Brand names: Crinone, Endometrin, Prometrium
Drug class: Progestins
ATC class: G03DA04
VA class: HS800
CAS number: 57-83-0

Medically reviewed by Drugs.com on Oct 23, 2023. Written by ASHP.

Introduction

Naturally occurring progestin.^{103 105 a}

Uses for Progesterone

Amenorrhea

Treatment of secondary amenorrhea.^{101 102 103 105}

Assisted Reproductive Technology

Used to support embryo implantation and early pregnancy as part of assisted reproductive technology (ART) treatment of infertile women.^{104 105 106}

Prevention of Endometrial Changes Associated with Estrogens

Reduction of the incidence of endometrial hyperplasia and the attendant risk of endometrial carcinoma in postmenopausal women receiving estrogen replacement therapy.¹⁰³

Uterine Bleeding

Treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology such as fibroids or uterine cancer.^{101 102}

Progesterone Dosage and Administration

Administration

Administer orally, parenterally, or intravaginally as a gel or insert.^{101 102 103 104 105}

Oral Administration

Administer once daily at bedtime.¹⁰³ Administration at bedtime may alleviate some adverse effects (e.g., dizziness, blurred vision).¹⁰³

If difficulty swallowing the capsule is experienced, administer in an upright position with adequate amounts of fluid (e.g., a glass of water).¹⁰³

IM Administration

Administer by IM injection.^{101 102}

Vaginal Administration

Progesterone vaginal gel (Crinone): Administer intravaginally every other day, every day, or twice daily.¹⁰⁵ Do not administer concurrently with other vaginal preparations.¹⁰⁵ If therapy with another agent administered intravaginally is needed, administer the other agent 6 hours before or after progesterone vaginal gel.¹⁰⁵

Progesterone vaginal insert (Endometrin): Administer intravaginally 2–3 times daily.¹⁰⁴ Concomitant use with other preparations administered intravaginally is not recommended.¹⁰⁴

Dosage

Individualize dosage according to the condition being treated and therapeutic response of the patient.^{101 102 103 104 105}

Progesterone 4% vaginal gel (Crinone): Each prefilled applicator delivers approximately 1.125 g of gel (45 mg of progesterone).¹⁰⁵

Progesterone 8% vaginal gel (Crinone): Each prefilled applicator delivers approximately 1.125 g of gel (90 mg of progesterone).¹⁰⁵

Progesterone vaginal insert (Endometrin): Appropriate dose for women ≥35 years of age not established.¹⁰⁴

Adults

Amenorrhea

Oral

400 mg daily for 10 days.¹⁰³

IM

5–10 mg daily for 6–8 consecutive days.^{101 102}

Withdrawal bleeding usually occurs within 48–72 hours after discontinuing therapy.^{101 102} Spontaneous normal cycles may occur in some patients after a single course of therapy.^{101 102}

Vaginal

Progesterone 4% vaginal gel (Crinone): Administer contents of one prefilled applicator every other day for a total of 6 doses.¹⁰⁵

For patients who do not respond to the 4% gel, administer the contents of one prefilled applicator of progesterone 8% vaginal gel (Crinone) every other day for a total of 6 doses.¹⁰⁵ Women who require the higher dose should receive Crinone 8% vaginal gel; increasing the volume of the 4% gel will not achieve the same progesterone concentrations as the 8% gel.¹⁰⁵

Assisted Reproductive Technology

Progesterone Supplementation/Replacement

Vaginal

Progesterone 8% vaginal gel (Crinone): For women who require progesterone supplementation, administer contents of one prefilled applicator once daily.¹⁰⁵ If pregnancy occurs, continue until placenta autonomy is achieved, up to 10–12 weeks.¹⁰⁵

Progesterone 8% vaginal gel (Crinone): For women who require progesterone replacement, administer contents of one prefilled applicator twice daily.¹⁰⁵ If pregnancy occurs, continue until placenta autonomy is achieved, up to 10–12 weeks.¹⁰⁵

Progesterone vaginal insert (Endometrin): One insert 2–3 times daily.¹⁰⁴ Start at oocyte retrieval; continue for up to 10 weeks.¹⁰⁴

Prevention of Endometrial Changes Associated with Estrogens

Oral

200 mg daily for 12 continuous days per 28-day cycle.¹⁰³

Uterine Bleeding

IM

5–10 mg daily for 6 days.^{101 102} When used concomitantly with estrogen therapy, initiate progesterone therapy after 2 weeks of estrogen therapy.^{101 102} Discontinue progesterone if menses occurs during the series of injections.^{101 102}

