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  • CLASSES

    Progestogens

    DEA CLASS

    Rx

    DESCRIPTION

    A progestin for intramuscular administration
    Indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth
    Not intended for use in women with multiple gestations or other risk factors for preterm birth

    COMMON BRAND NAMES

    Makena

    HOW SUPPLIED

    Hydroxyprogesterone Caproate/Makena Intramuscular Inj Sol: 1mL, 250mg

    DOSAGE & INDICATIONS

    For preterm delivery prophylaxis in females with a singleton pregnancy who have a history of singleton spontaneous preterm birth.
    NOTE: Hydroxyprogesterone is not intended for use in women with multiple gestations or other risk factors for preterm birth.
    Intramuscular dosage
    Adult and Adolescent pregnant females >= 16 years

    250 mg (1 mL) IM once weekly (every 7 days). Begin treatment anytime between 16 weeks and 0 days of pregnancy up to 20 weeks and 6 days of pregnancy. Continue once weekly until week 37 (through 36 weeks, 6 days) of gestation or delivery, whichever occurs first.

    Postmenopausal Adult females >= 50 years

    Safety and efficacy have not been established. Not intended for use in postmenopausal females.

    For the treatment of amenorrhea† and dysfunctional uterine bleeding†.
    Intramuscular dosage
    Adult females

    375 mg IM. May be repeated at 4-week intervals as needed.

    For the treatment of endometrial cancer†.
    Intramuscular dosage
    Adult females

    1000 mg IM up to 7 times per week for 12 weeks.

    To test for endogenous estrogen production†.
    Intramuscular dosage
    Adult females

    250 mg IM once; repeat for confirmation at 4 weeks. Bleeding should occur 7—14 days after the injection.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    250 mg IM once weekly (every 7 days) for preterm delivery prophylaxis.

    Geriatric

    Safety and efficacy have not been established.

    Adolescents

    >= 16 years: 250 mg IM once weekly (every 7 days) for preterm delivery prophylaxis.
    < 16 years: Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Hydroxyprogesterone is contraindicated for use in patients with active hepatic disease.

    Renal Impairment

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

    ADMINISTRATION

    Injectable Administration

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

    Intramuscular Administration

    Hydroxyprogesterone caproate injection is a clear, yellow solution. It is viscous and oily. Do not use if solid particles appear or if the solution is cloudy.
    Administer intramuscularly. DO NOT administer intravenously.
     
    Intramuscular injection:
    Draw up 1 mL (250 mg) of drug from the multi-dose glass vial into a 3 mL syringe with an 18 gauge needle, then change the needle to a 21 gauge 1½ inch needle for administration.
    Administer to the upper outer quadrant of the gluteus maximus. Slow injection (over 1 minute or longer) is recommended.
    Injection may cause irritation at the administration site. Applying pressure to the site may minimize bruising and swelling.
    Discard any unused product 5 weeks after first use.

    STORAGE

    Makena:
    - Discard entered multi-dose vial after 28 days
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton

    CONTRAINDICATIONS / PRECAUTIONS

    Intravenous administration

    Hydroxyprogesterone caproate injection is for intramuscular use only. Do not administer via intravenous administration.

    Benzyl alcohol hypersensitivity, polyoxyethylated castor oil hypersensitivity

    Hydroxyprogesterone caproate injection contains castor oil. Allergic reactions, including urticaria, pruritus, and angioedema have been reported with use of hydroxyprogesterone and other products containing castor oil. Therefore, use caution when administering to patients with polyoxyethylated castor oil hypersensitivity and discontinue use if allergic reactions occur. In addition, hydroxyprogesterone contains the preservative benzyl alcohol, which can cause adverse effects in patients with a benzyl alcohol hypersensitivity and should be avoided in these patients.

    Thromboembolic disease, thrombophlebitis

    Hydroxyprogesterone is contraindicated in patients with current or history of thrombosis or thromboembolic disease. If a thromboembolic event occurs, including thrombophlebitis or deep venous thrombus, discontinue hydroxyprogesterone immediately.

    Breast cancer, cervical cancer, uterine cancer, vaginal cancer

    Hydroxyprogesterone is contraindicated in patients with known or suspected breast cancer or other hormone-sensitive cancer, such as cervical cancer, uterine cancer, or vaginal cancer. A history of any of these conditions also contraindicates the use of hydroxyprogesterone.

