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Progesterone

Pronunciation

Pronunciation: proe-JES-ter-one
Class: Progestin

Trade Names

Crinone
- Vaginal gel 4% (45 mg)
- Vaginal gel 8% (90 mg)

Endometrin
- Vaginal insert 100 mg (micronized progesterone)

Progesterone in Oil
- Injection 50 mg/mL

Prometrium
- Capsules 100 mg (micronized progesterone)
- Capsules 200 mg (micronized progesterone)

Pharmacology

Inhibits secretion of pituitary gonadotropins, thereby preventing follicular maturation and ovulation; transforms proliferative endometrium into secretory endometrium.

Slideshow: Flashback: FDA Drug Approvals 2013

Progesterone is necessary to increase endometrial receptivity for implantation of an embryo and to maintain pregnancy.

Pharmacokinetics

Absorption

Rapidly absorbed from the GI tract (oral, IM). T max is 1.5 to 2.3 h (oral); 8.2 h (45 mg IM); 9.2 h (90 mg IM); 5.6 h (4% gel); 6.8 h (8% gel); 17.3 h (insert). C max is 17.3 to 60.6 ng/mL (oral); 39.1 ng/mL (45 mg IM); 53.8 ng/mL (90 mg IM); 13.2 ng/mL (4% gel); 14.9 ng/mL (8% gel); 19.9 ng/mL (insert). AUC is 43.3 to 175.7 ng•h/mL (oral); 806.3 ng•h/mL (45 mg IM); 1,378.9 ng•h/mL (90 mg IM); 288.6 ng•h/mL (4% gel); 296.8 ng•h/mL (8% gel); 284 ng•h/mL (insert).

Distribution

Protein binding is 96% to 99%, primarily to serum albumin (50% to 54%) and transcortin (43% to 48%).

Metabolism

Metabolized in the liver to pregnanediols and pregnanolones, which are conjugated to glucuronide and sulfate metabolites.

Elimination

Excreted in the kidney (50% to 60% metabolites), bile/feces (approximately 10% metabolites), and a small amount unchanged in the bile. Absorption half-life is 25 to 50 h (gel). Elimination half-life is approximately 28.1 h (45 mg IM), 19.6 h (90 mg IM), 55.1 h (4% gel), and 34.8 h (8% gel).

Special Populations

Renal Function Impairment

Use with caution and only with careful monitoring because metabolites are eliminated this way.

Hepatic Function Impairment

Contraindicated.

Indications and Usage

Injection

Amenorrhea and abnormal uterine bleeding caused by hormonal imbalance in the absence of organic pathology (eg, uterine cancer).

Gel

Progesterone supplementation or replacement as part of an assisted reproductive technology (ART) treatment for infertile women with progesterone deficiency.

Capsules

Prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving conjugated estrogen tablets.

Capsules and Gel

Use in secondary amenorrhea.

Vaginal Insert

Support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of an ART treatment program for infertile women.

Contraindications

Hypersensitivity to progestins or any other ingredients in these products; active or history of thrombophlebitis, thromboembolic disorders; active or recent history (within past year) of MI or stroke; peanut allergy (oral); cerebral hemorrhage (or history of); impaired liver function; breast or genital organ cancer; undiagnosed abnormal vaginal bleeding; missed abortion; ectopic pregnancy; as a diagnostic test for pregnancy; pregnancy or suspected pregnancy (oral).

Dosage and Administration

Amenorrhea
Adults

IM 5 to 10 mg/day for 6 to 8 consecutive days.

ART
Adults (8% gel)

Intravaginal 90 mg once daily for women requiring progesterone supplementation. In women with partial or complete ovarian failure who require progesterone replacement, 90 mg twice daily.

Adults

Vaginal Insert 100 mg vaginally 2 or 3 times daily starting at oocyte retrieval and continuing for up to 10 wk total duration.

Functional Uterine Bleeding
Adults

IM 5 to 10 mg/day for 6 days.

Prevention of Endometrial Hyperplasia
Adults

PO 200 mg in the evening for 12 days, sequentially per 28-day cycle.

Secondary Amenorrhea
Adults

PO Single 400 mg dose in the evening for 10 days. Intravaginal 45 mg of 4% gel every other day for up to 6 doses. In women who fail to respond, 90 mg of 8% gel every other day for up to 6 doses.

General Advice

Capsules
  • Because medication can cause drowsiness, administer prescribed dose in the evening.
  • Administer without regard to meals, but administer with food if GI upset occurs.
Gel
  • For intravaginal administration only. Not for dermal, ophthalmic, or oral administration.
  • Administer gel using prefilled disposable applicator.
  • Discard applicator after delivering dose. Do not save for future use.
  • Do not use concurrently with other intravaginal therapy. If other intravaginal therapy is used, administer at least 6 h before or after progesterone vaginal gel.
Injection
  • For IM injection only. Not for intradermal, subcutaneous, or intra-arterial administration.
  • Do not administer if particulate matter, cloudiness, or discoloration is noted.
  • Rotate injection sites.
Insert
  • Do not use concurrently with other intravaginal therapy.

