Oral: Prevention of endometrial hyperplasia in nonhysterectomized, postmenopausal women who are receiving conjugated estrogen tablets; secondary amenorrhea

I.M.: Amenorrhea; abnormal uterine bleeding due to hormonal imbalance

Intravaginal gel: Part of assisted reproductive technology (ART) for infertile women with progesterone deficiency; secondary amenorrhea

The following are also contraindicated in patients with allergies to their inactive ingredient:

Crinone® and Prochieve™ vaginal gels contain palm oil

Prometrium® capsules contain peanut oil

Oil for injection contains sesame oil

The risk of dementia may be increased in postmenopausal women; increased incidence was observed in women 65 years of age taking CEE in combination with MPA. An increased risk of invasive breast cancer was observed in postmenopausal women using CEE in combination with MPA. An increase in abnormal mammograms has also been reported with estrogen and progestin therapy.

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. Use with caution in patients with diseases that may be exacerbated by fluid retention, including asthma, epilepsy, migraine, diabetes or renal dysfunction. Use caution with history of depression. Patients should be warned that progesterone might cause transient dizziness or drowsiness during initial therapy. Whenever possible, progestins in combination with estrogens should be discontinued at least 4-6 weeks prior to surgeries associated with an increased risk of thromboembolism or during periods of prolonged immobilization. Progestins used in combination with estrogen should be used for shortest duration possible consistent with treatment goals. Conduct periodic risk:benefit assessments.

Injection (I.M.):

Cardiovascular: Edema

Central nervous system: Depression, fever, insomnia, somnolence

Dermatologic: Acne, allergic rash (rare), alopecia, hirsutism, pruritus, rash, urticaria

Endocrine & metabolic: Amenorrhea, breakthrough bleeding, breast tenderness, galactorrhea, menstrual flow changes, spotting

Gastrointestinal: Nausea, weight gain, weight loss

Genitourinary: Cervical erosion changes, cervical secretion changes

Hepatic: Cholestatic jaundice

Local: Pain at the injection site

Miscellaneous: Anaphylactoid reactions

Oral capsule (percentages reported when used in combination with or cycled with conjugated estrogens):

>10%:

Central nervous system: Headache (10% to 31%), dizziness (15% to 24%), depression (19%)

Endocrine & metabolic: Breast tenderness (27%), breast pain (6% to 16%)

Gastrointestinal: Abdominal pain (6% to 12%), abdominal bloating (10% to 20%)

Genitourinary: Urinary problems (11%)

Neuromuscular & skeletal: Joint pain (20%), musculoskeletal pain (6% to 12%)

Miscellaneous: Viral infection (7% to 12%)

5% to 10%:

Cardiovascular: Chest pain (7%)

Central nervous system: Fatigue (8% to 9%), emotional lability (6%), irritability (5% to 8%), worry (8%)

Gastrointestinal: Nausea/vomiting (8%), diarrhea (8%)

Respiratory: Upper respiratory tract infection (5%), cough (8%)

Miscellaneous: Night sweats (7%)

<5%: Abscess, accidental injury, acne, angina pectoris, anxiety, arthritis, breast cancer, breast biopsy, bronchitis, cholecystectomy, concentration impaired, confusion, constipation, dyspepsia, earache, edema, fever, fungal vaginitis, gastroenteritis, hemorrhagic rectum, hernia, herpes simplex, hiatus, hypertension, hypertonia, insomnia, leg cramps, leukorrhea, lymphadenopathy, muscle disorder, myalgia, nasal congestion, palpitation, personality disorder, pharyngitis, pneumonitis, sinusitis, somnolence, speech disorder, urinary tract infection, uterine fibroid, vaginal dryness, vaginitis, verruca, vision abnormal, wound debridement, xerostomia

Postmarketing and/or case reports: Aggression, alopecia, ALT increased, anaphylactic reaction, arthralgia, AST increased, asthma, blurred vision, choking, cholestasis, cholestatic hepatitis, circulatory collapse, consciousness depressed/loss, convulsion, depersonalization, diplopia, disorientation, drunk feeling, dysarthria, dysphagia, dyspnea, endometrial carcinoma, facial edema, feeling abnormal, gait abnormal, GGT increased, hepatic enzymes increased, hepatic failure, hepatic necrosis, hepatitis, hyperglycemia, hypersensitivity, hypotension, jaundice, liver function tests increased, menorrhagia, menstrual disorder, metrorrhagia, muscle cramps, ovarian cyst, pancreatitis (acute), paresthesia, pruritus, sedation, stupor, suicidal ideation, syncope, tachycardia, throat tightness, TIA, tinnitus, tongue swelling, urticaria, vertigo, visual disturbance, walking difficulty, weight increase/decrease

