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  • CLASSES

    Compounding Kits, Hormonal Agents
    Other Infertility Agents

    BOXED WARNING

    Breast cancer, cervical cancer, endometrial cancer, endometrial hyperplasia, new primary malignancy, ovarian cancer, uterine cancer, vaginal cancer

    Progesterone is contraindicated in patients with pre-existing breast cancer or cancer of reproductive organs, such as cervical cancer, endometrial cancer, ovarian cancer, uterine cancer, or vaginal cancer. Likewise, progesterone formulations should not be used in patients with undiagnosed vaginal bleeding. Progesterone, like other hormones, can influence hormonally-dependent cancers. HORMONE REPLACEMENT THERAPY (HRT): Oral progesterone labeling contains a boxed warning regarding the potential risk for breast cancer (new primary malignancy) in post-menopausal women receiving estrogen and progestin hormonal replacement therapy (HRT). The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. Progestins 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. The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of estrogen plus progestin. After a mean follow-up of 5.6 years, the WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for estrogen plus progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. Adding a progestin such as progesterone to estrogen HRT has been shown to reduce, but not completely eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen plus progestin HRT is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95% CI, 0.77 to 3.24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.

    Asthma, cardiac disease, renal disease

    Progesterone should be prescribed cautiously in patients with asthma, congestive heart failure, nephrotic syndrome or other renal disease, or cardiac disease. Hormonal contraceptives can cause fluid retention and may exacerbate any of the above conditions.

    Dementia, geriatric

    Estrogen/progestin combination therapy has been found to fail to prevent mild cognitive impairment (memory loss) and to increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in geriatric women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory).

    DEA CLASS

    Rx

    DESCRIPTION

    Naturally occurring progestin administered orally,vaginally, and parenterally
    Used to treat amenorrhea and abnormal uterine bleeding in women, and to prevent endometrial hyperplasia in postmenopausal women taking estrogen therapy, and off-label for premenstrual dysphoric disorder (PMDD)
    Also used to prevent early pregnancy failure in women with corpus luteum insufficiency and to reduce the risk for preterm birth in women with single gestation pregnancy and a history of spontaneous preterm delivery

    COMMON BRAND NAMES

    Crinone, Endometrin, First - Progesterone VGS, Prometrium

    HOW SUPPLIED

    Crinone Vaginal Gel: 4%, 8%
    Endometrin Vaginal Insert: 100mg
    First - Progesterone VGS Vaginal Supp: 100mg, 200mg
    Progesterone Intramuscular Inj Sol: 1mL, 50mg
    Progesterone/Prometrium Oral Cap: 100mg, 200mg

    DOSAGE & INDICATIONS

    For the treatment of amenorrhea.
    Intravaginal dosage (micronized gel)
    Adult females

    Administer the 4% or 8% gel PV every other day up to a total of 6 doses. Use the 8% gel for women who fail to respond to the 4% gel. Note that dosage increases from the 4% gel can only be accomplished by using the 8% gel. Increasing the volume of gel administered does not increase the amount of progesterone absorbed.

    Intramuscular dosage
    Adult females

    5 to 10 mg IM once daily for 6 to 8 days, usually started 8 to 10 days prior to the anticipated first day of menstruation. If the endometrium has been proliferative, withdrawal bleeding will generally occur within 48 to 72 hours following cessation of progesterone therapy. Cycles may return to normal after a single course of therapy.

    Oral dosage (micronized capsules, e.g., Prometrium)
    Adult females

    For the treatment of secondary amenorrhea, 400 mg PO as a single dose in the evening for 10 days.

    For the prevention of endometrial hyperplasia associated with conjugated estrogen replacement therapy in postmenopausal women who have an intact uterus.
    Oral dosage (micronized capsules, e.g., Prometrium)
    Adult females with an intact uterus

    200 mg PO given as a single dose in the evening for 12 sequential days of every 28-day cycle of daily estrogen therapy.

    For the treatment of dysfunctional uterine bleeding secondary to hormonal imbalance.
    Intramuscular dosage
    Adult females

    5 to 10 mg IM once daily for 6 days. If estrogen therapy is administered concomitantly, progesterone is usually administered after 2 weeks of estrogen therapy. Alternatively, a single dose of 50 to 100 mg IM may be given.

    For the treatment of infertility or for the prevention of early pregnancy failure† (e.g., miscarriage) in women with corpus luteum insufficiency†.
    NOTE: The optimal dose and route of progesterone administration has not been determined. Vaginal progesterone is often used preferentially over the intramuscular formulation secondary to comparable efficacy and decreased side effects (e.g., pain at the injection site, sterile abscess formation).
    To supplement or replace progesterone in women with infertility and corpus luteum insufficiency (e.g., progesterone deficiency) as part of an Assisted Reproductive Technology (ART) treatment program.
    Intramuscular dosage†
    Adult females

    25 to 100 mg IM once daily starting at oocyte retrieval and continuing during the luteal phase or until 10 to 12 weeks gestation.

    Vaginal dosage (Endometrin vaginal insert)
    Adult females

    100 mg administered vaginally 2 to 3 times per day starting the day after oocyte retrieval and continuing for up to 10 weeks total duration. Efficacy in women 35 years of age and older has not been established; the appropriate dosage in this age group has not been determined.

    Vaginal dosage (micronized gel)
    Adult females

    90 mg (8% gel) PV once daily. In women with partial or complete ovarian failure, a dose of 90 mg intravaginally twice daily is recommended. If pregnancy occurs, treatment may be continued until placental autonomy is achieved, up to 10 to 12 weeks of gestation.

    Intramuscular dosage†
    Adult females

    12.5 mg IM once daily at onset of ovulation. Two weeks therapy is usually sufficient, but may be continued for up to the 11th week of gestation.

    Vaginal dosage (extemporaneously compounded suppositories†)
    Adult females

    25 to 100 mg PV 1 to 2 times per day, initiated within several days of ovulation. Treatment is usually continued if the patient is pregnant to roughly the 11th week of gestation.