    Vaginal bleeding

    Hydroxyprogesterone is contraindicated in patients with undiagnosed abnormal vaginal bleeding unrelated to being pregnant.

    Cardiac disease, hypertension, preeclampsia

    Hydroxyprogesterone is contraindicated in patients with uncontrolled hypertension. Close monitoring of patients who develop hypertension while receiving therapy is recommended; careful consideration should be given to whether the benefit of use warrants continuation of therapy. Progestational drugs may cause some degree of fluid retention. Therefore, use hydroxyprogesterone cautiously in patients with preeclampsia, cardiac disease, or any other condition that might be influenced by this effect. Carefully monitor women with these conditions.

    Diabetes mellitus

    Hydroxyprogesterone should be used cautiously in patients with diabetes mellitus. Although the effects appear to be minimal during therapy with progestins, decreased glucose tolerance has been observed in some patients on progestin treatment. The mechanism of this decrease is unknown. Carefully monitor prediabetic and diabetic patients while on hydroxyprogesterone therapy.

    Depression, migraine, seizure disorder

    Hydroxyprogesterone should be used cautiously in patients with a history of depression. Progestins may exacerbate this condition in some patients. Monitor women who have a history of clinical depression and discontinue therapy if clinical depression recurs. In addition, progestational drugs may cause some degree of fluid retention. Therefore, use hydroxyprogesterone cautiously in patients with a history of migraine or seizure disorder or other condition that might be influenced by this effect. Carefully monitor women with these conditions.

    Asthma, renal disease

    Progestational drugs may cause some degree of fluid retention. Therefore, use hydroxyprogesterone cautiously in patients with renal disease, asthma, or any other condition that might be influenced by this effect. Carefully monitor women with these conditions.

    Labor, pregnancy

    Hydroxyprogesterone is intended for use during pregnancy in order to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth; it is used in the second and third trimesters. No adequate and well-controlled studies exist in women during the first trimester of pregnancy. Placebo-controlled studies in pregnant women (n = 310) who received weekly IM doses (250 mg) of hydroxyprogesterone in their second and third trimesters revealed no teratogenic risks to the infants from in utero exposure. In addition, no risks were observed during a long-term (2 to 5 years) follow-up on their 194 infants. Hydroxyprogesterone administration produced embryolethality in rhesus monkeys but not in cynomolgus monkeys exposed to 1 and 10 times the human dose equivalent every 7 days between days 20 and 146 of gestation. There were no teratogenic effects in either species. Hydroxyprogesterone is not intended for use to stop active preterm labor; its effect in active labor is unknown.

    Cholestasis, hepatic disease, hepatocellular cancer, jaundice

    Hydroxyprogesterone is contraindicated in patients with hepatocellular cancer, benign liver tumors, or active hepatic disease. Hydroxyprogesterone is extensively metabolized and hepatic impairment may reduce its elimination. In addition, hydroxyprogesterone is contraindicated in patients with symptomatic Intrahepatic Cholestasis of Pregnancy (ICP). Patients who develop jaundice while receiving therapy should be closely monitored; careful consideration should be given to whether the benefit of use warrants continuation of therapy.

    Breast-feeding

    According to the manufacturer, hydroxyprogesterone should be discontinued at week 37 of gestation or upon delivery; it is not expected that use would continue during the postpartum period. Detectable amounts of progestins have been identified in the milk of mothers receiving progestin treatment. Many studies have found no adverse effects of progestins on breast-feeding performance, or on the health, growth, or development of the infant.

    Children, infants, neonates

    Safety and effectiveness in children less than 16 years of age have not been established. Studies included a small number of pregnant women between the ages of 16 and 18; safety and efficacy are expected to be the same in women aged 16 years and above as for users 18 years and older. Hydroxyprogesterone is not indicated for use in neonates or infants, and studies continue to study the effect of hydroxyprogesterone on neonatal outcomes following maternal use.

    Geriatric, postmenopausal females

    Hydroxyprogesterone is not intended for use in geriatric or postmenopausal adult women. Safety and effectiveness in postmenopausal females have not been established.

