(proe JES ter one)
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Prometrium: 100 mg [contains fd&c red #40, fd&c yellow #10 (quinoline yellow), peanut oil]
Prometrium: 100 mg [DSC] [contains peanut oil]
Prometrium: 200 mg [contains fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow), peanut oil]
Prometrium: 200 mg [DSC] [contains peanut oil]
Generic: 100 mg, 200 mg
EC-RX Progesterone: 10% (30 g, 60 g); 20% (30 g, 60 g) [contains cetearyl alcohol]
Generic: 10% (60 g)
Crinone: 4% (1.125 g); 8% (1.125 g)
Endometrin: 100 mg (21 ea)
Generic: 50 mg/mL (10 mL)
First-Progesterone VGS 25: 25 mg (30 ea [DSC])
First-Progesterone VGS 50: 50 mg (30 ea [DSC])
First-Progesterone VGS 100: 100 mg (30 ea)
First-Progesterone VGS 200: 200 mg (30 ea)
First-Progesterone VGS 400: 400 mg (30 ea [DSC])
Brand Names: U.S.
- EC-RX Progesterone
- First-Progesterone VGS 100
- First-Progesterone VGS 200
- First-Progesterone VGS 25 [DSC]
- First-Progesterone VGS 400 [DSC]
- First-Progesterone VGS 50 [DSC]
Natural steroid hormone that induces secretory changes in the endometrium, promotes mammary gland development, relaxes uterine smooth muscle, blocks follicular maturation and ovulation, and maintains pregnancy. When used as part of an ART program in the luteal phase, progesterone supports embryo implantation.
Vaginal gel: Prolonged; Absorption half-life: Vaginal gel: ~25 to 50 hours
Urine (50% to 60% as metabolites); bile, feces (~10%)
Time to Peak
Oral: Within 3 hours; IM: ~8 hours; Intravaginal gel: 3.55 ± 2.48 to 7 ± 2.88 hours; Vaginal insert: 17.3 to 24 hours
Vaginal gel: 5 to 20 minutes
~96% to 99%, primarily to albumin (50% to 54%) and cortisol-binding protein (43% to 48%)
Use: Labeled Indications
Oral: Prevention of endometrial hyperplasia in nonhysterectomized, postmenopausal women who are receiving conjugated estrogens; treatment of secondary amenorrhea
IM: Treatment of amenorrhea or abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer
Intravaginal gel: Part of assisted reproductive technology (ART) for infertile women with progesterone deficiency; treatment of secondary amenorrhea
Vaginal insert: To support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of ART for infertile women
Oral: Hypersensitivity to progesterone or any component of the formulation, including peanuts/peanut oil; undiagnosed abnormal genital bleeding; breast cancer (known, suspected, or history of); active deep vein thrombosis, pulmonary embolism, or history of these conditions; active or history of arterial thromboembolic disease (eg, stroke, MI); hepatic impairment or disease; pregnancy.
IM: Hypersensitivity to progesterone or any component of the formulation, including sesame oil/seeds; active or history of thrombophlebitis, thromboembolic disorders, or cerebral apoplexy; undiagnosed vaginal bleeding; hepatic impairment or disease; known or suspected malignancy of the breast or genital organs; missed abortion.
Intravaginal gel: Hypersensitivity to progesterone or any component of the formulation, including palm oil; undiagnosed vaginal bleeding; hepatic impairment or disease; known or suspected malignancy of the breast or genital organs; missed abortion; active thrombophlebitis or thromboembolic disorders, or a history of hormone-associated thrombophlebitis or thromboembolic disorders.
Vaginal insert: Hypersensitivity to progesterone or any component of the formulation; undiagnosed vaginal bleeding; known missed abortion or ectopic pregnancy; hepatic disease; known or suspected malignancy of the breast or genital organs; active or history of arterial or venous thromboembolism or severe thrombophlebitis.
Canadian labeling: Additional contraindications (not in the US labeling):
Capsules: Hypersensitivity to soya; endometrial hyperplasia; classical migraine; partial or complete loss of vision due to ophthalmic vascular disease
Intravaginal gel: Acute porphyria, cerebral apoplexy
Vaginal insert/tablet: Porphyria; undiagnosed vaginal bleeding
Documentation of allergenic cross-reactivity for progestins is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Amenorrhea: IM: 5 to 10 mg/day for 6 to 8 consecutive days.