    For the treatment of symptoms associated with premenstrual syndrome (PMS)†.
    Oral dosage (micronized capsules, e.g., Prometrium)
    Adults

    Initially, 300 mg PO 4 times per day has been used; then adjusted to patient response; however, progesterone efficacy for PMS is questionable. In one study, alprazolam was superior to progesterone or placebo overall. Progesterone was better than alprazolam for physical symptoms; alprazolam was better for controlling mood. Progesterone was administered from day 18 of the cycle to the first day of menses with a taper on the first 2 menstrual days. Dosing was flexible; patients could receive up to twelve 300-mg capsules/day if necessary. The actual dose taken during the third treatment cycle was 1,760 mg/day PO. The authors concluded that progesterone was ineffective for PMS.

    For preterm delivery prophylaxis†.
    Vaginal dosage (extemporaneously compounded suppositories)
    Adult females

    The usual dosage is 100 mg or 200 mg vaginally as a suppository once daily at bedtime starting at at 16 to 24 weeks gestation and continuing through 34 weeks gestation. Progesterone helps reduce the risk for preterm birth in selected patients. In women with single gestation pregnancy and a history of spontaneous preterm delivery, antenatal progesterone therapy effectively decreases the risk of a recurrent preterm delivery. It is not yet clear if the drug is routinely beneficial at reducing risk for preterm birth in multiple gestation pregnancies.

    Vaginal dosage (progesterone 8% vaginal gel)
    Adult females

    1 applicator (each applicator delivers 1.125 grams gel containing 90 mg progesterone) vaginally once daily at bedtime starting at at 16 to 24 weeks gestation and continuing through 34 weeks gestation. Progesterone helps reduce the risk for preterm birth in selected patients. In women with single gestation pregnancy and a history of spontaneous preterm delivery, antenatal progesterone therapy effectively decreases the risk of a recurrent preterm delivery. In one study, vaginal progesterone gel was also associated with a significant reduction in the rate of preterm birth before 28 weeks and 35 weeks, and a significant reduction in the incidence of neonatal respiratory distress syndrome, any neonatal morbidity or mortality event, and birth weight less than 1500 grams. It is not yet clear if the drug is routinely beneficial at reducing risk for preterm birth in multiple gestation pregnancies.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Dependent on indication for therapy, and dosage route/formulation selected.

    Elderly

    Dependent on indication for therapy, and dosage route/formulation selected.

    Adolescents

    Dependent on indication for therapy, and dosage route/formulation selected.

    Children

    Not indicated in prepubescent females.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Progesterone is considered contraindicated for use in patients with significant hepatic disease.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Administer progesterone with or without food; evening dosing is suggested.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intramuscular Administration

    Administer intramuscularly. Never administer intravenously.
    Shake vial thoroughly prior to withdrawing dose into the syringe.
     
    Intramuscular injection:
    Injections cause irritation at the injection site.
    Inject deeply into a large muscle mass. Rotate sites of injection.

    Intravaginal Administration

    Intravaginal gel (Crinone, Prochieve):
    Use disposable applicators supplied by the manufacturer.
    Instruct patient on proper administration. The Patient Information Sheet contains special instructions for using the applicator at altitudes above 2500 feet in order to avoid a partial release of the gel before vaginal insertion.
     
    Intravaginal suppositories (Endometrin):
    Use disposable applicators supplied by the manufacturer.
    Patients should be instructed to place the thin end of the applicator filled with the insert well into the vagina while standing, sitting, or lying on her back with her knees bent. The plunger on the applicator should be pushed to release the insert. Discard the applicator after each use.

    Extemporaneous Compounding-Vaginal

    Extemporaneous Intravaginal Suppositories preparation:
    One compounding formula that has been used is as follows:
    710 mg (0.71 grams) progesterone powder
    33.7 grams polyethylene glycol 400
    22.3 grams polyethylene glycol 6000
    This formulation makes 28 suppositories containing 25 mg progesterone per suppository.

    Other Administration Route(s)

    Intrauterine device (IUD) Administration
    NOTE: This drug is discontinued in the US.
    The system can be inserted into the uterus at any time during the menstrual cycle by a trained health-care professional. The preferred time for insertion is at the end of a menstrual cycle or within 2 days to reduce the risk of inserting when there is an undiagnosed pregnancy.
     
    Intrauterine device (Progestasert):
    Replace every 12 months.
    The retrieval threads should be visible.

    STORAGE

    Generic:
    - Avoid excessive heat (above 104 degrees F)
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton
    Crinone:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Endometrin :
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    First - Progesterone MC 10:
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    First - Progesterone MC 5:
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    First - Progesterone VGS:
    - After compounding, store product in the refrigerator (between 36 to 46 degrees F)
    - Prior to compounding, store at room temperature (between 59 to 86 degrees F)
    - Product can be stored for up to 90 days after the day on which it was compounded
    - Protect from light
    Prochieve:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Prometrium:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Breast cancer, cervical cancer, endometrial cancer, endometrial hyperplasia, new primary malignancy, ovarian cancer, uterine cancer, vaginal cancer

    Progesterone is contraindicated in patients with pre-existing breast cancer or cancer of reproductive organs, such as cervical cancer, endometrial cancer, ovarian cancer, uterine cancer, or vaginal cancer. Likewise, progesterone formulations should not be used in patients with undiagnosed vaginal bleeding. Progesterone, like other hormones, can influence hormonally-dependent cancers. HORMONE REPLACEMENT THERAPY (HRT): Oral progesterone labeling contains a boxed warning regarding the potential risk for breast cancer (new primary malignancy) in post-menopausal women receiving estrogen and progestin hormonal replacement therapy (HRT). The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. Progestins 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. The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of estrogen plus progestin. After a mean follow-up of 5.6 years, the WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for estrogen plus progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. Adding a progestin such as progesterone to estrogen HRT has been shown to reduce, but not completely eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen plus progestin HRT is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95% CI, 0.77 to 3.24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.

    Hepatic disease

    Progesterone products are contraindicated in patients with hepatic disease or known hepatic dysfunction.

    Benzyl alcohol hypersensitivity, intravenous administration, pulmonary oil microembolism, sesame oil hypersensitivity

    Progesterone injections are formulated in oil and are for intramuscular use only. Never administer via intravenous administration. Oil microembolization, such as pulmonary oil microembolism, may occur if inadvertently administered intravenously, which may result in serious reactions. Some injection formulations are made from sesame oil and are not for use in patients with sesame oil hypersensitivity. Benzyl alcohol is also contained in some injection formulas, so use with caution in patients with benzyl alcohol hypersensitivity.

