Medroxyprogesterone Acetate

In five clinical studies of depo-subQ provera (medroxyprogesterone acetate) 104 involving 2,325 women (282 treated for up to 6 months, 1,780 treated for up to 1 year and 263 treated for up to 2 years), 9% of women discontinued treatment for adverse reactions. Among these 212 women, the most common reasons for discontinuation were:

• Uterine bleeding irregularities (35%, n=75)
• Increased weight (18%, n=39)
• Decreased libido (11%, n=23)
• Acne (10%, n=21)
• Injection site reactions (6%, n=12)

Adverse reactions reported by 5% or more of all women in these clinical trials included:

• Headache (9%)
• Intermenstrual bleeding (7%)
• Increased weight (6%)
• Amenorrhea (6%)
• Injection site reactions (5%)

Adverse reactions reported by 1% to < 5% of all women in these clinical trials included:

General disorders: fatigue, injection site pain

Gastrointestinal disorders: abdominal distention, abdominal pain, diarrhea, nausea

Infections: bronchitis, influenza, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, urinary tract infection, vaginal candidiasis, vaginitis, vaginitis bacterial

Investigations: abnormal cervix smear

Musculoskeletal, connective tissue, and bone disorders: arthralgia, back pain, limb pain

Nervous system disorders: dizziness, insomnia

Psychiatric disorders: anxiety, depression, irritability, decreased libido

Reproductive system and breast disorders: breast pain, breast tenderness, menometrorrhagia, menorrhagia, menstruation irregular, uterine hemorrhage, vaginal hemorrhage

Skin disorders: acne

Vascular disorders: hot flushes

Postmarketing Experience

There have been rare cases of osteoporosis including osteoporotic fractures reported postmarketing in patients taking DEPO-PROVERA Contraceptive Injection. In addition, infrequent voluntary reports of anaphylaxis and anaphylactoid reaction have been received associated with use of Depo-Provera CI (150 mg).

The following additional reactions have been reported with Depo-Provera Contraceptive Injection and may occur with use of depo-subQ provera 104:

General disorders: asthenia, axillary swelling, chills, chest pain, fever, excessive thirst

Blood and lymphatic system disorders: anemia, blood dyscrasia

Cardiac disorders: tachycardia

Gastrointestinal disorders: gastrointestinal disturbances, rectal bleeding

Hepato-biliary disorders: jaundice

Immune system disorders: allergic reaction

Infections:genitourinary infections

Investigations: decreased glucose tolerance

Musculoskeletal, connective tissue, and bone disorders: loss of bone mineral density, scleroderma

Neoplasms: breast cancer, cervical cancer

Nervous system disorders: convulsions, facial palsy, fainting, paralysis, paresthesia, somnolence

Psychiatric disorders: increased libido, nervousness

Reproductive system and breast disorders: breast lumps, galactorrhea, nipple discharge or bleeding, oligomenorrhea, prevention of lactation, prolonged anovulation, unexpected pregnancy, uterine hyperplasia, vaginal cyst

Respiratory disorders: asthma, dyspnea, hoarseness

Skin disorders: angioedema, dry skin, increased body odor, melasma, pruritus, urticaria

Vascular disorders: deep vein thrombosis, pulmonary embolus, thrombophlebitis

Your doctor or pharmacist can provide more information about medroxyprogesterone.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Contraindications

• Active thrombophlebitis, current or past history of thromboembolic disorders, or cerebrovascular disease.134 b c e

• Undiagnosed vaginal bleeding.134 b c e

• Known or suspected pregnancy.134 b c e

• Liver dysfunction or disease.134 b c e

• Known or suspected malignancy of the breast.134 b c e

• Known hypersensitivity to medroxyprogesterone or any ingredient in the formulation.134 b c e

• Use as a pregnancy test.134 b e

Warnings/Precautions

Warnings

Effects on Bone

When used IM or sub-Q as a contraceptive or sub-Q for the management of endometriosis, possible increased rate of bone loss, especially during initial years of therapy.134 135 136 137 138 139 c e Bone loss is greater with increasing duration of therapy; may not be reversible.134 c e (See Boxed Warning.)

Use as a long-term contraceptive (e.g., >2 years) only if other contraceptive methods are inadequate and benefits are expected to outweigh risks.134 c e Evaluate BMD periodically when used long term; consider patient’s age (adult or adolescent) and skeletal maturity when evaluating BMD results.134 c e

Consider other therapies in women with existing risk factors for osteoporosis, since use of medroxyprogesterone may pose additional risk.134 c e

When used for the management of endometriosis, evaluate BMD prior to initiating a second course of therapy.c

Effects of BMD changes in women receiving medroxyprogesterone acetate in fixed combination with estradiol cypionate (Lunelle) not established.131

Thromboembolic Disorders

Possible thromboembolic and thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis).131 134 b c d e Observe patients for these effects; discontinue immediately and do not readminister if these disorders occur or are suspected.131 134 b c d e

Bleeding Irregularities

When used as a contraceptive, possible breakthrough or irregular vaginal bleeding; rarely may be heavy or continuous.131 134 c e If abnormal bleeding persists or is severe, consider organic pathology and perform adequate diagnostic tests in patients with undiagnosed vaginal bleeding.131 134 c e

Carcinoma of Reproductive Organs and Breast

Depo-Provera contraceptive injection associated with slight or no increased risk of breast cancer; no increase in risk of ovarian or cervical cancer, reduced risk of endometrial cancer.134 c e

When used with estrogen replacement therapy in postmenopausal women, reduced risk of endometrial cancer compared with estrogen use alone.111 Perform diagnostic tests (including endometrial sampling) in women with undiagnosed, persistent, or abnormal vaginal bleeding.111

Addition of medroxyprogesterone to estrogen replacement therapy increases the risk of breast cancer beyond that associated with estrogen use alone.117 121 128 129

Fetal/Neonatal Morbidity and Mortality

Potential adverse effects on the fetus when administered within the first 4 months of pregnancy (masculinization of the female fetus, hypospadias in male neonates, low birth weight).131 134 b d e (See Contraindications under Cautions.)