Storage/Stability

Store capsules and insert between 59° and 86°F . Protect capsules from excessive moisture.

Store injection and vaginal gel between 68° and 77°F.

Drug Interactions

CYP3A4 inhibitors (eg, ketoconazole)

May inhibit progesterone metabolism, increasing plasma levels and the risk of adverse reactions.

Rifamycins (eg, rifampin)

Progesterone levels may be reduced, decreasing efficacy.

Laboratory Test Interactions

Altered metyrapone test; increased sulfobromophthalein retention and other hepatic function tests; increase in prothrombin factors VII, VIII, IX, and X; altered pregnanediol determination; increase in protein-bound iodine and butanol-extractable protein-bound iodine; decrease in T3 uptake.

Adverse Reactions

Cardiovascular

Angina pectoris, hypertension, palpitation, syncope (less than 5%); circulatory collapse, congenital heart disease, hypertension, hypotension, patent ductus arteriosus, syncope with or without hypotension, tachycardia, ventricular septal defect (postmarketing).

CNS

Somnolence (27%); dizziness (24%); headache (17%); nervousness (16%); depression (11%); decreased libido (10%); fatigue (9%); irritability (8%); emotional lability (6%); aggressive reactions, anxiety, asthenia, confusion, forgetfulness, hypertonia, impaired concentration, insomnia, migraine, personality disorder, speech disorder, tremor (less than 5%); abnormal gait, aggression, depersonalization, depressed consciousness, difficulty walking, disorientation, dysarthria, feeling abnormal, feeling drunk, loss of consciousness, paresthesia, sedation, seizures, stupor, suicidal ideation, transient ischemic attack (postmarketing).

Dermatologic

Acne, increased sweating, pruritus, rash, seborrhea, skin discoloration, skin disorder, urticaria, verruca, wound debridement (less than 5%); alopecia, hirsutism (postmarketing).

EENT

Abnormal vision, conjunctivitis, earache, nasal congestion, pharyngitis, rhinitis (less than 5%); blurred vision, diplopia, throat tightness, tinnitus, vertigo, visual disturbance (postmarketing).

GI

Constipation (27%); nausea (22%); abdominal pain (20%); diarrhea (8%); vomiting (5%); dry mouth, dyspepsia, eructation, flatulence, gastritis, gastroenteritis, hemorrhagic rectum, hernia hiatus, toothache (less than 5%); abdominal distention (4%); acute pancreatitis, dysphagia, swollen tongue (postmarketing).

Genitourinary

Breast enlargement (40%); perineal pain (17%); breast pain (16%); nocturia (13%); ovarian hyperstimulation syndrome, vaginal discharge (7%); dyspareunia (6%); genital pruritus, moniliasis (5%); uterine spasm (4%); vaginal bleeding (3%); cystitis, dysmenorrhea, dysuria, fungal vaginitis, leucorrhea, micturition frequency, premenstrual tension, uterine fibroid, UTI, vaginal dryness, vaginitis (less than 5%); amenorrhea, breakthrough bleeding, breast tenderness, change in menstrual flow, changes in cervical erosion and secretions, endometrial carcinoma, galactorrhea, intrauterine death, menorrhagia, menstrual disorder, metrorrhagia, ovarian cyst, spontaneous abortion, spotting (postmarketing).

Hepatic

Cholestasis, cholestatic hepatitis, hepatic enzymes increased, hepatic failure, hepatic necrosis, hepatitis, increased LFTs, jaundice (postmarketing).

Hematologic-Lymphatic

Anemia, lymphadenopathy, purpura (less than 5%).

Hypersensitivity

Allergic reaction, allergy (less than 5%); anaphylactic reactions, hypersensitivity (postmarketing).

Lab Tests

Increased ALT, AST, blood glucose, and gamma-glutamyl transferase (postmarketing).

Local

Post-oocyte retrieval pain (28%).

Metabolic-Nutritional

Edema, peripheral edema, thirst (less than 5%); decreased and increased weight (postmarketing).

Musculoskeletal

Musculoskeletal pain (12%); arthralgia, back pain (8%); arthritis, leg cramps, leg pain, muscle disorder, myalgia, skeletal pain (less than 5%); muscle cramp (postmarketing).

Respiratory

Cough (8%); upper respiratory tract infection (5%); asthma, bronchitis, dyspnea, hyperventilation, pneumonitis, sinusitis (less than 5%); choking (postmarketing).

Miscellaneous

Cramps (15%); viral infection (12%); pain (8%); bloating (7%); abnormal crying, abscess, accidental injury, benign cyst, chest pain, decreased appetite, fever, herpes simplex, hot flashes, infection, influenza-like symptoms, water retention, xerophthalmia (less than 5%); cleft lip, cleft palate, face edema (postmarketing).