Cautions for Progesterone

Contraindications

• Undiagnosed vaginal bleeding.^{101 102 103 105}

• Known or suspected breast or genital cancer; history of breast cancer.^{101 102 103 104 105}

• Active DVT or pulmonary embolism; history of DVT or pulmonary embolism.¹⁰³

• Active or recent arterial thromboembolic disease (e.g., stroke, MI), thrombophlebitis, or cerebral apoplexy.^{101 102 103 104 105}

• Liver disease or dysfunction.^{101 102 103 104 105}

• Missed abortion or ectopic pregnancy.^{101 102 104 105}

• Use as a pregnancy test.¹⁰¹

• Progesterone capsules are contraindicated in pregnant women and those with suspected pregnancy.¹⁰³ Not effective for any purpose during pregnancy.¹⁰³

• Known hypersensitivity to progesterone or any ingredient in the formulation.^{101 102 103 104 105}

• Progesterone capsules (Prometrium): Known hypersensitivity to peanuts because the capsules contain peanut oil.¹⁰³

Warnings/Precautions

Warnings

Cardiovascular or Cerebrovascular Disorders

Possible cardiac disorders (MI) or thromboembolic and thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular disorders, retinal thrombosis).^{101 102 103 104 105} Observe patients for these effects; discontinue immediately and do not readminister if these disorders occur or are suspected.^{101 102 103 104 105} (See Contraindications under Cautions.)

Progesterone capsules (Prometrium): Syncope and hypotension reported.¹⁰³

Ocular Effects

If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; migraine; or retinal vascular lesions occur, discontinue and initiate appropriate diagnostic and therapeutic measures.^{101 102 103} Do not reinitiate therapy if ocular examination reveals evidence of papilledema or retinal vascular lesions.^{101 102 103}

Sensitivity Reactions

Peanut Hypersensitivity

Progesterone capsules (Prometrium) contain peanut oil.¹⁰³ Do not use in patients with peanut allergy.¹⁰³ (See Contraindications under Cautions.)

General Precautions

Fluid Retention

May cause some degree of fluid retention.^{101 102 103 105} Use with caution and careful monitoring in patients with conditions (e.g., asthma, seizure disorders, migraine headache, cardiac or renal impairment) that might be aggravated by fluid retention.^{101 102 103 105}

Bleeding Irregularities

Possible breakthrough or irregular vaginal bleeding.^{101 102 103 105} Perform adequate diagnostic tests in patients with undiagnosed vaginal bleeding.^{101 102 103 105}

Depression

Possible depression.^{101 102 103 104 105} Exercise caution in women with a history of depression; discontinue if severe depression recurs during use.^{101 102 103 104 105}

Physical Examination and Follow-up

Physical examination prior to initiation of therapy advised.^{101 102 103 105} Physical examination should include special attention to the breasts and pelvic organs and should include a Papanicolaou test (Pap smear) and relevant laboratory tests.^{101 102 103 105}

Carcinoma of the Breast

Addition of progesterone to estrogen replacement therapy may increase the risk of breast cancer beyond that associated with estrogen use alone.¹⁰³

Metabolic Effects

Possible adverse effects on carbohydrate and lipid metabolism.^{101 102 105} Monitor patients with hyperlipidemias or diabetes mellitus carefully.^{101 102 105}

Prolonged Therapy

Effect of long-term therapy on pituitary, ovarian, adrenal, hepatic, or uterine function not determined.¹⁰³

Climacteric

Onset of climacteric may be masked in women.^{101 102}

Estrogen Therapy

When used in combination with an estrogen, consider the cautions, precautions, and contraindications associated with estrogens.¹⁰³

CNS Effects

Progesterone capsules (Prometrium): Transient dizziness reported.¹⁰³ Use caution when driving or operating machinery.¹⁰³

Progesterone capsules (Prometrium): Extreme dizziness and/or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, and shortness of breath reported; women who experience these adverse effects should consult their healthcare provider.¹⁰³

Specific Populations

Pregnancy

Used to support embryo implantation and maintain pregnancy as a component of ART treatment in infertile women.^{104 105 106} Such use is associated with increased ongoing pregnancy rates.^{104 105 106}

Progesterone capsules (Prometrium): Category B.¹⁰³

Lactation

Progestins are distributed into milk.^{102 103 104 105} Caution advised.^{102 103 104 105}

Pediatric Use

Safety and efficacy not established.^{102 103 104 105} Not indicated in pediatric patients.^{103 104}

Adult Use

Vaginal inserts (Endometrin): Efficacy not established in women ≥35 years of age.¹⁰⁴

Geriatric Use

Progesterone injection, vaginal inserts, and gel: Safety and efficacy not established in patients >65 years of age.^{102 104 105}