Intravaginal gel: 45 mg (4% gel) every other day for up to a total of 6 doses; if response is inadequate, may increase to 90 mg (8% gel) at same schedule.
Oral: 400 mg once daily at bedtime for 10 days.
ART in patients who require progesterone supplementation:
Intravaginal gel: 90 mg (8% gel) once daily. If pregnancy occurs, may continue treatment for up to 10 to 12 weeks.
Intravaginal insert: 100 mg 2 to 3 times daily starting the day after oocyte retrieval and continuing for up to 10 weeks.
ART in patients with partial or complete ovarian failure:
Intravaginal gel: 90 mg (8% gel) twice daily. If pregnancy occurs, continue treatment for up to 10 to 12 weeks.
Endometrial hyperplasia, prevention (in postmenopausal women with a uterus who are receiving conjugated estrogen daily): Oral: 200 mg once daily at bedtime for 12 days sequentially per 28-day cycle.
Uterine bleeding (functional): IM: 5 to 10 mg/day for 6 doses.
Prevention of spontaneous preterm delivery (singleton pregnancy and prior preterm birth or short cervix) (off-label use): Intravaginal gel: 90 mg (8% gel) once daily (Hassan 2011; O'Brien 2009). Treatment initiation is recommended before or at gestational week 24 (ACOG 2012).
Refer to adult dosing.
Dosing: Renal Impairment
Injection, oral: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Use with caution.
Intravaginal gel, insert: There are no dosage adjustments provided in the manufacturer’s labeling.
Dosing: Hepatic Impairment
Use is contraindicated in hepatic impairment or disease.
IM: Administer deep IM only. May cause injection-site irritation.
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 on each side, push plunger into applicator until it snaps into place; twist off cap counterclockwise; gently insert into vagina and push plunger.
Vaginal insert: Insert tablet in vagina using disposable applicator provided.
Oral: For patients who experience difficulty swallowing the capsules, taking with a full glass of water in the standing position may be beneficial.
Injection, intravaginal gel: Store at 20°C to 25°C (68°F to 77°F).
Capsule, vaginal insert: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Protect capsules from excessive moisture.
Anticoagulants: Progestins may diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Antifungal Agents (Vaginal): May diminish the therapeutic effect of Progesterone. Avoid combination
Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
C1 inhibitors: Progestins may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy
CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates. Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification
Enzalutamide: May decrease the serum concentration of CYP2C19 Substrates. Conversely, concentrations of active metabolites may be increased for those drugs activated by CYP2C19. Management: Concurrent use of enzalutamide with CYP2C19 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C19 substrate should be performed with caution and close monitoring. Consider therapy modification
Herbs (Progestogenic Properties) (eg, Bloodroot, Yucca): May enhance the adverse/toxic effect of Progestins. Monitor therapy
Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification
Pomalidomide: Progestins may enhance the thrombogenic effect of Pomalidomide. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Management: Ulipristal for uterine fibroids (Canadian indication): avoid progestins within 12 days of stopping ulipristal; as emergency contraceptive (U.S. indication): avoid progestins within 5 days of stopping ulipristal. Avoid combination
Increased sulfobromophthalein retention and other hepatic function tests; coagulation tests (increase in prothrombin factors VII, VIII, IX, and X); altered metyrapone test; altered pregnanediol determinations; thyroid function (increase in PBI and butanol extractable protein bound iodine, and decrease in T uptake values).