    Infertility

    Progesterone at high doses is an antifertility drug and high doses of progesterone injection would be expected to impair fertility until the cessation of treatment. Women of childbearing age may expect some degree of infertility during treatment with progesterone injection at high doses.

    Ectopic pregnancy, incomplete abortion, pregnancy

    Select progesterone products are specifically labeled for use to provide luteal support during early pregnancy. Animal studies involving oral, vaginal, or in utero administration of progesterone have not indicated evidence of fetal harm. Progesterone vaginal gel may be used to support early pregnancy as part of an Assisted Reproductive Technology (ART) program; if pregnancy occurs, the gel is typically continued for 10 to 12 weeks until placental production of progesterone is adequate to support the pregnancy. Similarly, progesterone vaginal inserts are used for up to 10 weeks in ART. Progesterone should only be used during early pregnancy under the observation of an ART specialist. Data suggest that vaginal progesterone is effective in preventing preterm delivery and associated neonatal complications, especially during high-risk singleton pregnancy; administration usually is initiated at 16 to 24 weeks gestation and continues through 34 weeks gestation. Progesterone should not be used if there is ectopic pregnancy, missed/ incomplete abortion, or during diagnostic tests for pregnancy. Progesterone capsules are only indicated in postmenopausal women, and thus this dosage form is specifically contraindicated for use during pregnancy.

    Breast-feeding

    Detectable amounts of drug have been identified in the milk of mothers receiving progestational drugs. The effect of this on the breast-feeding infant has not been determined. In general, use of progestins has not had adverse effects on lactation. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for progesterone and the potential adverse effects on the breast-fed infant.

    Children, infants, neonates

    The safety and effectiveness of progesterone formulations have not been established in children or infants. The safety and efficacy of progesterone have only been established in females of reproductive age. Use of progesterone in female children before menarche is not usually indicated. In neonates, inadvertent exposure to progesterone injections, which may contain benzyl alcohol, can result in a "gasping syndrome".

    Cerebrovascular disease, coronary artery disease, hypercholesterolemia, hypertension, myocardial infarction, obesity, stroke, thromboembolic disease, thromboembolism, thrombophlebitis, tobacco smoking, visual disturbance

    Progesterone is contraindicated in patients with a history of thrombophlebitis, active or previous history of thromboembolism or thromboembolic disease (including stroke and myocardial infarction). Patients with risk factors for heart disease, thromboembolism, and stroke (e.g., known cerebrovascular disease, hypertension, diabetes mellitus, tobacco smoking, hypercholesterolemia, obesity, etc.) should be monitored closely and managed appropriately. During use of progesterone in patients without a history of thrombosis, the provider should be alert to the earliest manifestations of thrombotic disorder (thrombophlebitis, heart attack, cerebrovascular disorder such as stroke or focal headache with symptoms consistent with cerebral ischemia, pulmonary embolism, or unexplained visual disturbance with ocular pain, which might indicate retinal thrombosis). Should any of these occur or be suspected, progesterone therapy should be discontinued immediately. HORMONAL REPLACEMENT THERAPY (HRT): Progesterone, when used with estrogen therapy for postmenopausal hormone replacement, is associated with cardiovascular and thromboembolic risks, which are highlighted in the oral progesterone boxed warnings. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with estrogen-progestin therapy, relative to placebo. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen plus progestin HRT vs. women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. Estrogens with or without a progestin such as progesterone should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease) in postmenopausal women. In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. Studies have also shown no cardiovascular benefit to the use of estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD. In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke.

    Diabetes mellitus, hyperlipidemia

    Progesterone should be used cautiously in patients with diabetes mellitus. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination treatment. There are possible risks which may be associated with the use of progestin treatment, including adverse effects on carbohydrate and lipid metabolism. The dosage used may be important in minimizing these adverse effects. Use with caution in patients with known hyperlipidemia.

    Asthma, cardiac disease, renal disease

    Progesterone should be prescribed cautiously in patients with asthma, congestive heart failure, nephrotic syndrome or other renal disease, or cardiac disease. Hormonal contraceptives can cause fluid retention and may exacerbate any of the above conditions.

    Depression, migraine, seizure disorder

    Progesterone should be used cautiously in patients with a history of major depression, migraine, or seizure disorder. Progestins may exacerbate these conditions in some patients. If a patient receiving progesterone develops changes in migraine patterns, or a focal migraine with symptoms consistent with cerebral ischemia, or a severe headache pattern that may indicate a cerebrovascular disorder, consider discontinuation of the drug. Some cases of seizures following administration of progestins have been reported.

    Infection, inflammation

    An intrauterine device containing progesterone should not be used if there is any infection or inflammation in the female reproductive tract. There is a risk of infection progressing to pelvic inflammatory disease. Exposure to sexually transmitted disease also increases this risk.

    Peanut hypersensitivity

    Prometrium (progesterone) capsules should not be used in patients with peanut hypersensitivity. This product is formulated with peanut oil.

    Driving or operating machinery

    Progesterone may cause transient dizziness in some patients. Use caution when driving or operating machinery.

    Dementia, geriatric

    Estrogen/progestin combination therapy has been found to fail to prevent mild cognitive impairment (memory loss) and to increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in geriatric women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory).