    ADVERSE REACTIONS

    Severe

    premature labor / Delayed / 16.0-16.0
    thromboembolism / Delayed / 0-1.0
    pulmonary embolism / Delayed / Incidence not known
    retinal thrombosis / Delayed / Incidence not known
    stroke / Early / Incidence not known
    fetal death / Delayed / Incidence not known
    fetal abortion / Delayed / Incidence not known

    Moderate

    hypertension / Early / 0-8.8
    erythema / Early / Incidence not known
    depression / Delayed / Incidence not known
    hot flashes / Early / Incidence not known
    fluid retention / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    edema / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    vaginal bleeding / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 34.8-34.8
    urticaria / Rapid / 12.3-12.3
    emotional lability / Early / 1.0-10.0
    pruritus / Rapid / 7.7-7.7
    nausea / Early / 5.8-5.8
    diarrhea / Early / 2.3-2.3
    rash (unspecified) / Early / Incidence not known
    infection / Delayed / Incidence not known
    skin irritation / Early / Incidence not known
    vomiting / Early / Incidence not known
    irritability / Delayed / Incidence not known
    anxiety / Delayed / Incidence not known
    fever / Early / Incidence not known
    dizziness / Early / Incidence not known
    headache / Early / Incidence not known
    fatigue / Early / Incidence not known
    breast discharge / Delayed / Incidence not known
    mastalgia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    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. (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    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. (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    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. (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Codeine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Dextromethorphan: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Diphenhydramine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Hydrocodone: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Oxycodone: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Pentazocine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Propoxyphene: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Pseudoephedrine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Acetaminophen; Tramadol: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    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: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (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) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes would have a similar effect. Other such drugs include cimetidine, clarithromycin, danazol, diltiazem, erythromycin, fluconazole, itraconazole, troleandomycin, verapamil, and voriconazole. This list is not inclusive of all drugs that inhibit CYP3A4.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes would have a similar effect. Other such drugs include cimetidine, clarithromycin, danazol, diltiazem, erythromycin, fluconazole, itraconazole, troleandomycin, verapamil, and voriconazole. This list is not inclusive of all drugs that inhibit CYP3A4.
    Amprenavir: (Major) Progestins may decrease the serum concentrations of amprenavir, which could lead to loss of virologic response and possible viral resistance. Oral contraceptives and non-oral combination contraceptives should not be administered with amprenavir. Alternative methods of non-hormonal contraception are recommended if amprenavir is prescribed. 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. It is not known if amprenavir alters the metabolism of 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.
    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.
    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 hydroxyprogesterone caproate. 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.
    Axitinib: (Minor) Monitor patients for decreased efficacy of axitinib if coadministration with hydroxyprogesterone is necessary. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Hydroxyprogesterone is a CYP1A2 inducer in vitro. Theoretically, exposure to axitinib may be decreased.
    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.
    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: (Severe) Bosentan is a significant inducer of CYP3A hepatic enzymes. 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. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. In addition, bosentan is teratogenic and is contraindicated during pregnancy. An interaction study has demonstrated that coadministration of bosentan and an oral contraceptive product (ethinyl estradiol; norethindrone) produced average decreases in norethindrone and ethinyl estradiol serum concentrations of 14% and 31%, respectively; however, decreases in drug exposure were are as high as 56% and 66%, respectively, in individual subjects. Hormonal contraceptives should not be used as the sole method to prevent pregnancy in patients receiving bosentan. Effective contraception through additional forms of contraception must be practiced. The manufacturer recommends that follow-up pregnancy tests be obtained monthly for women of childbearing potential taking bosentan. Additionally, estrogens and progestins used for hormone replacement therapy 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.
    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.
    Bupropion: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2B6 isoenzymes. The metabolism of drugs metabolized by CYP2B6, such as bupropion may be increased during treatment with hydroxyprogesterone.
    Bupropion; Naltrexone: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2B6 isoenzymes. The metabolism of drugs metabolized by CYP2B6, such as bupropion may be increased during treatment with hydroxyprogesterone.
    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.
    Ceritinib: (Moderate) Monitor for increased hydroxyprogesterone adverse effects if coadministered with ceritinib. In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. Theoretically, the metabolism of hydroxyprogesterone may be inhibited by ceritinib, a CYP3A4 inhibitor.
    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) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes would have a similar effect. Other such drugs include cimetidine, clarithromycin, danazol, diltiazem, erythromycin, fluconazole, itraconazole, troleandomycin, verapamil, and voriconazole. This list is not inclusive of all drugs that inhibit CYP3A4.
    Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin with hydroxyprogesterone may result in increased serum concentrations of hydroxyprogesterone. Hydroxyprogesterone is a substrate of the hepatic isoenzyme CYP3A4; ciprofloxacin is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Clarithromycin: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes would have a similar effect. Other such drugs include cimetidine, clarithromycin, danazol, diltiazem, erythromycin, fluconazole, itraconazole, troleandomycin, verapamil, and voriconazole. This list is not inclusive of all drugs that inhibit CYP3A4.