Ectopic Pregnancy

Consider the possibility of ectopic pregnancy if pregnancy or severe abdominal pain occurs in women using medroxyprogesterone contraception.134 b c e

Ocular Effects

If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; or retinal vascular lesions occur, discontinue and initiate appropriate diagnostic and therapeutic measures.131 134 e Do not reinitiate therapy if ocular examination reveals evidence of papilledema or retinal vascular lesions.134 b c d e

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis and anaphylactoid reactions reported.131 134 b c d e Institute appropriate measures if anaphylactic/anaphylactoid reaction occurs.131 134 c e

Possible allergic reactions, including urticaria, pruritus, angioedema, generalized rash (with or without pruritus).131 b d

General Precautions

Physical Examination and Follow-up

Annual medical history and physical examination advised.131 134 b c d e Physical examination may be deferred until after initiation of parenteral medroxyprogesterone if requested by the woman and judged appropriate by the clinician.131 134 c d e Physical examination should include special attention to BP, breasts, abdomen, and pelvic organs and should include a Papanicolaou test (Pap smear) and relevant laboratory tests.131 134 b c d e Exercise particular care in women with a strong family history of breast cancer or those who have breast nodules.131 134 b c d e

Fluid Retention

Fluid retention may occur.131 134 b c d e Exercise caution and carefully monitor patients with conditions (seizures, migraine headache, asthma, cardiac impairment, renal impairment) that might be aggravated by fluid retention.131 134 b c d e

Weight Change

Possible weight gain.131 134 a c e

Fertility

Contraceptive effect is prolonged.134 c e Median time to conception after the last dose of parenteral medroxyprogesterone (Depo-Provera Contraceptive Injection) is 10 months (range: 4–31 months) and is unrelated to the duration of contraceptive use.134 e

Median time to ovulation was 10 months after last injection of depo-subQ provera 104 and 80% of women ovulated within 1 year; ovulation may occur as early as 14 weeks after a single dose.c

Depression

Possible depression.131 134 b d e Exercise caution in women with a history of depression; discontinue if severe depression recurs during use.131 134 b c d e

Seizures

Seizures reported with IM contraceptive use.134 d e

Injection Site Reactions

Injection site reactions, including persistent skin changes (e.g., small areas of induration or atrophy), reported with sub-Q administration.c

Sexually Transmitted Diseases

Does not protect against HIV or other sexually transmitted infections.134 c e

Endocrine and Metabolic Effects

Possible decreased glucose tolerance.131 134 b c d e Monitor diabetic patients carefully.131 134 b c d e

Prolonged Therapy

Effect of long-term therapy on pituitary, ovarian, adrenal, hepatic, or uterine function not determined.b d

Climacteric

Onset of climacteric may be masked in women.b d

Hepatic Effects

Possible hepatic dysfunction (e.g., jaundice); discontinue therapy and reevaluate patient if such manifestations occur or are suspected.134 c e

Estrogen Therapy

Medroxyprogesterone may adversely affect some beneficial estrogen-associated metabolic effects (lipid metabolism, glucose tolerance).111 113 114 115 116

When used in fixed combination with conjugated estrogens or estradiol cypionate, consider the cautions, precautions, and contraindications associated with estrogens.111 131

Specific Populations

Pregnancy

Category X.131 134 b d e (See Contraindications and also Fetal/Neonatal Morbidity and Mortality, under Cautions.)

Lactation

Distributed into milk.131 134 b c d e No evidence of adverse developmental or behavioral effects through puberty found in infants exposed to the drug via breast milk.134 c e

Pediatric Use

Safety and efficacy not established.b c d

Not indicated before menarche.134 c e Possible loss of BMD with parenteral medroxyprogesterone; loss of BMD is of particular concern during adolescence.134 c e (See Boxed Warning and Effects on Bone under Cautions.)

Safety and efficacy of parenteral medroxyprogesterone in postmenarchal adolescents expected to be the same as in adult women.134 c e

Hepatic Impairment

Contraindicated in patients with liver dysfunction or disease.134 b c e

Common Adverse Effects

Menstrual abnormalities (amenorrhea; frequent, irregular, prolonged, or infrequent bleeding), abdominal pain or discomfort, weight changes, dizziness, headache, asthenia, nervousness.134 c e

Absorption

Bioavailability

Rapidly absorbed from the GI tract; peak plasma concentrations achieved within 2–4 hours.b

Peak plasma concentrations attained approximately 1 week following sub-Q injection.c

Food

Food increases peak plasma concentrations and AUC.b

Distribution

Extent

Distributed into human milk.134 c e

Plasma Protein Binding

Approximately 86–90% (primarily albumin).131 c b

Elimination

Metabolism

Metabolized in the liver by ring A and/or side-chain hydroxylation.131 b c

Elimination Route

Excreted in urine, principally as glucuronide conjugates.131 b

Half-life

Oral doses: Approximately 12 hours (single dose) or 17 hours (multiple doses).b

IM doses: 50 days reported for Depo-Provera Contraceptive Injection;134 15 days reported for Lunelle Monthly Contraceptive Injection.131

Sub-Q doses: approximately 40 days for depo-subQ provera 104.c

Special Populations

In patients with advanced liver disease, clearance is reduced.b

Storage

Oral

Tablets

20–25°C.b

Parenteral

Injection

20–25°C.134 c e