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  • CLASSES

    Progestogens

    DEA CLASS

    Rx

    DESCRIPTION

    A progestin for intramuscular administration; may be given subcutaneously using an auto-injector
    One product, Makena, is indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth; not fur use in women with multiple gestation; however, postmarket studies have not confirmed efficacy and the FDA has recommended market removal
    Generic injections used in female conditions such as amenorrhea, dysfunctional uterine bleeding, and advanced endometrial cancer

    COMMON BRAND NAMES

    Makena

    HOW SUPPLIED

    Hydroxyprogesterone Caproate/Makena Intramuscular Inj Sol: 1mL, 250mg
    Makena Subcutaneous 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.
    Intramuscular dosage (single and multi-dose vials Makena only)
    Adult and Adolescent pregnant females 16 years and older

    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. The effectiveness of hydroxyprogesterone is based on improvement in the proportion of women who delivered at less than 37 weeks of gestation. There are no controlled trials demonstrating a direct clinical benefit, such as improvement in neonatal mortality and morbidity. LIMITATION OF USE: Hydroxyprogesterone is not intended for use in women with multiple gestations or other risk factors for preterm birth.

    Subcutaneous dosage (Makena auto-injector only)
    Adult and Adolescent pregnant females 16 years and older

    275 mg (1.1 mL) subcutaneously 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. The effectiveness of hydroxyprogesterone is based on improvement in the proportion of women who delivered at less than 37 weeks of gestation. There are no controlled trials demonstrating a direct clinical benefit, such as improvement in neonatal mortality and morbidity. LIMITATION OF USE: Hydroxyprogesterone is not intended for use in women with multiple gestations or other risk factors for preterm birth.

    For the treatment of inoperable, recurrent, and metastatic endometrial cancer.
    Intramuscular dosage
    Adult females

    1,000 mg or more per week IM (range 1 gram IM once weekly to 1 gram IM once daily). Discontinue when relapse occurs, or after 12 weeks with no objective response. May be used in advanced stage concomitantly with other anticancer therapy (surgery, a radiation, or chemotherapy, or combination of these). Treatment results reported to date have been better in histologically well-differentiated forms of endometrial adenocarcinoma.

    For the treatment of amenorrhea (primary or secondary) or for dysfunctional uterine bleeding due to hormonal imbalance in the absence of organic pathology.
    Intramuscular dosage
    Adult and Adolescent females

    375 mg IM as a single dose, given at any time. Next dose may begin after 4 days of desquamation or, if there is no bleeding, 21 days after the initial single dose. If no response after 4 cycles, discontinue. The number of cycles used and when to use cyclic dosing is dependent on the indication for use and whether estrogen therapy is used concurrently. A suggested cyclic cycle with estrogen is as follows (28-day cycle; repeated every 4 weeks) Day 1 of each cycle: Estradiol Valerate Injection (20 mg IM); then, 2 weeks after Day 1: Hydroxyprogesterone Caproate 250 mg IM; then Estradiol Valerate (5 mg IM) 4 weeks after Day 1: This is Day 1 of the next cycle. Repeat as indicated. If estrogen deficiency has been prolonged in patients with amenorrhea, menstruation may not occur until estrogen has been given for several months. Discontinue when cyclic therapy no longer required.

    To test for endogenous estrogen production ("Medical D and C").
    Intramuscular dosage
    Adult females

    250 mg IM once; repeat for confirmation at 4 weeks after the first injection. Discontinue after the second dose. Bleeding should occur 7 to 14 days after the injection.

    MAXIMUM DOSAGE

    Adults

    For Makena (preterm labor prophylaxis): 250 mg IM once weekly (every 7 days); 275 mg subcutaneously once weekly (every 7 days). Dysfunctional uterine bleeding/amenorrhea: 375 mg/dose IM. For endometrial cancer: 1,000 mg/dose IM.

    Geriatric

    Dysfunctional uterine bleeding: 375 mg/dose IM. For endometrial cancer: 1,000 mg/dose IM.

    Adolescents

    16 years and older: For Makena (preterm labor prophylaxis): 250 mg IM once weekly (every 7 days); 275 mg subcutaneously once weekly (every 7 days). Amenorrhea: 375 mg/dose IM.
    Less than 16 years: Safety and efficacy have not been established for preterm labor prophylaxis. Amenorrhea: 375 mg/dose IM.

    Children

    Safety and efficacy have not been established. Not indicated in children pre-menarche.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    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.
    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.

    Intramuscular Administration

    Administer hydroxyprogesterone caproate injection from the vial intramuscularly. DO NOT administer intravenously.
     
    Intramuscular injection (Makena single-use and multi-dose vials ONLY):
    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 1.5-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.
    Rotate injection sites with each injection
    Storage of multiple-dose vials: Store at controlled room temperature 20 to 25 degrees C (68 to 77 degrees F). Do not refrigerate or freeze. Store upright, protected from light, in the original carton. Discard any unused product within 5 weeks of first use.[43316]
     
    Intramuscular injection (generic products, 250 mg/mL)
    Because of the low viscosity of the vehicle, may administer with a small gauge needle. Inject deeply into the upper outer quadrant of the gluteal muscle following the usual precautions for IM injection.
    The injection provides a high concentration in a small volume; particular care should be taken to administer the full dose.
    Storage of multiple-dose vials: Storage instructions may vary between products; refer to the product label for specific storage information.