Progesterone capsules (Prometrium): Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.¹⁰³ Select dose with caution; start at the lower end of the dosing range due to the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.¹⁰³

Hepatic Impairment

Contraindicated in patients with liver dysfunction or disease.^{101 102 103 104 105}

Progesterone capsules (Prometrium): If indicated in patients with mild to moderate hepatic dysfunction, monitor patient closely.¹⁰³

Renal Impairment

Progesterone injection and capsules: Safety and efficacy not established in patients with renal impairment.^{102 103} Use with caution; carefully monitor patients with renal impairment.¹⁰³

Common Adverse Effects

Menstrual abnormalities (amenorrhea; breakthrough bleeding and/or spotting; changes in menstrual flow), weight changes, dizziness, headache, abdominal pain and/or distention, breast tenderness and/or pain, fatigue, musculoskeletal pain, joint pain.^{101 102 103 104 105}

Injection site pain.^{101 102}

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction possible with drugs that are inhibitors of CYP3A4.^{103 104}

Vaginal Preparations

Progesterone vaginal gel (Crinone): Do not administer concurrently with other vaginal preparations.¹⁰⁵ If therapy with another agent administered intravaginally is needed, administer the other agent 6 hours before or after progesterone vaginal gel.¹⁰⁵

Progesterone vaginal insert (Endometrin): Concomitant administration with another vaginal preparation may alter release and absorption of progesterone.¹⁰⁴ Concomitant use with other preparations administered intravaginally is not recommended.¹⁰⁴

Specific Drugs

Progesterone Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from the GI tract; peak plasma concentrations achieved within 3 hours.¹⁰³

Peak plasma concentrations attained in 8–9 hours following IM administration.^{102 105}

Peak plasma concentrations attained in 5–7 hours following administration of progesterone vaginal gel.¹⁰⁵ Absorption is prolonged due to sustained-release properties of this preparation.¹⁰⁵

Peak plasma concentrations reached in 17–24 hours following administration of progesterone vaginal insert.¹⁰⁴

Food

Food increases bioavailability of progesterone capsules.¹⁰³

Distribution

Extent

Distributed into human milk.^{102 103 104 105}

Plasma Protein Binding

96–99% (mainly albumin).^{103 104 105}

Elimination

Metabolism

Metabolized in the liver to pregnanediols and pregnanolones, followed by glucuronide and sulfate conjugation.^{102 103 104} Further metabolism may occur in the GI tract.¹⁰⁴

Elimination Route

Excreted in urine and bile, mainly as metabolites.^{102 103 104}

Following administration of progesterone injection, 50-60% of metabolites are excreted by the kidneys, while approximately 10% are excreted by the bile and feces.^{104 105} A small portion is excreted in the bile unchanged.^{104 105}

Half-life

IM doses: 20–30 hours.¹⁰⁵

Vaginal gel: 30–60 hours.¹⁰⁵

Stability

Storage

Oral

Capsules

Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).¹⁰³

Parenteral

Injection

15–30°C.¹⁰²

Vaginal

Gel and Inserts

25°C (may be exposed to 15–30°C).^{104 105}

Actions

• Formed from steroid precursors in the ovary, testis, adrenal cortex, and placenta; secreted mainly from the corpus luteum of the ovary during the latter half of the menstrual cycle.^a

• Required for implantation of the ovum and for maintenance of pregnancy.^a

• Transforms a proliferative endometrium into a secretory one.^a

• Stimulates growth of mammary alveolar tissue and relaxes uterine smooth muscle.^a

• Minimal estrogenic and androgenic activity.^a

Advice to Patients

• Importance of reading the manufacturer's patient information.^{102 103 104 105}

• Importance of advising patients of anticipated menstrual effects.^{102 103}

• Progesterone capsules (Prometrium): Importance of using caution when driving or operating machinery, especially during the initiation of therapy.¹⁰³

• Progesterone vaginal gel (Crinone): Importance of following special instructions if the gel is used at altitudes >2500 feet.¹⁰⁵

• Importance of discontinuing therapy and contacting clinician if sudden partial or complete vision loss, blurred vision, bulging of the eyes, double vision, or migraine occur.^{101 102 103 104 105}

• Importance of discontinuing therapy and contacting clinician if any symptoms of thromboembolic and thrombotic disorders occurs.^{101 102 103 104 105}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{101 102 103}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.^{101 102 103 104 105}

• Advise women using the vaginal gel or insert not to use other vaginal preparations.^{104 105} If therapy with another agent administered intravaginally is needed in a women using the gel, administer the other agent 6 hours before or after progesterone vaginal gel.¹⁰⁵

• Importance of informing patients of other important precautionary information.^{101 102 103 104 105} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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