Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Oil, Intramuscular:
Makena: 250 mg/mL (5 mL) [contains benzyl alcohol, benzyl benzoate, castor oil (ricine oil)]
Makena: 250 mg/mL (1 mL) [contains benzyl benzoate, castor oil (ricine oil)]
Generic: 250 mg/mL (1 mL, 5 mL)
Oil, Intramuscular [preservative free]:
Generic: 250 mg/mL (1 mL)
Solution, Intramuscular:
Generic: 1.25 g/5 mL (5 mL)
Solution Auto-injector, Subcutaneous [preservative free]:
Makena: 275 mg/1.1 mL (1.1 mL) [contains benzyl benzoate, castor oil (ricine oil)]
Pharmacology
Mechanism of Action
Hydroxyprogesterone is a synthetic progestin. The mechanism by which hydroxyprogesterone reduces the risk of recurrent preterm birth is not known. Hydroxyprogesterone caproate may induce regressive changes in uterine adenocarcinoma.
Pharmacokinetics/Pharmacodynamics
Distribution
Extensively bound to plasma proteins including albumin and corticosteroid-binding globulins
Metabolism
Hepatic via CYP3A4 and 3A5; forms metabolites
Excretion
Urine (~30%) and feces (~50%); primarily as metabolites
Time to Peak
Serum: IM: Nonpregnant females: 3 to 7 days; Pregnant females (singleton pregnancies): 1 to 7 days
Half-Life Elimination
Nonpregnant females: ~8 days; Pregnant females (singleton pregnancies): 16.4 ± 3.6 days
Use in Specific Populations
Special Populations: Hepatic Function Impairment
Extensively metabolized; hepatic impairment may reduce the elimination of hydroxyprogesterone.
Use: Labeled Indications
Pregnancy indications: Preterm birth (Makena): To reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.
Limitation of use: Safety and efficacy have been demonstrated only in women with a prior spontaneous singleton preterm birth. Use is not intended for women with multiple gestations or other risk factors for preterm birth.
Non-pregnancy indications (generic product): Treatment of advanced (stage III or IV) uterine adenocarcinoma; management of amenorrhea (primary and secondary) and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology (eg, submucous fibroids or uterine cancer); as a test for endogenous estrogen production; production of secretory endometrium and desquamation.
Contraindications
Hypersensitivity to hydroxyprogesterone caproate or any component of the formulation; current or history of thrombosis or thromboembolic disorders; breast cancer or other hormone-sensitive cancer (known, suspected, or history of); undiagnosed abnormal vaginal bleeding unrelated to pregnancy; cholestatic jaundice of pregnancy; liver tumors (benign or malignant) or active liver disease; missed abortion; uncontrolled hypertension; as a diagnostic test for pregnancy.
Documentation of allergenic cross-reactivity for progestins is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Dosage and Administration
Dosing: Adult
Pregnancy indications: Preterm birth (Makena): Pregnant females ≥16 years of age: Note: Treatment may begin between 16 weeks 0 days and 20 weeks 6 days of gestation. Continue weekly administration until 37 weeks (through 36 weeks, 6 days) gestation or until delivery, whichever comes first.
IM (vial): 250 mg once weekly (every 7 days).
SubQ (auto-injector): 275 mg once weekly (every 7 days).
Non-pregnancy indications (generic product):
Amenorrhea (primary and secondary) or abnormal uterine bleeding due to hormonal imbalance: IM:
Single dose therapy: 375 mg as a single dose; begin at any time or
Cyclic therapy schedule: 250 mg on day 15 of each 28-day cycle for 4 cycles (in combination with estradiol valerate); begin cyclic therapy schedule after 4 days of desquamation. If there is no bleeding, begin cyclic therapy schedule 21 days after the 375 mg single dose schedule.
Production of secretory endometrium and desquamation: IM:
Patients not on estrogen therapy: Cyclic therapy schedule: 250 mg on day 15 of each 28-day cycle (in combination with estradiol valerate); may begin at any time; continue until cyclic therapy is no longer required.
Patients currently on estrogen therapy:
Single dose therapy: 375 mg as a single dose; begin at any time or
Cyclic therapy schedule: 250 mg on day 15 of each 28-day cycle (in combination with estradiol valerate); begin cyclic therapy schedule after 4 days of desquamation. If there is no bleeding, begin cyclic therapy schedule 21 days after the 375 mg single dose schedule. Continue until cyclic therapy is no longer required.