    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.
    Clozapine: (Moderate) Caution is advisable during concurrent use of hydroxyprogesterone with clozapine. Hydroxyprogesterone induces CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. When initiating clozapine or adding a weak to moderate CYP1A2 inducer to a pre-existing clozapine regimen, monitor for decreased effectiveness and consider increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
    Cobicistat: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with hydroxyprogesterone caproate. 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 hydroxyprogesterone caproate. 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 hydroxyprogesterone caproate. 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) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes would have a similar effect. Other such drugs include cimetidine, clarithromycin, danazol, diltiazem, erythromycin, fluconazole, itraconazole, troleandomycin, verapamil, and voriconazole. This list is not inclusive of all drugs that inhibit CYP3A4.
    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: (Minor) The plasma concentrations of hydroxyprogesterone may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while hydroxyprogesterone is a CYP3A4 substrate.
    Darunavir; Cobicistat: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with hydroxyprogesterone caproate. 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. (Minor) The plasma concentrations of hydroxyprogesterone may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while hydroxyprogesterone is a CYP3A4 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of hydroxyprogesterone with ritonavir may result in elevated hydroxyprogesterone plasma concentrations. Hydroxyprogesterone is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Diltiazem: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes, like dilitiazem, would have a similar effect.
    Efavirenz: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2B6 isoenzymes. The metabolism of drugs metabolized by CYP2B6, such as efavirenz may be increased during treatment with hydroxyprogesterone.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2B6 isoenzymes. The metabolism of drugs metabolized by CYP2B6, such as efavirenz may be increased during treatment with hydroxyprogesterone.
    Elbasvir; Grazoprevir: (Moderate) Administering hydroxyprogesterone with elbasvir; grazoprevir may result in elevated hydroxyprogesterone plasma concentrations. Hydroxyprogesterone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    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.
    Erythromycin: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes, like erythromycin, would have a similar effect.
    Erythromycin; Sulfisoxazole: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes, like erythromycin, would have a similar effect.
    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) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes, like fluconazole, would have a similar effect.
    Fosamprenavir: (Major) Clinically significant hepatic transaminase elevations may occur with concomitant use of fosamprenavir, boosted with ritonavir, and oral contraceptives; fosamprenavir should not be coadministered with oral contraceptives. 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. Oral contraceptives and non-oral combination contraceptives should not be administered with fosamprenavir. Alternative methods of non-hormonal contraception are recommended. 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. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro. 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 drospirenone, consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors, such as atazanavir, long-term and concomitantly. Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium.
    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: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (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. (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.
    Halothane: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as halothane may be increased during treatment with hydroxyprogesterone.
    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.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with hydroxyprogesterone, a CYP3A substrate, as hydroxyprogesterone toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    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.
    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.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with hydroxyprogesterone may result in increased serum concentrations of hydroxyprogesterone. Hydroxyprogesterone is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones. The clinical effect hydroxyprogesterone may be reduced in patients taking rifamycins (e.g., rifampin, rifabutin, rifapentine) concomitantly.
    Isoniazid, INH; Rifampin: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones. The clinical effect hydroxyprogesterone may be reduced in patients taking rifamycins (e.g., rifampin, rifabutin, rifapentine) concomitantly.
    Itraconazole: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes, like itraconazole, would have a similar effect.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and hydroxyprogesterone concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydroxyprogesterone, can increase hydroxyprogesterone exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ketoconazole: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of hydroxyprogesterone; monitor for potential reduction in efficacy. Hydroxyprogesterone is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of hydroxyprogesterone; monitor for potential reduction in efficacy. Hydroxyprogesterone is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    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.
    Loperamide: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with hydroxyprogesterone. Loperamide is metabolized by the hepatic enzyme CYP2B6; hydroxyprogesterone is an inducer of this enzyme.
    Loperamide; Simethicone: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with hydroxyprogesterone. Loperamide is metabolized by the hepatic enzyme CYP2B6; hydroxyprogesterone is an inducer of this enzyme.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of hydroxyprogesterone with ritonavir may result in elevated hydroxyprogesterone plasma concentrations. Hydroxyprogesterone is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and hydroxyprogesterone concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as hydroxyprogesterone, can increase hydroxyprogesterone exposure leading to increased or prolonged therapeutic effects and adverse events.