Precautions

Warnings

Capsules: Progestins and estrogens should not be used for prevention of CV disease. The Women's Health Initiative study reported increased risks of MI, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during 5 yr of treatment with oral conjugated estrogens combined with medroxyprogesterone. In addition, increased risk of developing probable dementia was reported in postmenopausal women 65 yr of age and older during 4 yr of treatment with oral conjugated estrogens plus medroxyprogesterone. Although other doses of oral conjugated estrogens with medroxyprogesterone and other combinations and dosage forms of estrogens and progestins were not studied, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, prescribe estrogens with or without progestins at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.


Pregnancy

Category B (capsules).

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Elderly

Use with caution, usually starting at the low end of the dosage range, because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Benzyl alcohol

Injection may contain benzyl alcohol.

Birth defects

There is an increased risk of minor birth defects with use during first 4 mo of pregnancy.

Cancer

May increase risk of breast and/or ovarian cancer.

CV

Discontinue treatment if signs of MI, cerebrovascular disorders, arterial or venous thromboembolism, thrombophlebitis, or retinal thrombosis are suspected. Syncope and hypotension may occur.

Depression

Carefully observe patients with history of depression.

Fluid retention

Use cautiously when conditions that might be affected by this factor are present (eg, asthma, cardiac or renal function impairment, epilepsy).

Glucose tolerance

Because decreased glucose tolerance has been reported, use with caution and carefully observe patients who have a history of diabetes.

Immobilization

Discontinue during prolonged immobilization.

Ophthalmic effects

Discontinue medication if there are any sudden changes in vision or other serious ophthalmic effects.

Peanut oil

Capsule contains peanut oil; do not use in patients allergic to peanuts.

Surgery

Discontinue estrogens with progestins at least 4 to 6 wk before surgery of the type associated with increased risk of thromboembolism.

Vaginal bleeding

With irregular vaginal bleeding, including breakthrough bleeding, consider nonfunctional causes and undertake adequate diagnostic measures.

Overdosage

Symptoms

No studies on overdosage have been conducted.

Patient Information

  • Advise patient to read patient information leaflet before using the first time and with each refill.
  • Instruct diabetic patient taking estrogen and progesterone to monitor blood glucose more frequently when therapy is started and to inform health care provider of significant changes in readings.
  • Teach patient proper method of breast self-examination, and remind patient to perform monthly.
  • Instruct patient to immediately report any of the following symptoms to health care provider: abnormal vaginal bleeding; breast lumps; coughing up blood; crushing chest pain or heaviness in chest; depression; dizziness or fainting; pain in groin or calves; persistent pain, pus, or bleeding at injection site; severe abdominal pain; sharp chest pain; sudden severe headache; sudden shortness of breath; tremors or seizure; vision or speech problems; weakness or numbness of arms or legs; yellowing of the skin or eyes.
  • Advise patient that drug may cause dizziness and/or drowsiness and to use caution while driving or performing other tasks requiring mental alertness, coordination, or physical dexterity until tolerance is determined.
  • Advise patient that follow-up visits and examinations, including Pap smear, will be required to monitor therapy and to keep appointments.
  • Capsules
  • Advise patient to take prescribed dose in the evening to minimize problems with medication-induced drowsiness or dizziness.
  • Remind patient using progesterone for prevention of endometrial hyperplasia to take prescribed dose once daily for 12 days per 28-day cycle.
  • Remind patient using progesterone for treating secondary amenorrhea to take prescribed dose once daily for 10 days.
  • Advise patient to take each dose without regard to meals but to take with food if stomach upset occurs.
  • Vaginal gel
  • Review instructions for preparing the applicator and administering the gel.
  • If gel will be used at altitudes above 762 m, review special instructions for preparing the applicator to prevent partial release of gel before vaginal insertion.
  • Instruct patient to discard applicator after use and not to save for future use.
  • Advise patient that gel should not be used at the same time as other intravaginal products. If other intravaginal therapy is being used, instruct patient to administer at least 6 h before or after the progesterone vaginal gel.
  • Advise patient that small, white globules may appear as a discharge, even several days after using gel, but that this is normal and of no concern.
  • Advise patient to discontinue use and notify health care provider if vaginal irritation develops while using the medication.
  • Vaginal inserts
  • Advise patients not to use vaginal inserts with other vaginal products.
  • Advise patients to report irregular vaginal bleeding to health care provider as soon as possible.
  • Advise patients to use exactly as prescribed.
  • Inform patients that if they miss a dose, to insert the next dose as soon as they remember, but not to use more than their daily dose.
  • Injection
  • Advise patient that injection will be prepared and administered by health care provider in a medical setting.

Copyright © 2009 Wolters Kluwer Health.

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