    Subcutaneous Administration

    Hydroxyprogesterone auto-injector is a single-use, pre-filled, disposable device containing a 27-gauge, 0.5-inch needle.
    Each auto-injector delivers 1 dose subcutaneously in the back of the upper arm.
    For subcutaneous use only.
    The device is intended for use by a health-care professional to administer to a patient. The patient should not self-administer the injection.
    Read the Instructions for Use before administration.
     
    Subcutaneous injection (Makena auto-injector):
    Inspect the auto-injector for any damage; do not use if it appears damaged or broken, or if cap is missing or not secure.
    Inspect the liquid through the viewing window;an air bubble may be noticed, this is normal.
    Wash hands with soap and water and wipe the injection site with an alcohol swab; allow the site to dry on its own. Do not fan or blow on the injection site. Do not touch the site again before injecting. 
    Only use the back of either upper arm for the injection site. Do not use in areas where the skin is tender, bruised, red, scaly, raised, thick, or hard. Avoid areas with scars, tattoos, or stretch marks. Rotate the injection site to the alternate arm from the previous week. 
    To remove the cap, twist the cap counter clockwise (this will break the red safety seal), and pull straight off. After the cap is removed, a few drops of the liquid may appear - this is normal. The auto-injector should be used or discarded once the cap is removed. Do not recap for later use. Do not use the auto-injector if the device is dropped.
    To inject, support the upper arm with the opposite hand. On the relaxed outstretched arm to be injected, gently place the auto-injector at a 90 degree angle to the injection site (back of upper arm). Check that the viewing window is seen clearly.
    It will take approximately 15 seconds for the full dose to be delivered. Push down while supporting the upper arm with the opposite hand. A click will occur when the injections begins. Hold the auto-injector against the arm.
    While holding against the arm, watch the viewing window until it turns completely orange before removing the injector from the injection site.
    It is normal if there is slight bleeding after injection. If this occurs, hold a cotton ball or gauze on the area with light pressure for a few seconds. Do not rub the area.
    After completing injection, dispose of auto-injector and cap in a sharps disposal container immediately after use.

    STORAGE

    Makena:
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Do not refrigerate
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton
    - Store upright

    CONTRAINDICATIONS / PRECAUTIONS

    Intravenous administration

    Hydroxyprogesterone caproate injection is for intramuscular or subcutaneous 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 caproate multi-dose vials contain 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, thromboembolism, thrombophlebitis

    Hydroxyprogesterone is contraindicated in patients with current or history of thromboembolism 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. Data from the placebo-controlled clinical trial and the infant follow-up safety study did not show a difference in adverse developmental outcomes between children of hydroxyprogesterone-treated women and children of control subjects. The data are insufficient to determine a drug-associated risk of adverse developmental outcomes as none of the hydroxyprogesterone-treated women received the drug during the first trimester of pregnancy. 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 monkey 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

    Hydroxyprogesterone is considered compatible with breast-feeding. Detectable amounts of progestins have been identified in the milk of mothers receiving progestin treatment. Low levels of progestins are present in human milk with the use of progestin-containing products, including hydroxyprogesterone caproate. Published studies have reported no adverse effects of progestins on the breast-fed child or on milk production.

    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.