    ADVERSE REACTIONS

    Severe

    spontaneous fetal abortion / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    retinal thrombosis / Delayed / Incidence not known
    stroke / Early / Incidence not known
    thromboembolism / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    dementia / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    breast cancer / Delayed / Incidence not known
    ovarian cancer / Delayed / Incidence not known
    endometrial cancer / Delayed / Incidence not known

    Moderate

    vaginitis / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known
    dyspareunia / Delayed / Incidence not known
    cervicitis / Delayed / Incidence not known
    fluid retention / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    edema / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    dysarthria / Delayed / Incidence not known
    migraine / Early / Incidence not known
    uterine pain / Early / Incidence not known
    erythema / Early / Incidence not known
    hot flashes / Early / Incidence not known
    cholestasis / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    dysphagia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    impaired cognition / Early / Incidence not known
    endometrial hyperplasia / Delayed / Incidence not known
    vaginal bleeding / Delayed / Incidence not known

    Mild

    nocturia / Early / Incidence not known
    perineal pain / Early / Incidence not known
    menstrual irregularity / Delayed / Incidence not known
    weight gain / Delayed / Incidence not known
    libido increase / Delayed / Incidence not known
    melasma / Delayed / Incidence not known
    mastalgia / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    vaginal discharge / Delayed / Incidence not known
    dysmenorrhea / Delayed / Incidence not known
    breast enlargement / Delayed / Incidence not known
    breakthrough bleeding / Delayed / Incidence not known
    leukorrhea / Delayed / Incidence not known
    weakness / Early / Incidence not known
    vaginal irritation / Early / Incidence not known
    hirsutism / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    tremor / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    syncope / Early / Incidence not known
    insomnia / Early / Incidence not known
    dizziness / Early / Incidence not known
    fatigue / Early / Incidence not known
    headache / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    emotional lability / Early / Incidence not known
    drowsiness / Early / Incidence not known
    irritability / Delayed / Incidence not known
    infection / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    rash / Early / Incidence not known
    fever / Early / Incidence not known
    skin discoloration / Delayed / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    seborrhea / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    appetite stimulation / Delayed / Incidence not known
    diarrhea / Early / Incidence not known
    vomiting / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known
    nausea / Early / Incidence not known
    eructation / Early / Incidence not known
    xerophthalmia / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    sinusitis / Delayed / Incidence not known
    increased urinary frequency / Early / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    purpura / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Acetaminophen; Butalbital; Caffeine: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Acetohexamide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Alogliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Alogliptin; Metformin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Alogliptin; Pioglitazone: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Alpha-glucosidase Inhibitors: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Amobarbital: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Amoxicillin; Clarithromycin; Lansoprazole: (Minor) The metabolism of progesterone may be inhibited by clarithromycin, an inhibitor of the CYP3A4 hepatic enzyme.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) The metabolism of progesterone may be inhibited by clarithromycin, an inhibitor of the CYP3A4 hepatic enzyme.
    Amprenavir: (Major) Oral contraceptives and non-oral combination contraceptives should not be administered with amprenavir. Alternative methods of non-hormonal contraception are recommended. Clinically significant hepatic enzyme (transaminase) elevations may occur with concomitant use. Additionally, hormonal contraceptives, estrogens, and progestins may decrease the serum concentrations of amprenavir, which could lead to loss of virologic response and possible viral resistance. Additionally, data on the effects that other protease inhibitors have on the serum concentrations of estrogens and progestins are complex; some protease inhibitors increase and others decrease the metabolism of hormonal contraceptives. Coadministration of medroxyprogesterone, a CYP3A substrate with amprenavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. It is not known if amprenavir alters the metabolism of other hormonal contraceptives or other estrogen or progestin products. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms. In women receiving oral contraceptives containing the progestin drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors concomitantly.
    Apalutamide: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as apalutamide. Concurrent administration of apalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. Progestins are CYP3A4 substrates and apalutamide is a strong CYP3A4 inducer. If the hormone is used for contraception, an alternate or additional form of contraception should be considered. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of apalutamide. Monitor hormonal replacement therapy for loss of efficacy while on apalutamide, with dose adjustments as needed. Women taking hormonal replacement and apalutamide should report breakthrough bleeding to their prescribers.
    Aprepitant, Fosaprepitant: (Major) If aprepitant, fosaprepitant is coadministered with hormonal contraceptives, including hormonal contraceptive devices (skin patches, implants, and hormonal IUDs), use an alternative or back-up non-hormonal method of contraception (e.g., condoms, spermicides) during treatment and for at least 1 month following the last dose of aprepitant, fosaprepitant. The efficacy of progestins may be reduced when coadministered with aprepitant, fosaprepitant and for 28 days after the last dose. The exact mechanism for this interaction has not been described. Progestins are CYP3A4 substrates and aprepitant, fosaprepitant is a CYP3A4 inducer; however, aprepitant, fosaprepitant is also a dose-dependent weak-to-moderate CYP3A4 inhibitor. When administered as an oral 3-day regimen (125mg/80mg/80mg) in combination with ondansetron and dexamethasone, aprepitant decreased trough concentrations of ethinyl estradiol and norethindrone by up to 64% for 3 weeks post-treatment. When ethinyl estradiol and norgestimate were administered on days 1 to 21 and aprepitant (40mg) give as a single dose on day 8, the AUC of ethinyl estradiol decreased by 4% on day 8 and by 29% on day 12; the AUC of norelgestromin increased by 18% on day 8, and decreased by 10% on day 12. Trough concentrations of both ethinyl estradiol and norelgestromin were generally lower after coadministration of aprepitant (40mg) on day 8 compared to administration without aprepitant. Specific studies have not been done with other hormonal contraceptives (e.g., progestins, non-oral combination contraceptives), an alternative or additional non-hormonal method of birth control during treatment and for 28 days after treatment is prudent to avoid potential for contraceptive failure. The clinical significance of this is not known since aprepitant, fosaprepitant is only used intermittently.
    Armodafinil: (Major) Armodafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of estrogens and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during armodafinil therapy and continued for one month after armodafinil discontinuation.
    Artemether; Lumefantrine: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e.progesterone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Atazanavir; Cobicistat: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Barbiturates: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Betamethasone; Clotrimazole: (Moderate) Vaginal preparations of progesterone (e.g., Crinone, Endometrin, and Prochieve) should not be used with other intravaginal products (e.g., vaginal antifungals, such as clotrimazole, miconazole nitrate, terconazole, or tioconazole vaginal) as concurrent use may alter progesterone release and absorption from the vagina. Separate the times of administration to avoid the interaction. The manufacturers of Crinone and Prochieve indicate that other intravaginal products can be used as long as 6 hours has lapsed either before or after vaginal administration of progesterone. Endometrin is generally not recommended for use with other vaginal products (e.g., antifungal products) as this may alter progesterone release and absorption from the vaginal insert and the potential for interaction has not been formally assessed; use other vaginal products if medically necessary, but be aware that the response to Endometrin may be altered.
    Bexarotene: (Major) Bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously during oral bexarotene therapy. It is strongly recommended that one of the forms of contraception be non-hormonal. Additionally, because of possible CYP3A4 induction, bexarotene may also decrease the efficacy of hormones used for hormone replacement therapy.
