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Progesterone

Pronunciation

Class: Progestins
ATC Class: G03DA04
VA Class: HS800
CAS Number: 57-83-0
Brands: Crinone, Endometrin, Prometrium

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

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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

Interactions for Progesterone

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

Drug

Interaction

Comments

Conjugated estrogens

Progesterone capsules: Decreased estradiol AUC, increased estrone and equilin AUCs103

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.

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

Progesterone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Bulk

Powder

Progesterone Powder Micronized or Microcrystalline for Prescription Compounding

Oral

Capsules

100 mg

Prometrium (with peanut oil)

Abbott

200 mg

Prometrium (with peanut oil)

Abbott

Parenteral

Injection

50 mg/mL*

Progesterone Injection (with benzyl alcohol 10% and sesame oil)

Vaginal

Gel

4%

Crinone (available in prefilled, disposable applicators)

Watson

8%

Crinone (available in prefilled, disposable applicators)

Watson

Insert

100 mg

Endometrin (with disposable applicators)

Ferring

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Progesterone 100MG Capsules (TEVA PHARMACEUTICALS USA): 30/$60.99 or 90/$169.97

Progesterone Micronized 200MG Capsules (TEVA PHARMACEUTICALS USA): 30/$115.99 or 90/$325.97

Prometrium 100MG Capsules (ABBOTT): 30/$72.99 or 90/$194.97

Prometrium 200MG Capsules (ABBOTT): 30/$127.00 or 90/$349.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 2, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

101. Abraxis Pharmaceutical Products, Inc. Progesterone injection prescribing information. Schaumburg, IL; 2006 Jun.

102. Watson Laboratories. Progesterone injection prescribing information. Corona, CA; 2007 Jan.

103. Solvay Pharmaceuticals, Inc. Prometrium(progesterone) capsule prescribing information. Marietta, GA; 2004 Dec.

104. Ferring Pharmaceuticals, Inc. Endometrin(progesterone) vaginal insert prescribing information. Suffern, NY; Jun 2007.

105. Columbia Laboratories, Inc. Crinone (progesterone) bioadhesive vaginal gel prescribing information. Livingston, NJ; 2006 Dec.

106. Daya S, Gunby J. Luteal phase support in assisted reproductive cycles. Cochrane Database of Systematic Reviews. 2004, Issue 3. Art. no.:CD004830. DOI: 10.1002/14651858. CD004830.

a. AHFS Drug Information 2007. McEvoy GK, ed. Progesterone. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 3237-3238.

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