    ADVERSE REACTIONS

    Severe

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

    Moderate

    hypertension / Early / 0-8.8
    erythema / Early / Incidence not known
    hot flashes / Early / Incidence not known
    depression / Delayed / 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
    hyperglycemia / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 4.5-34.8
    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
    infection / Delayed / Incidence not known
    rash / Early / Incidence not known
    skin irritation / Early / Incidence not known
    vomiting / Early / Incidence not known
    irritability / Delayed / Incidence not known
    headache / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    fever / Early / Incidence not known
    fatigue / Early / Incidence not known
    dizziness / Early / Incidence not known
    breast discharge / Delayed / Incidence not known
    mastalgia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Minor) Progestins, like hydroxyprogesterone, 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.
    Acetohexamide: (Minor) Progestins, like hydroxyprogesterone, 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.
    Albiglutide: (Minor) Progestins, like hydroxyprogesterone, 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) Progestins, like hydroxyprogesterone, 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; Metformin: (Minor) Progestins, like hydroxyprogesterone, 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; Pioglitazone: (Minor) Progestins, like hydroxyprogesterone, 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.
    Antidiabetic Agents: (Minor) Progestins, like hydroxyprogesterone, 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.
    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.
    Bromocriptine: (Minor) Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women. Hydroxyprogesterone can cause amenorrhea and, therefore, counteract the desired effects of bromocriptine. Concurrent use is not recommended.
    Canagliflozin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Canagliflozin; Metformin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Chlorpropamide: (Minor) Progestins, like hydroxyprogesterone, 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.
    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.
    Dapagliflozin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Dapagliflozin; Metformin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Dapagliflozin; Saxagliptin: (Minor) Progestins, like hydroxyprogesterone, 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.
    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.
    Darunavir; Cobicistat; 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.
    Dulaglutide: (Minor) Progestins, like hydroxyprogesterone, 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.
    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.
    Elvitegravir; Cobicistat; 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.
    Elvitegravir; Cobicistat; 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.
    Empagliflozin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Empagliflozin; Linagliptin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Empagliflozin; Linagliptin; Metformin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Empagliflozin; Metformin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Ertugliflozin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Ertugliflozin; Metformin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Ertugliflozin; Sitagliptin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Exenatide: (Minor) Progestins, like hydroxyprogesterone, 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: (Minor) Progestins, like hydroxyprogesterone, can impair glucose tolerance. Patients receiving antidiabetic agents should be closely monitored for signs indicating changes in diabetic control when therapy with progestins is instituted or discontinued.
    Glimepiride; Pioglitazone: (Minor) Progestins, like hydroxyprogesterone, 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, like hydroxyprogesterone, 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, like hydroxyprogesterone, 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) Progestins, like hydroxyprogesterone, 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, like hydroxyprogesterone, 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) Progestins, like hydroxyprogesterone, 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.
    Insulin Aspart: (Minor) Progestins, like hydroxyprogesterone, 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.
    Insulin Aspart; Insulin Aspart Protamine: (Minor) Progestins, like hydroxyprogesterone, 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.
    Insulin Degludec; Liraglutide: (Minor) Progestins, like hydroxyprogesterone, 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.
    Insulin Detemir: (Minor) Progestins, like hydroxyprogesterone, 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.
    Insulin Glargine: (Minor) Progestins, like hydroxyprogesterone, 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.
    Insulin Glargine; Lixisenatide: (Minor) Progestins, like hydroxyprogesterone, 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.
    Insulin Glulisine: (Minor) Progestins, like hydroxyprogesterone, 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.
    Insulin Lispro: (Minor) Progestins, like hydroxyprogesterone, 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.
    Insulin Lispro; Insulin Lispro Protamine: (Minor) Progestins, like hydroxyprogesterone, 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.
    Insulin, Inhaled: (Minor) Progestins, like hydroxyprogesterone, 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.
    Isophane Insulin (NPH): (Minor) Progestins, like hydroxyprogesterone, 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.
    Lente Insulin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Linagliptin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Linagliptin; Metformin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Liraglutide: (Minor) Progestins, like hydroxyprogesterone, 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.
    Lixisenatide: (Minor) Progestins, like hydroxyprogesterone, 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: (Minor) Progestins, like hydroxyprogesterone, 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; Pioglitazone: (Minor) Progestins, like hydroxyprogesterone, 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; Repaglinide: (Minor) Progestins, like hydroxyprogesterone, 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; Rosiglitazone: (Minor) Progestins, like hydroxyprogesterone, 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) Progestins, like hydroxyprogesterone, 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; Sitagliptin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Miglitol: (Minor) Progestins, like hydroxyprogesterone, 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.
    Nateglinide: (Minor) Progestins, like hydroxyprogesterone, 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.
    Pioglitazone: (Minor) Progestins, like hydroxyprogesterone, 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.
    Pramlintide: (Minor) Progestins, like hydroxyprogesterone, 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.
    Regular Insulin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Regular Insulin; Isophane Insulin (NPH): (Minor) Progestins, like hydroxyprogesterone, 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.
    Repaglinide: (Minor) Progestins, like hydroxyprogesterone, 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.
    Rosiglitazone: (Minor) Progestins, like hydroxyprogesterone, 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.
    Saxagliptin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Semaglutide: (Minor) Progestins, like hydroxyprogesterone, 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.
    Simvastatin; Sitagliptin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Sitagliptin: (Minor) Progestins, like hydroxyprogesterone, 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.
    Tolazamide: (Minor) Progestins, like hydroxyprogesterone, 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, like hydroxyprogesterone, 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.
    Ultralente Insulin: (Minor) Progestins, like hydroxyprogesterone, 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.

    PREGNANCY AND LACTATION

    Pregnancy

    Hydroxyprogesterone is considered compatible with breast-feeding. Detectable amounts of progestins have been identified in the milk of mothers receiving progestin treatment. Low levels of progestins are present in human milk with the use of progestin-containing products, including hydroxyprogesterone caproate. Published studies have reported no adverse effects of progestins on the breast-fed child or on milk production.

    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 and subcutaneous 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 intramuscular 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 (CYP450) isoenzymes and drug transporters: 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.

    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.

    Subcutaneous Route

    In a bioavailability study in 120 healthy post-menopausal women, comparable systemic exposure was seen when hydroxyprogesterone caproate was administered subcutaneously with the auto-injector (1.1 mL) in the back of the upper arm and when hydroxyprogesterone caproate was dosed intramuscularly (1 mL) in the upper outer quadrant of the gluteus maximus.