    Bosentan: (Major) Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. Bosentan is teratogenic. To prevent pregnancy, females of reproductive potential must use 2 acceptable contraception methods during treatment and for 1 month after discontinuation of bosentan therapy. The patient may choose 1 highly effective contraceptive form, including an intrauterine device (IUD) or tubal sterilization, a combination of a hormonal contraceptive with a barrier method, or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Hormonal contraceptives, including oral contraceptives or non-oral combination contraceptives (injectable, transdermal, and implantable contraceptives) may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes and bosentan is a significant inducer of CYP3A enzymes. Decreases in hormonal exposure have been documented in drug interaction studies of bosentan with hormonal contraception. Additionally, estrogens and progestins used for hormone replacement therapy (HRT) may also be less effective; patients should be monitored for changes in efficacy such as breakthrough bleeding or an increase in hot flashes. Dosage adjustments may be necessary.
    Brigatinib: (Major) Females of reproductive potential should use effective non-hormonal contraception during concomitant treatment with progesterone and brigatinib, and for at least 4 months after the final dose of brigatinib. Progesterone is a CYP3A4 substrate. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Coadministration of brigatinib may reduce the efficacy of hormonal contraceptives; brigatinib can cause fetal harm if administered to a pregnant woman.
    Bromocriptine: (Minor) Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women. Progestins can cause amenorrhea and, therefore, counteract the desired effects of bromocriptine. Concurrent use is not recommended; an alternate form of contraception is recommended during bromocriptine therapy.
    Butabarbital: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Canagliflozin; Metformin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Carbamazepine: (Major) Concomitant use of carbamazepine with hormonal products may render the hormonal product less effective. The plasma concentrations of the hormones may be decreased because carbamazepine induces the activity of hepatic metabolic enzymes. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs, or higher-dose hormonal regimens may be indicated where acceptable or applicable as pregnancy has been reported in patients taking the hepatic enzyme inducing drug phenytoin concurrently with hormonal contraceptives. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Patients taking progestins for other indications may need to be monitored for reductions in clinical effect of the progestin.
    Chlorpropamide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Cimetidine: (Minor) The metabolism of progesterone may be inhibited by cimetidine, an inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Clarithromycin: (Minor) The metabolism of progesterone may be inhibited by clarithromycin, an inhibitor of the CYP3A4 hepatic enzyme.
    Clobazam: (Major) The addition of non-hormonal forms of contraception are recommended during concurrent use of clobazam and hormonal contraceptives. Concurrent administration of clobazam, a weak CYP3A4 inducer, with progestins may increase the elimination of these hormones. The additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for indications other than contraception may need to be monitored for reduced clinical effect while on clobazam, with dose adjustments made based on clinical efficacy.
    Clotrimazole: (Moderate) Vaginal preparations of progesterone (e.g., Crinone, Endometrin, and Prochieve) should not be used with other intravaginal products (e.g., vaginal antifungals, such as clotrimazole, miconazole nitrate, terconazole, or tioconazole vaginal) as concurrent use may alter progesterone release and absorption from the vagina. Separate the times of administration to avoid the interaction. The manufacturers of Crinone and Prochieve indicate that other intravaginal products can be used as long as 6 hours has lapsed either before or after vaginal administration of progesterone. Endometrin is generally not recommended for use with other vaginal products (e.g., antifungal products) as this may alter progesterone release and absorption from the vaginal insert and the potential for interaction has not been formally assessed; use other vaginal products if medically necessary, but be aware that the response to Endometrin may be altered.
    Cobicistat: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Danazol: (Minor) The metabolism of progesterone may be inhibited by danazol, a known inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Dapagliflozin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Dapagliflozin; Metformin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Dapagliflozin; Saxagliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Darunavir; Cobicistat: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
    Diltiazem: (Minor) The metabolism of progesterone may be decreased by inhibitors of cytochrome P450 3A4 hepatic enzymes, such as diltiazem.
    Doxorubicin: (Minor) Enhanced doxorubicin-induced neutropenia and thrombocytopenia may occur if coadministered with progesterone.
    Empagliflozin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Empagliflozin; Linagliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Empagliflozin; Metformin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Enzalutamide: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as enzalutamide. Concurrent administration of enzalutamide with progestins, oral contraceptives, or non-oral combination contraceptives may reduce hormonal concentrations. If used for contraception, an alternate or additional form of contraception should be considered. Highier-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of enzalutamide. Patients taking hormonal replacement therapy may need to be monitored for reduced clinical effect while on enzalutamide, with dose adjustments made based on clinical efficacy. Women taking hormonal replacement and enzalutamide should report breakthrough bleeding, hot flashes, or other symptoms to their prescribers.
    Ertugliflozin; Metformin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Ertugliflozin; Sitagliptin: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Erythromycin: (Minor) The metabolism of progesterone may be inhibited by erythromycin, an inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Erythromycin; Sulfisoxazole: (Minor) The metabolism of progesterone may be inhibited by erythromycin, an inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Felbamate: (Major) Based on very limited data, it appears felbamate can accelerate the clearance of the estrogen component of some oral contraceptives. Patients who experience breakthrough bleeding while receiving these drugs together should notify their prescribers. An alternate or additional form of contraception should be used during concomitant treatment. Additionally, patients taking non-oral combination contraceptives or estrogens or progestins for hormone replacement therapy may also experience reduced clinical efficacy; dosage adjustments may be necessary.
    Fluconazole: (Minor) The metabolism of progesterone may be inhibited by fluconazole, an inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Food: (Minor) Food can increase the bioavailability of progesterone administered orally.
    Fosamprenavir: (Major) Oral contraceptives and non-oral combination contraceptives should not be administered with fosamprenavir. Alternative methods of non-hormonal contraception are recommended. Fosamprenavir should not be coadministered with oral contraceptives as clinically significant hepatic enzyme (transaminase) elevations may occur with concomitant use. Additionally, hormonal contraceptives, estrogens, and progestins may decrease the serum concentrations of fosamprenavir's active metabolite, amprenavir, which could lead to loss of virologic response and possible viral resistance. Additionally, data on the effects that other protease inhibitors have on the serum concentrations of estrogens and progestins are complex; some protease inhibitors increase and others decrease the metabolism of hormonal contraceptives. Coadministration of medroxyprogesterone, a CYP3A substrate with fosamprenavir, a strong CYP3A inhibitor. should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. It is not known if fosamprenavir alters the metabolism of other hormonal contraceptives or other estrogen or progestin products. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms. In women receiving oral contraceptives containing the progestin drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors concomitantly.
    Glimepiride: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glimepiride; Pioglitazone: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glimepiride; Rosiglitazone: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glipizide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glipizide; Metformin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glyburide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glyburide; Metformin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Griseofulvin: (Major) The concurrent use of griseofulvin and oral contraceptives can reduce contraceptive efficacy and result in an unintended pregnancy and/or breakthrough bleeding. This risk is particularly serious because griseofulvin is contraindicated during pregnancy due to the risk of teratogenic and abortifacient effects. An alternate or additional form of contraception should be used during concomitant treatment and continued for 1 month after griseofulvin discontinuation. If these drugs are used together, counsel the patient about the risk of pregnancy and teratogenic effects, and instruct the patient to notify the prescriber if they experience breakthrough bleeding while receiving these drugs together. Additionally, patients taking non-oral combination contraceptives or progestins for hormone replacement therapy may also experience reduced clinical efficacy.
    Hydantoins: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy.