Frequency not defined:
Cardiovascular: Cerebral thrombosis, edema, pulmonary embolism, retinal thrombosis
Central nervous system: Cerebral edema, depression, drowsiness, insomnia
Dermatologic: Acne vulgaris, alopecia, hirsutism, pruritus, skin rash, urticaria
Endocrine & metabolic: Amenorrhea, change in menstrual flow, galactorrhea, weight gain, weight loss
Genitourinary: Breakthrough bleeding, breast tenderness, cervical erosion, change in cervical secretions, spotting
Hepatic: Cholestatic jaundice
Hypersensitivity: Anaphylactoid reaction
Local: Erythema at injection site, irritation at injection site, pain at injection site
Ophthalmic: Optic neuritis
<1%, postmarketing, and/or case reports: Allergic dermatitis
Oral (percentages reported when used in combination with or cycled with conjugated estrogens):
Central nervous system: Headache (16% to 31%), dizziness (15% to 24%), depression (19%)
Endocrine & metabolic: Breast tenderness (27%), mastalgia (6% to 16%)
Gastrointestinal: Abdominal pain (10% to 20%), bloating (8% to 12%)
Genitourinary: Urination disorder (11%)
Infection: Viral infection (12%)
Neuromuscular & skeletal: Arthralgia (20%), musculoskeletal pain (12%)
1% to 10%:
Cardiovascular: Chest pain (7%)
Central nervous system: Anxiety (8%), fatigue (8%), irritability (8%)
Gastrointestinal: Nausea (≤8%), vomiting (≤8%), diarrhea (7% to 8%), cholecystectomy (<5%), constipation (<5%)
Genitourinary: Vaginal discharge (10%)
Hematologic & oncologic: Malignant neoplasm of breast (<5%)
Respiratory: Cough (8%)
<1%, postmarketing and/or case reports: Abnormal gait, acute pancreatitis, aggressive behavior, alopecia, anaphylaxis, arthralgia, asthma, blurred vision, choking sensation, cholestasis, cholestatic hepatitis, circulatory shock, confusion, depersonalization, diplopia, disorientation, dysarthria, dysphagia, dyspnea, endometrial carcinoma, facial edema, feeling abnormal, increased liver enzymes, hepatic failure, hepatic necrosis, hepatitis, hyperglycemia, hypermenorrhea, hypersensitivity reaction, hypertension, hypotension, impaired consciousness, intoxicated feeling, jaundice, loss of consciousness, menstrual disease, muscle cramps, ovarian cyst, paresthesia, pharyngeal edema, pruritus, sedation, seizure, slurred speech, stupor, suicidal ideation, syncope, tachycardia, tinnitus, tongue edema, transient ischemic attacks, urticaria, uterine hemorrhage, vertigo, visual disturbance, weight gain, weight loss
Vaginal gel (percentages reported with ART):
Central nervous system: Drowsiness (27%), headache (13% to 17%), nervousness (16%), depression (11%)
Endocrine & metabolic: Decreased libido (11%)
Gastrointestinal: Constipation (27%), nausea (7% to 22%), abdominal cramps (15%), abdominal pain (12%)
Genitourinary: Breast hypertrophy (40%), perineal pain (17%), mastalgia (13%), nocturia (13%)
1% to 10%:
Central nervous system: Pain (8%), dizziness (5%)
Dermatologic: Genital pruritus (5%)
Gastrointestinal: Diarrhea (8%), bloating (7%), vomiting (5%)
Genitourinary: Vaginal discharge (7%), dyspareunia (6%), genital candidiasis (5%)
Neuromuscular & skeletal: Arthralgia (8%)
Vaginal insert (percentages reported with ART):
Central nervous system: Pain (post-oocyte retrieval pain: 25% to 28%)
Gastrointestinal: Abdominal pain (12%)
1% to 10%:
Central nervous system: Headache (3% to 4%), fatigue (2% to 3%)
Endocrine & metabolic: Ovarian hyperstimulation syndrome (7%)
Gastrointestinal: Nausea (7% to 8%), abdominal distention (4%), constipation (2% to 3%), vomiting (2% to 3%)
Genitourinary: Uterine spasm (3% to 4%), vaginal hemorrhage (3%), urinary tract infection (1% to 2%)
<1%, postmarketing, and/or case reports: Genital pruritus, local discomfort, peripheral edema, urticaria, vulvovaginal burning, vulvovaginal irritation
Concerns related to adverse effects:
• Breast cancer: [US Boxed Warning]: In the Women's Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in women ≥65 years with daily conjugated estrogens combined with medroxyprogesterone. This risk may be associated with duration of use and declines once combined therapy is discontinued (Chlebowski 2009). The risk of invasive breast cancer was decreased in postmenopausal women with a hysterectomy using CE only, regardless of weight. However, the risk was not significantly decreased in women at high risk for breast cancer (family history of breast cancer, personal history of benign breast disease) (Anderson 2012). An increase in abnormal mammogram findings has also been reported with estrogen in combination with progestin therapy. Use is contraindicated in patients with known or suspected breast cancer.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Dementia: [US Boxed Warning]: Progestin plus estrogens should not be used for the prevention of dementia. In the Women's Health Initiative Memory Study (WHIMS), an increased risk of developing probable dementia was observed in women ≥65 years with daily conjugated estrogens combined with medroxyprogesterone.