Vaginal gel (percentages reported with ART); also refer to oral capsule reactions listing for additional effects noted with progesterone:

>10%:

Central nervous system: Somnolence (27%), headache (13% to 17%), nervousness (16%), depression (11%)

Endocrine & metabolic: Breast enlargement (40%), breast pain (13%), libido decreased (11%)

Gastrointestinal: Constipation (27%), nausea (7% to 22%), cramps (15%), abdominal pain (12%)

Genitourinary: Perineal pain (17%), nocturia (13%)

5% to 10%:

Central nervous system: Pain (8%), dizziness (5%)

Gastrointestinal: Diarrhea (8%), bloating (7%), vomiting (5%)

Genitourinary: Vaginal discharge (7%), dyspareunia (6%), genital moniliasis (5%), genital pruritus (5%)

Neuromuscular & skeletal: Arthralgia (8%)

CYP2C19 inducers: May decrease the levels/effects of progesterone. Example inducers include aminoglutethimide, carbamazepine, phenytoin, and rifampin.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of progesterone. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

Estrogen: Plasma concentrations of estrogen may be increased by progesterone.

Intravaginal medications: Do not use progesterone gel within 6 hours of any other intravaginal medications.

Food: Food increases oral bioavailability.

Herb/Nutraceutical: St John's wort may decrease progesterone levels.

Absorption: Vaginal gel: Prolonged

Absorption half-life: 25-50 hours

Protein binding: 96% to 99%

Metabolism: Hepatic to metabolites

Half-life elimination: Vaginal gel: 5-20 minutes

Time to peak: Oral: Within 3 hours

Excretion: Urine, bile, feces

I.M.: Female:

Amenorrhea: 5-10 mg/day for 6-8 consecutive days

Functional uterine bleeding: 5-10 mg/day for 6 doses

Oral: Female:

Prevention of endometrial hyperplasia (in postmenopausal women with a uterus who are receiving daily conjugated estrogen tablets): 200 mg as a single daily dose every evening for 12 days sequentially per 28-day cycle

Amenorrhea: 400 mg every evening for 10 days

Intravaginal gel: Female:

ART in women who require progesterone supplementation: 90 mg (8% gel) once daily; if pregnancy occurs, may continue treatment for up to 10-12 weeks

ART in women with partial or complete ovarian failure: 90 mg (8% gel) intravaginally twice daily; if pregnancy occurs, may continue up to 10-12 weeks

Secondary amenorrhea: 45 mg (4% gel) intravaginally every other day for up to 6 doses; women who fail to respond may be increased to 90 mg (8% gel) every other day for up to 6 doses

I.M.: Administer deep I.M. only

Intravaginal: Vaginal gel: (A small amount of gel will remain in the applicator following insertion): Administer into the vagina directly from sealed applicator. Remove applicator from wrapper; holding applicator by thickest end, shake down to move contents to thin end; while holding applicator by flat section of thick end, twist off tab; gently insert into vagina and squeeze thick end of applicator.

For use at altitudes above 2500 feet: Remove applicator from wrapper; hold applicator on both sides of bubble in the thick end; using a lancet, make a single puncture in the bubble to relieve air pressure; holding applicator by thickest end, shake down to move contents to thin end; while holding applicator by flat section of thick end, twist off tab; gently insert into vagina and squeeze thick end of applicator.

Vaginal gel: A small amount of gel will remain in the applicator following insertion. Administer into the vagina directly from sealed applicator. Remove applicator from wrapper; holding applicator by thickest end, shake down to move contents to thin end; while holding applicator by flat section of thick end, twist off tab; gently insert into vagina and squeeze thick end of applicator.

Capsule (Prometrium®): 100 mg, 200 mg [contains peanut oil]

Gel, vaginal (Crinone®, Prochieve™): 4% (45 mg); 8% (90 mg) [contains palm oil; prefilled applicators]

Injection, oil: 50 mg/mL (10 mL) [contains benzyl alcohol 10%, sesame oil]

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk,"Pediatrics, 2001, 108(3):776-89.

American College of Obstetricians and Gynecologists, "ACOG Committee Opinion. Use of Progesterone to Reduce Preterm Birth,"Obstet Gynecol, 2003, 102(5 Pt 1):1115-6.