    Incretin Mimetics: (Moderate) Incretin mimetics slow gastric emptying and should be used with caution in patients receiving oral medications that require minimum threshold concentrations for efficacy, such as progestin-only oral contraceptives. Some incretin mimetics make specific recommendations to reduce the risk for interaction. Taking an oral contraceptive (OC) at least 1 hour before an incretin mimetic injection should reduce the risk of an effect on contraceptive or hormonal absorption. For Lixisenatide, the manufacturer recommends taking the OC 1 hour before injection or 11 hours after injection to reduce the effect on absorption. Additionally, progestins can impair glucose tolerance. Monitor blood glucose more carefully during initiation or discontinuation of hormone replacement or hormonal contraceptive treatment. Patients receiving incretin mimetics should be closely monitored for changes in glycemic control.
    Indinavir: (Moderate) Indinavir decreases the metabolism of oral contraceptives and non-oral combination contraceptives; the AUC for ethinyl estradiol and norethindrone increased by 24+/-17% and 26+/-14%, respectively, when coadministered with indinavir. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as indinavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives with PIs should use an additional barrier method of contraception such as condoms.
    Insulins: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs such as rifampin, rifabutin, or rifapentine. Concurrent administration of these drugs with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins may increase the hormone's elimination. In addition, free estrogen-hormone concentrations are decreased because rifampin increases estrogenic protein binding ability. Additionally, like other anti-infectives, rifampin indirectly inhibits the enterohepatic recirculation of estrogen through disruption of GI flora growth. Women taking both hormones and any of these drugs should report breakthrough bleeding to their prescribers; it is estimated that 70% of women taking oral contraceptives and rifampin experience menstrual abnormalities, and 6% become pregnant. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifampin, rifabutin, or rifapentine. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. In one review, the authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under recognized or under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or newer combined contraceptive deliveries (e.g., patches, rings) are not available. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifampin, rifabutin, or rifapentine, with dose adjustments made based on clinical efficacy.
    Isoniazid, INH; Rifampin: (Major) Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs such as rifampin, rifabutin, or rifapentine. Concurrent administration of these drugs with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins may increase the hormone's elimination. In addition, free estrogen-hormone concentrations are decreased because rifampin increases estrogenic protein binding ability. Additionally, like other anti-infectives, rifampin indirectly inhibits the enterohepatic recirculation of estrogen through disruption of GI flora growth. Women taking both hormones and any of these drugs should report breakthrough bleeding to their prescribers; it is estimated that 70% of women taking oral contraceptives and rifampin experience menstrual abnormalities, and 6% become pregnant. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifampin, rifabutin, or rifapentine. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. In one review, the authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under recognized or under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or newer combined contraceptive deliveries (e.g., patches, rings) are not available. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifampin, rifabutin, or rifapentine, with dose adjustments made based on clinical efficacy.
    Itraconazole: (Minor) The metabolism of progesterone may be inhibited by itraconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Ketoconazole: (Minor) The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Lesinurad: (Major) Hormonal contraceptives, including combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins. This includes injectable, transdermal, and implantable forms. Hormonal contraceptives may not be reliable when coadministered with lesinurad. Females should use additional, non-hormonal methods of contraception and not rely solely on hormonal contraceptive methods when taking lesinurad.
    Lesinurad; Allopurinol: (Major) Hormonal contraceptives, including combination oral contraceptives, non-oral combination contraceptives, and contraceptives containing only progestins. This includes injectable, transdermal, and implantable forms. Hormonal contraceptives may not be reliable when coadministered with lesinurad. Females should use additional, non-hormonal methods of contraception and not rely solely on hormonal contraceptive methods when taking lesinurad.
    Linagliptin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Linagliptin; Metformin: (Minor) Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 mcg of ethinyl estradiol per day. The presence or absence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Lorlatinib: (Major) Women taking both progestins and lorlatinib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed lorlatinib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of lorlatinib. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Progestins are CYP3A4 substrates and lorlatinib is a moderate CYP3A4 inducer.
    Meglitinides: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Mephobarbital: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Metformin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Metformin; Pioglitazone: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Metformin; Repaglinide: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Metformin; Rosiglitazone: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance.
    Metformin; Saxagliptin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Metformin; Sitagliptin: (Minor) Patients receiving antidiabetic agents like metformin should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued. Progestins can impair glucose tolerance. (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Methohexital: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Miconazole: (Moderate) Vaginal preparations of progesterone (e.g., Crinone, Endometrin, and Prochieve) should not be used with other intravaginal products (e.g., vaginal antifungals, such as clotrimazole, miconazole nitrate, terconazole, or tioconazole vaginal) as concurrent use may alter progesterone release and absorption from the vagina. Separate the times of administration to avoid the interaction. The manufacturers of Crinone and Prochieve indicate that other intravaginal products can be used as long as 6 hours has lapsed either before or after vaginal administration of progesterone. Endometrin is generally not recommended for use with other vaginal products (e.g., antifungal products) as this may alter progesterone release and absorption from the vaginal insert and the potential for interaction has not been formally assessed; use other vaginal products if medically necessary, but be aware that the response to Endometrin may be altered.
    Miconazole; Petrolatum; Zinc Oxide: (Moderate) Vaginal preparations of progesterone (e.g., Crinone, Endometrin, and Prochieve) should not be used with other intravaginal products (e.g., vaginal antifungals, such as clotrimazole, miconazole nitrate, terconazole, or tioconazole vaginal) as concurrent use may alter progesterone release and absorption from the vagina. Separate the times of administration to avoid the interaction. The manufacturers of Crinone and Prochieve indicate that other intravaginal products can be used as long as 6 hours has lapsed either before or after vaginal administration of progesterone. Endometrin is generally not recommended for use with other vaginal products (e.g., antifungal products) as this may alter progesterone release and absorption from the vaginal insert and the potential for interaction has not been formally assessed; use other vaginal products if medically necessary, but be aware that the response to Endometrin may be altered.
    Modafinil: (Major) Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of the progestins in these products. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. If these drugs are used together, monitor patients for a decrease in clinical effects; patients should report breakthrough bleeding to their prescriber. Dosage adjustments may be necessary.
    Nelfinavir: (Major) Nelfinavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration with ethinyl estradiol; norethindrone results in a 47% decrease in ethinyl estradiol plasma concentrations and an 18% decrease in norethindrone plasma concentrations. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as nelfinavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
    Nevirapine: (Moderate) Nevirapine may decrease plasma concentrations of oral contraceptives and non-oral combination contraceptives (i.e., ethinyl estradiol and norethindrone). However despite lower exposures, literature suggests that use of nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. Thus, the manufacturer states that no dose adjustments are needed when these drugs are used for contraception in combination with nevirapine. When these oral contraceptives are used for hormone replacement and given with nevirapine, the therapeutic effect of the hormonal therapy should be monitored.