    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: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation. (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. (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.
    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.
    Methadone: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2B6 isoenzymes. The metabolism of drugs metabolized by CYP2B6, such as methadone may be increased during treatment with hydroxyprogesterone.
    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.
    Mitotane: (Major) Use caution if mitotane and hydroxyprogesterone are used concomitantly, and monitor for decreased efficacy of hydroxyprogesterone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and hydroxyprogesterone is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of hydroxyprogesterone.
    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.
    Netupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Hydroxyprogesterone has been shown to be a primary 3A4 substrate in-vitro. The plasma concentrations of hydroxyprogesterone can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
    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.
    Nicotine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as nicotine may be increased during treatment with hydroxyprogesterone.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of hydroxyprogesterone with ritonavir may result in elevated hydroxyprogesterone plasma concentrations. Hydroxyprogesterone is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Oritavancin: (Major) Hydroxyprogesterone is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of hydroxyprogesterone may be reduced if these drugs are administered concurrently.
    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.
    Pioglitazone: (Major) Coadministration of pioglitazone with oral contraceptives can accelerate the rate of metabolism of hormonal contraceptives. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy during pioglitazone use or the use of an alternative or additional method of contraception can be considered. In addition, estrogens, progestins, and oral contraceptives may alter glucose tolerance, necessitating monitoring of blood glucose on hormone initiation.
    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.
    Ribociclib: (Minor) Use caution if coadministration of ribociclib with hydroxyprogesterone is necessary, as the systemic exposure of hydroxyprogesterone may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and hydroxyprogesterone is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Minor) Use caution if coadministration of ribociclib with hydroxyprogesterone is necessary, as the systemic exposure of hydroxyprogesterone may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and hydroxyprogesterone is a CYP3A4 substrate.
    Rifabutin: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones. The clinical effect hydroxyprogesterone may be reduced in patients taking rifamycins (e.g., rifampin, rifabutin, rifapentine) concomitantly.
    Rifampin: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones. The clinical effect hydroxyprogesterone may be reduced in patients taking rifamycins (e.g., rifampin, rifabutin, rifapentine) concomitantly.
    Rifamycins: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones. The clinical effect hydroxyprogesterone may be reduced in patients taking rifamycins (e.g., rifampin, rifabutin, rifapentine) concomitantly.
    Rifapentine: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones. The clinical effect hydroxyprogesterone may be reduced in patients taking rifamycins (e.g., rifampin, rifabutin, rifapentine) concomitantly.
    Ritonavir: (Moderate) Concurrent administration of hydroxyprogesterone with ritonavir may result in elevated hydroxyprogesterone plasma concentrations. Hydroxyprogesterone is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    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.
    Saquinavir: (Minor) Coadministration of hydroxyprogesterone, a primary 3A4 substrate and saquinavir, a strong CYP3A4 inhibitor may increase the serum concentration of hydroxyprogesterone.
    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.
    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.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with hydroxyprogesterone. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Hydroxyprogesterone is an in vitro inducer of CYP2B6; velpatasvir is a CYP2B6 substrate.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with hydroxyprogesterone. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Hydroxyprogesterone is an in vitro inducer of CYP2B6; velpatasvir is a CYP2B6 substrate.
    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.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and hydroxyprogesterone is necessary, as the systemic exposure of hydroxyprogesterone may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of hydroxyprogesterone; consider increasing the dose of hydroxyprogesterone if necessary. Hydroxyprogesterone is a CYP3A4 substrate in vitro. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Terbinafine: (Moderate) Due to the risk for breakthrough fungal infections, caution is advised when administering terbinafine with hydroxyprogesterone. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may decrease the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP1A2; hydroxyprogesterone induces this enzyme. Monitor patients for breakthrough fungal infections.
    Theophylline, Aminophylline: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP1A2 isoenzymes. The metabolism of drugs metabolized by CYP1A2, such as theophylline, aminophylline may be increased during treatment with hydroxyprogesterone.
    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.
    Tizanidine: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP1A2 isoenzymes. The metabolism of drugs metabolized by CYP1A2, such as tizanidine may be increased during treatment with hydroxyprogesterone.
    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) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes, like verapamil, would have a similar effect.
    Vemurafenib: (Major) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as hydroxyprogesterone, could be expected with concurrent use. Use caution, and monitor therapeutic effects of hydroxyprogesterone when coadministered with vemurafenib.
    Verapamil: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes, like verapamil, would have a similar effect.
    Voriconazole: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes, like voriconazole, would have a similar effect.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, hydroxyprogesterone should be discontinued at week 37 of gestation or upon delivery; it is not expected that use would continue during the postpartum period. Detectable amounts of progestins have been identified in the milk of mothers receiving progestin treatment. Many studies have found no adverse effects of progestins on breast-feeding performance, or on the health, growth, or development of the infant.

