medroxyprogesterone (Rx)

>10%

SC

• Dysfunctional uterine bleeding (irregular, increase, decrease, spotting) (18%)

1-10%

SC

• Headache (9%)
• Increased weight (7%)
• Amenorrhea (6%)
• Injection site reactions (6%)
• Vaginitis, including candidiasis and bacterial (5%)
• Abdominal pain (4%)
• Urinary tract infections (4%)
• Acne (4%)
• Depression (3%)
• Decreased libido (3%)
• Nausea (3%)
• Back pain (3%)
• Breast pain/tenderness (2%)
• Fatigue (2%)
• Anxiety (1%)
• Irritability (1%)
• Dizziness (1%)

<1%

SC

• Breast lump
• Anemia
• Drug hypersensitivity
• Weight decreased
• Fluid retention
• Facial palsy
• Syncope
• Paresthesia
• Somnolence
• Tachycardia
• Hot flushes
• Asthma
• Dyspnea
• Diarrhea
• Abdominal distension
• Urticaria
• Pruritus
• Dry skin
• Dysmenorrhea
• Galactorrhea
• Dyspareunia
• Chest pain

Frequency Not Defined

IM

• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Changes in cervical erosion and cervical secretions
• Breast tenderness and galactorrhea
• Erectile dysfunction
• Headache
• Dizziness
• Somnolence
• Convulsions
• Nervousness
• Euphoria
• Mental depression
• Insomnia
• Edema
• Pyrexia
• Fatigue
• Malaise
• Injection site reaction (eg, pain/tenderness, persistent atrophy/indentation/dimpling)
• Change in weight
• Cholestatic jaundice
• Skin sensitivity reactions
• Acne
• Alopecia
• Hirsutism
• Rash (allergic) with and without pruritus
• Anaphylactoid reactions
• Angioedema
• Nausea
• Corticoid-like effects (eg, Cushingoid syndrome)
• Hypercalcemia

PO

• Genitourinary system: Abnormal uterine bleeding (irregular, increase, decrease), change in menstrual flow, breakthrough bleeding, spotting, amenorrhea, changes in cervical erosion and cervical secretions
• Breast: Breast tenderness, mastodynia, galactorrhea
• Cardiovascular: Thromboembolic disorders (eg, thrombophlebitis, pulmonary embolism)
• Gastrointestinal: Nausea, cholestatic jaundice
• Skin: Sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash have occurred. Acne, alopecia and hirsutism have been reported.
• Eyes: Neuro-ocular lesions, for example, retinal thrombosis, and optic neuritis.
• Central nervous system: Mental depression, insomnia, somnolence, dizziness, headache, nervousness.
• Miscellaneous: Hypersensitivity reactions (for example, anaphylaxis and anaphylactoid reactions, angioedema), rash (allergic) with and without pruritus, change in weight (increase or decrease), pyrexia, edema/fluid retention, fatigue, decreased glucose tolerance.

Estrogen plus progestin therapy

• Genitourinary system: Abnormal uterine bleeding/spotting, or flow; breakthrough bleeding; spotting; dysmenorrheal/pelvic pain; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.
• Breasts: Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.
• Cardiovascular: Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.
• Gastrointestinal: Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis; enlargement of hepatic hemangiomas.
• Skin: Chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.
• Eyes: Retinal vascular thrombosis, intolerance to contact lenses.
• Central nervous system: Headache, migraine, dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia.
• Miscellaneous: Increase or decrease in weight, reduced carbohydrate tolerance, aggravation of porphyria, edema, arthralgias, leg cramps, changes in libido, urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides

Contraindications

Undiagnosed abnormal genital bleeding

Known, suspected, or history of breast cancer

Known or suspected estrogen- or progesterone-dependent neoplasia

Active DVT, PE, or a history of these conditions

Active arterial thromboembolic disease (eg, stroke, MI), or a history of these conditions

Known anaphylactic reaction or angioedema

Known liver impairment or disease

Known or suspected pregnancy

Cautions

Use caution in patients with asthma, diabetes mellitus, history of depression, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas

Prolonged use of SC or IM use may result in significant loss of bone density; long-term use is not recommended (ie, >2 years) as birth control method or medical therapy for endometriosis-associated pain unless other options considered inadequate

In women with osteoporosis risk factors, other birth control methods or therapies for endometriosis-associated pain should be considered risk/benefit analysis for SC use; SC can pose an additional risk in patients with risk factors for osteoporosis (eg, metabolic bone disease, chronic alcohol and/or tobacco use, anorexia nervosa, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids)

Consider ectopic pregnancy if a woman receiving therapy becomes pregnant or complains of severe abdominal pain

Provide emergency medical treatment if anaphylaxis occurs

Not for use in children prior to menarche

Inform medroxyprogesterone contraceptive does not protect against HIV infection and other sexually transmitted diseases

Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer

In some epidemiologic studies, use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer; however, duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association

Depression and other mood disorders have been reported; discontinue if it occurs

Most women experienced changes in menstrual bleeding patterns, such as amenorrhea, irregular unpredictable spotting or bleeding, prolonged spotting or bleeding, or heavy bleeding; in cases of unexpected abnormal vaginal bleeding, adequate diagnostic measures are indicated

Monitor blood pressure at regular intervals with estrogen plus progestin therapy

In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis; consider discontinuation of treatment if pancreatitis occurs

Progestins may cause some degree of fluid retention; women with condition influenced by fluid retention including epilepsy, migraine, asthma, cardiac or renal dysfunction, require careful observation

Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur

Therapy should be discontinued pending examination if there is a sudden partial or complete loss of vision, or if there is a sudden onset of proptosis; diplopia or migraine; if examination reveals papilledema or retinal vascular lesions, medication should be withdrawn

Patients may exhibit suppressed adrenal function; medroxyprogesterone acetate may have cortisol-like glucocorticoid activity and provide negative feedback to hypothalamus or pituitary; this may result in decreased plasma cortisol levels, decreased cortisol secretion, and low plasma ACTH levels; use of sterile aqueous suspension may, due to its cortisol-like glucocorticoid activity, also produce Cushingoid symptoms such as weight gain, edema/fluid retention, and facial swelling

Monitor patients for hepatic dysfunction periodically and temporarily interrupt therapy if patient develops hepatic dysfunction; do not resume use until markers of liver function return to normal

Any multidose use of vials may lead to contamination unless strict aseptic technique is observed

Treatment with progestin may mask the onset of the climacteric

Persistent injection site reactions may occur after administration due to inadvertent SC administration or release of drug into SC space while removing the needle

Some patients receiving progestins may exhibit a decrease in glucose tolerance; therefore, patients with diabetes may be at greater risk of hyperglycemia

Delayed return of ovulation or fertility

• Return to ovulation is likely to be delayed after stopping SC injection
• Median time to ovulation was 10 months after last injection
• Earliest return to ovulation was 6 months after last injection

Cardiovascular disorders

• An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy
• Discontinue estrogen plus progestin therapy immediately if any of these events occur or be suspected,
• Risk factors for arterial vascular disease (eg, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) should be managed appropriately

Malignant neoplasms

• Studies of addition of progestin for ≥10 days of cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone; possible risks associated with the use of progestins with estrogens compared to estrogen-alone regimens include an increased risk of breast cancer
• Monitor women with a strong family history of breast cancer
• Use may mask onset of menopause in women treated for endometrial cancer

Pregnancy

There is no use for medroxyprogesterone in pregnancy and therefore should be discontinued during pregnant

Women who may have been exposed to medroxyprogesterone injections had little or no increased risk of birth defects in early pregnancy

It is unknown whether medroxyprogesterone acetate can cause fetal harm when administered to a pregnant woman

Fertility

• Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until discontinuing treatment

Lactation

Published studies report the presence of medroxyprogesterone acetate in human milk

Exercise caution when medroxyprogesterone acetate is administered to a nursing woman

Although medroxyprogesterone acetate is detectable in the milk of mothers receiving DMPA-IM, milk composition, quality, and amount do not appear to be adversely affected

Effects on milk production and lactation initiation/duration remain unclear when administered before 6 weeks after delivery

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Progestin inhibits the secretion of gonadotropins, which primarily prevents follicular maturation and ovulation and causes thickening cervical mucus; these actions contribute to its contraceptive effects

Suppression of serum estradiol concentrations is likely to be responsible for the therapeutic effect on endometriosis-associated pain

Absorption

Peak plasma concentration

• Oral (single dose): 1.01 ng/mL (2 x 10-mg doses); 0.805 ng/mL (8 x 2.5-mg doses)
• Oral (multiple doses): 0.71 ng/mL (10-mg dose)

Peak plasma time

• Oral (single dose): 2.65 ng/mL (2 x 10-mg doses); 2.22 ng/mL (8 x 2.5-mg doses)
• Oral (multiple doses): 2.83 ng/mL (10-mg dose)

AUC

• Oral (single dose): 6.95 ng/mL (2 x 10-mg doses); 5.62 ng/mL (8 x 2.5-mg doses)
• Oral (multiple doses): 6.01 ng/mL (10-mg dose)

Distribution

Protein bound: ~90%

Vd

• Oral (single dose): 78,024 L (2 x 10-mg doses); 62,748 L (8 x 2.5-mg doses)
• Oral (multiple doses): 40,654 ng/mL (10-mg dose)

Metabolism

• Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine

Elimination

Half-life

• Oral (single dose): 12.1 hr (2 x 10-mg doses); 11.6 hr (8 x 2.5-mg doses)
• Oral (multiple doses): 16.6 ng/mL (10-mg dose)