104 Subcutaneous)
104 mg/0.65 mL (per 0.65 mL): $63.16
Suspension Prefilled Syringe (medroxyPROGESTERone Acetate Intramuscular)
150 mg/mL (per mL): $66.00 - $115.20
Tablets (medroxyPROGESTERone Acetate Oral)
2.5 mg (per each): $0.31
5 mg (per each): $0.47
10 mg (per each): $0.49
Tablets (Provera Oral)
2.5 mg (per each): $3.14
5 mg (per each): $4.72
10 mg (per each): $6.16
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