    Oxcarbazepine: (Major) Progestins are susceptible to drug interactions with hepatic enzyme inducing drugs such as oxcarbazepine. Concurrent administration of oxcarbazepine progestins may increase the hormone's elimination. A high percentage of breakthrough bleeding has been reported in the literature from the combined use of oxcarbazepine and oral contraceptives; the results of one study demonstrated that the mean AUC of ethinyl estradiol/levonorgestrel was decreased by 52% when coadministered with oxcarbazepine. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs, or higher-dose hormonal regimens may be indicated where acceptable or applicable as pregnancy has been reported in patients taking the hepatic enzyme inducing drug phenytoin concurrently with hormonal contraceptives. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on oxcarbazepine, with dose adjustments made based on clinical efficacy.
    Pentobarbital: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Phenobarbital: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Phentermine; Topiramate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Pramlintide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with progestins.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Either additive or antagonistic effects could potentially occur if prasterone is combined with progestins.
    Primidone: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Rifabutin: (Major) Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs such as rifampin, rifabutin, or rifapentine. Concurrent administration of these drugs with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins may increase the hormone's elimination. In addition, free estrogen-hormone concentrations are decreased because rifampin increases estrogenic protein binding ability. Additionally, like other anti-infectives, rifampin indirectly inhibits the enterohepatic recirculation of estrogen through disruption of GI flora growth. Women taking both hormones and any of these drugs should report breakthrough bleeding to their prescribers; it is estimated that 70% of women taking oral contraceptives and rifampin experience menstrual abnormalities, and 6% become pregnant. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifampin, rifabutin, or rifapentine. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. In one review, the authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under recognized or under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or newer combined contraceptive deliveries (e.g., patches, rings) are not available. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifampin, rifabutin, or rifapentine, with dose adjustments made based on clinical efficacy.
    Rifampin: (Major) Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs such as rifampin, rifabutin, or rifapentine. Concurrent administration of these drugs with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins may increase the hormone's elimination. In addition, free estrogen-hormone concentrations are decreased because rifampin increases estrogenic protein binding ability. Additionally, like other anti-infectives, rifampin indirectly inhibits the enterohepatic recirculation of estrogen through disruption of GI flora growth. Women taking both hormones and any of these drugs should report breakthrough bleeding to their prescribers; it is estimated that 70% of women taking oral contraceptives and rifampin experience menstrual abnormalities, and 6% become pregnant. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifampin, rifabutin, or rifapentine. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. In one review, the authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under recognized or under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or newer combined contraceptive deliveries (e.g., patches, rings) are not available. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifampin, rifabutin, or rifapentine, with dose adjustments made based on clinical efficacy.
    Rifamycins: (Major) Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs such as rifampin, rifabutin, or rifapentine. Concurrent administration of these drugs with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins may increase the hormone's elimination. In addition, free estrogen-hormone concentrations are decreased because rifampin increases estrogenic protein binding ability. Additionally, like other anti-infectives, rifampin indirectly inhibits the enterohepatic recirculation of estrogen through disruption of GI flora growth. Women taking both hormones and any of these drugs should report breakthrough bleeding to their prescribers; it is estimated that 70% of women taking oral contraceptives and rifampin experience menstrual abnormalities, and 6% become pregnant. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifampin, rifabutin, or rifapentine. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. In one review, the authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under recognized or under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or newer combined contraceptive deliveries (e.g., patches, rings) are not available. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifampin, rifabutin, or rifapentine, with dose adjustments made based on clinical efficacy.
    Rifapentine: (Major) Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs such as rifampin, rifabutin, or rifapentine. Concurrent administration of these drugs with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins may increase the hormone's elimination. In addition, free estrogen-hormone concentrations are decreased because rifampin increases estrogenic protein binding ability. Additionally, like other anti-infectives, rifampin indirectly inhibits the enterohepatic recirculation of estrogen through disruption of GI flora growth. Women taking both hormones and any of these drugs should report breakthrough bleeding to their prescribers; it is estimated that 70% of women taking oral contraceptives and rifampin experience menstrual abnormalities, and 6% become pregnant. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifampin, rifabutin, or rifapentine. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. In one review, the authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under recognized or under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or newer combined contraceptive deliveries (e.g., patches, rings) are not available. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifampin, rifabutin, or rifapentine, with dose adjustments made based on clinical efficacy.
    Saxagliptin: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Secobarbital: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Simvastatin; Sitagliptin: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by concurrent progesterone. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of procedure results.
    Sitagliptin: (Minor) Progestins can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued.
    Sodium Iodide: (Moderate) Progesterone is known to decrease the uptake of iodide into thyroid tissue. In order to increase thyroid uptake and optimize exposure of thyroid tissue to the radionucleotide sodium iodide I-131, consider withholding progesterone prior to treatment with sodium iodide I-131.
    St. John's Wort, Hypericum perforatum: (Major) It is possible that, as with other CYP3A4 inducers, St. John's Wort could reduce the therapeutic efficacy of progestin-only contraceptives. Women should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's Wort concurrently with their hormones. Avoidance of these combinations is recommended.
    Sulfonylureas: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Thiopental: (Major) Avoid coadministration. Barbiturates induce hepatic enzymes and can accelerate the rate of metabolism of hormones, including progestins. For patients on hormone replacement treatments (HRT) with progestins, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. For women taking hormonal contraception for birth control, loss of efficacy may lead to breakthrough bleeding and an increased risk for pregnancy. Pregnancy has been reported during therapy with hormonal contraceptives in patients receiving barbiturates. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; these women should ensure adequate folate supplementation.
    Tipranavir: (Major) Tipranavir increases the metabolism of hormonal contraceptives, including combined oral contraceptives and non-oral combination contraceptives; concentrations of ethinyl estradiol decrease by 50% when coadministered. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by tipranavir with ritonavir, 33% of subjects developed a rash. Women receiving combined hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as tipranavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. Alternate methods of non-hormonal contraception should be used in patients receiving tipranavir. Because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
    Tolazamide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Tolbutamide: (Minor) Progestins can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Topiramate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception may also be needed.
    Trandolapril; Verapamil: (Minor) The metabolism of progesterone may be inhibited by verapamil, an inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Ulipristal: (Major) Avoid concurrent use of ulipristal and progestin-containing hormonal contraceptives or other progestins. Such contraceptives may be started or resumed no sooner than 5 days after ulipristal treatment. A reliable barrier method of contraception should be used during the same menstrual cycle in which ulipristal was administered (until the next menstrual period). Ulipristal may may reduce the effectiveness of progestin-containing hormonal contraceptives by competitively binding at the progesterone receptor. The concurrent use of emergency contraceptives containing levonorgestrel is not recommended, for similar reason. The effectiveness of other progestins may also be impaired.
    Verapamil: (Minor) The metabolism of progesterone may be inhibited by verapamil, an inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Voriconazole: (Minor) The metabolism of progesterone may be inhibited by voriconazole, which which inhibits CYP3A4 hepatic enzymes.