    MECHANISM OF ACTION

    Hydroxyprogesterone caproate is a synthetic progestin. The mechanism by which hydroxyprogesterone prevents preterm delivery is not fully understood, partially because the mechanisms for the onset of preterm labor are not fully understood. Progesterone is thought to be an important hormone in the maintenance of pregnancy both in early gestation as well as later in pregnancy. Progesterone is a smooth muscle relaxant in several organs, including the uterus during pregnancy. Progesterone also inhibits oxytocin's actions on the myometrium, and it prevents the formation of gap junctions between myometrial cells; formation of gap junctions are necessary for labor initiation. Additionally, both animal and limited human data suggest that changes in the concentration of progesterone and/or the progesterone/estrogen ratio may be partially responsible for the initiation of labor. In animals, a drop in the concentration of progesterone and an increase in estrogen occurs before labor begins.

    PHARMACOKINETICS

    Hydroxyprogesterone caproate is administered via intramuscular (IM) injection. Hydroxyprogesterone is extensively bound to plasma proteins including albumin and corticosteroid binding globulins. Hydroxyprogesterone is excreted in the urine and feces as both conjugated metabolites (predominantly) and free steroid. Hydroxyprogesterone caproate is metabolized by human hepatocytes, both by phase I and phase II reactions. The drug undergoes extensive reduction, hydroxylation, and conjugation. Conjugated metabolites include sulfated, glucuronidated, and acetylated products. During hydroxyprogesterone caproate metabolism, the caproate group is retained. In vitro data also indicate that metabolism occurs primarily via CYP3A4 and CYP3A5 isoenzymes. Following IM administration to pregnant women at 10 to 12 weeks gestation, approximately 50% and 30% of the dose was recovered in the feces and urine, respectively.
     
    Affected cytochrome P450 isoenzymes: CYP3A4, CYP3A5
    Hydroxyprogesterone appears to be metabolized by CYP3A4 and CYP3A5. It is possible that interactions with CYP3A enzyme inhibitors or inducers may occur. However, no drug-drug interaction studies have been performed in vivo in the treatment population of interest to discern clinical relevance of potential interactions. Hydroxyprogesterone is not likely to inhibit the activity of CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 at therapeutic doses. An in vitro inhibition study using human liver microsomes and CYP isoform-selective substrates indicated that hydroxyprogesterone increased the metabolic rate of CYP1A2, CYP2A6, and CYP2B6 by approximately 80%, 150%, and 80%, respectively; in a second in vitro study, hydroxyprogesterone did not induce or inhibit CYP1A2, CYP2A6, or CYP2B6 activity. Overall, the findings indicate that a minimal potential for CYP1A2, CYP2A6, and CYP2B6 related drug-drug interactions, at the clinically relevant concentrations, is possible with use of hydroxyprogesterone.

    Intramuscular Route

    Following administration of a 250 mg IM dose of hydroxyprogesterone caproate, the elimination half-life of the parent compound and the mono-hydroxylated metabolites were 16. 4 (+/- 3.6) days and 19.7 (+/- 6.2) days, respectively. Following a single IM injection of hydroxyprogesterone caproate (1,000 mg), peak serum concentrations occurred after 3 to 7 days in non-pregnant female subjects. Mean maximal concentration (Cmax) was estimated to be 27.8 ng/mL and the mean time to maximum concentration (Tmax) was 4.6 days, respectively; the elimination half-life was 7.8 days. Once-weekly IM administration resulted in a trough concentration of 60 ng/mL after 13 weeks.