• Endometrial cancer: Progesterone is used to reduce the risk of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving conjugated estrogens. The use of unopposed estrogen in women with an intact uterus is associated with an increased risk of endometrial cancer. The addition of a progestin to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Adequate diagnostic measures, including endometrial sampling if indicated, should be performed to rule out malignancy in postmenopausal women with undiagnosed abnormal persistent or recurring vaginal bleeding. Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestin in women with residual endometriosis posthysterectomy.
• Fluid retention: May cause fluid retention; use with caution in patients with diseases which may be exacerbated by fluid retention, including asthma, cardiac impairment, epilepsy, migraine, and diabetes.
• Ovarian cancer: Progesterone plus estrogen therapy may increase the risk of ovarian cancer; however, the absolute risk to an individual woman is small. Although results from various studies are not consistent, risk does not appear to be significantly associated with the duration of therapy. In one study, the risk decreased after 2 years following discontinuation of therapy (Mørch 2009). Although the risk of ovarian cancer is rare, women who are at an increased risk (eg, family history) should be counseled about the association (NAMS 2012).
• Retinal vascular thrombosis: 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.
• Cardiovascular disease: [US Boxed Warning]: Progestin plus estrogen should not be used for the prevention of cardiovascular disease. In the WHI studies, an increased risk of DVT, PE, stroke, and myocardial infarction was observed in women ≥65 years with daily conjugated estrogens combined with medroxyprogesterone. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Risk factors should be managed appropriately; discontinue use if adverse cardiovascular events occur or are suspected.
• Depression: Use with caution in patients with a history of depression.
• Diabetes: Use with caution in patients with diabetes; decreased glucose tolerance may occur.
• Hepatic impairment: Use is contraindicated in hepatic impairment or disease.
• Renal impairment: Use with caution in patients with renal impairment; progestins may cause fluid retention.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Pediatric: Not for use prior to menarche.
• Surgical patients: Whenever possible, progestins in combination with estrogens should be discontinued at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
• Palm oil: Some products may contain palm oil.
• Peanut oil: Some products may contain peanut oil.
• Sesame oil: Some products may contain sesame oil.
• Risks vs benefits: Oral: [US Boxed Warning]: Progestin with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Before prescribing estrogen therapy to postmenopausal women, the risks and benefits must be weighed for each patient. Women should be informed of these risks and benefits, as well as possible effects of progestin when added to estrogen therapy. Patients should be reevaluated as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from WHI studies, which evaluated oral conjugated estrogens with medroxyprogesterone relative to placebo in postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied. Outcomes reported from clinical trials using conjugated estrogens with medroxyprogesterone should be assumed to be similar for other doses and other dosage forms of estrogens and progestins until comparable data becomes available.
Routine physical examination that includes blood pressure and Papanicolaou smear, breast exam, mammogram. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding. Signs and symptoms of thromboembolic disorders, vision changes
Pregnancy Risk Factor
The oral capsules are contraindicated for use during pregnancy.
Adverse events have not been observed following oral administration in animal reproduction studies. Adverse events following maternal use in pregnancy (eg, hypospadias, congenital heart disease, cleft lip/palate) have been noted in postmarketing data; however, a causal relationship has not been clearly established. Use of vaginal progesterone may be considered to decrease the risk of recurrent spontaneous preterm birth in women with a singleton pregnancy and prior spontaneous preterm singleton birth (therapy may begin at 16 to 24 weeks, regardless of cervical length). It may also be used to prevent spontaneous preterm birth in women with a singleton pregnancy who have a cervix <20 mm before or at 24 weeks' gestation. Use is not recommended as an intervention for women with multiple gestations (ACOG 2012). The vaginal gel and insert are indicated for use in ART.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience fatigue, insomnia, increased hunger, constipation, acne, hair loss, hair growth, abdominal pain, abdominal cramps, weight loss, bloating, diarrhea, enlarged breasts, tender breasts, muscle pain, back pain, loss of strength and energy, decreased libido, or injection site irritation. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, shortness of breath, coughing up blood, excessive weight gain, abnormal gait, severe headache, severe nausea, vomiting, severe dizziness, passing out, bulging eyes, vision changes, lump in breast, breast soreness or pain, nipple discharge, flushing, tachycardia, abnormal heartbeat, vaginitis, vaginal bleeding, painful urination, polyuria, depression, mood changes, memory impairment, seizures, swelling of arms or legs, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), or pelvic pain (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
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- Drug class: progestins