    PREGNANCY AND LACTATION

    Pregnancy

    Detectable amounts of drug have been identified in the milk of mothers receiving progestational drugs. The effect of this on the breast-feeding infant has not been determined. In general, use of progestins has not had adverse effects on lactation. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for progesterone and the potential adverse effects on the breast-fed infant.

    MECHANISM OF ACTION

    Progesterone is a naturally occurring steroid that is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate estrogen, progesterone transforms a proliferative endometrium into a secretory endometrium. Progesterone is essential for the development of decidual tissue, and the effect of progesterone on the differentiation of glandular epithelia and stroma has been extensively studied. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain the pregnancy. Normal or near-normal endometrial responses to oral estradiol and intramuscular progesterone have been noted in functionally agonadal women through the sixth decade of life. Progesterone administration decreases the circulatory levels of gonadotropins.
     
    Progesterone can be used to achieve normalized progesterone levels in women with secondary amenorrhea. When a woman does not produce enough progesterone, menstrual irregularities may occur. Progesterone can thus help re-establish normal menstrual cycles in pre-menopausal women with such irregularities.
     
    The primary role of progesterone when used in the menopausal woman is for a protective effect that reductes the risk of endometrial hyperplasia when used with estrogen in the woman with an intact uterus. Micronized oral progesterone does not appear to have adverse effects on serum lipid profiles when used in regimens for hormone replacement therapy (HRT).
     
    Progesterone has also been used historically as a contraceptive, including in intrauterine contraceptive devices (IUDs). The primary contraceptive effect of exogenous progestins involves the suppression of the midcycle surge of luteinizing hormone (LH). The exact mechanism of action, however, is unknown. At the cellular level, progestins diffuse freely into target cells and bind to the progesterone receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH surge, thereby preventing follicular maturation and ovulation. Additional mechanisms may be involved in the contraceptive effect. Other actions of progestins include alterations in the endometrium that can impair implantation and an increase in cervical mucus viscosity which inhibits sperm migration into the uterus.

    PHARMACOKINETICS

    Progesterone is administered orally (Prometrium micronized soft gelatin capsules), intramuscularly, intravaginally (Crinone gel, Prochieve gel), or as a component of an intrauterine device (IUD). Vaginal suppositories are also compounded for use, however, pharmacokinetic data is unavailable. Once in the systemic circulation, progesterone is extensively (96—99%) bound to cortisol binding globulin, sex hormone binding globulin, and albumin. The drug is metabolized hepatically to pregnanediol and conjugated with glucuronic acid. The plasma elimination half-life ranges 5—20 minutes. The metabolites are excreted primarily in the urine (50—60%). About 10% is eliminated via the bile and feces.

    Oral Route

    After oral administration, progesterone is significantly absorbed with peak serum concentration occurring within 3 hours. The absolute bioavailability, however, is not known.

    Intramuscular Route

    The absorption of progesterone following intramuscular injection is rapid, and the effects last for about 24 hours.

    Other Route(s)

    Vaginal Route
    Following intravaginal administration of progesterone gel, absorption is prolonged with an absorption half-life of approximately 25—50 hours.
     
    Intrauterine Route
    Intrauterine devices release progesterone at an average rate of 65 mcg/day by membrane controlled diffusion. Local absorption of progesterone into the uterine epithelium readily occurs. Systemic absorption from an IUD is clinically insignificant.