Test for endogenous estrogen production: IM: 250 mg as a single dose (bleeding 7 to 14 days after administration indicates endogenous estrogen); may repeat once 4 weeks after initial dose.
Uterine adenocarcinoma (advanced): IM: 1,000 mg one or more times a week (1,000 to 7,000 mg/week); discontinue upon relapse.
Note: While approved for the treatment of advanced adenocarcinoma (stage III or IV) of the uterine corpus, chemotherapy may be preferable to progestin therapy in the management of advanced disease. Based on a systematic review, response to hormonal therapy is inversely proportional to tumor grade (Decruze 2007).
Dosing: Pediatric
Preterm birth, prevention: Adolescents ≥16 years: Makena: IM: 250 mg every 7 days; treatment should be initiated between 16 weeks 0 days and 20 weeks 6 days of gestation; can be continued up to 37 weeks gestation (ie, 36 weeks 6 days) or until delivery, whichever occurs first.
Administration
IM:
Generic product (nonpregnancy indications): For IM use only. Administer IM into the upper outer quadrant of the gluteus maximus.
Makena vial: For IM use only. Withdraw dose using an 18-gauge needle; inject dose using a 21-gauge 11/2 inch needle. Administer IM by slow injection (≥1 minute) into the upper outer quadrant of the gluteus maximus; alternate injection sites. Solution is viscous and oily; do not use if solution is cloudy or contains solid particles. Apply pressure to injection site to decrease bruising and swelling.
SubQ:
Makena auto-injector: For subcutaneous use only. Use immediately once cap is removed. Administer in the back of either upper arm; solution is viscous and oily and requires ~15 seconds to deliver the dose; rotate injection sites weekly. Do not inject if skin is tender, bruised, red, scaly, raised, thick or hard; avoid areas with scars, tattoos or stretch marks. Apply light pressure with gauze or cotton ball to injection site if bleeding occurs; do not rub. See manufacturer’s instructions for use for additional administration information.
Storage
Makena:
Auto-injector: Store at 20°C to 25°C (68°F to 77°F); protect from light. Do not refrigerate or freeze.
Vial: Store upright at 20°C to 25°C (68°F to 77°F); protect from light. Discard multidose vial within 5 weeks of initial use; do not refrigerate or freeze.
Generic product: Store upright at controlled room temperature of 20°C to 25°C (68°F to 77°F); protect from light. Discard unused product within 28 days of initial use. Storage at low temperatures may result in separation of crystalline material which redissolves with a hot water bath.
Drug Interactions
Anticoagulants: Progestins may diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
C1 inhibitors: Progestins may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Consider therapy modification
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
Herbs (Progestogenic Properties) (eg, Bloodroot, Yucca): May enhance the adverse/toxic effect of Progestins. Monitor therapy
Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification
MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification
Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification
Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Pomalidomide: Progestins may enhance the thrombogenic effect of Pomalidomide. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Ulipristal: Progestins may diminish the therapeutic effect of Ulipristal. Ulipristal may diminish the therapeutic effect of Progestins. Management: Ulipristal for uterine fibroids (Canadian indication): avoid progestins within 12 days of stopping ulipristal; as emergency contraceptive (U.S. indication): avoid progestins within 5 days of stopping ulipristal. Avoid combination
Adverse Reactions
>10%:
Dermatologic: Urticaria (12%)
Genitourinary: Premature labor (admission: 16%)
Local: Pain at injection site (7% to 35%), swelling at injection site (17%)
1% to 10%:
Cardiovascular: Preeclampsia (≤9%)
Dermatologic: Pruritus (8%)
Endocrine & metabolic: Gestational diabetes (6%)
Gastrointestinal: Nausea (6%), diarrhea (2%)
Genitourinary: Oligohydramnios (4%)
Local: Local pruritus (6%), injection site nodule (5%)
<1%, postmarketing, and/or case reports: Cellulitis at injection site, cervical changes (cervical incompetency), cervical dilation, cervical shortening, chest discomfort, dizziness, dyspnea, erythema at injection site, fatigue, fever, headache, hot flash, injection site reaction, irritation at injection site, local hypersensitivity reaction, premature rupture of membranes, pulmonary embolism, rash at injection site, skin rash, urinary tract infection, urticaria at injection site, vomiting, warm sensation at injection site
Warnings/Precautions
Concerns related to adverse events:
- Hypersensitivity: Hypersensitivity and allergic-like reactions (eg, urticaria, pruritus, angioedema) have been reported. Consider discontinuing if allergic reactions occur.
- Retinal vascular thrombosis: May cause retinal vascular thrombosis; discontinue pending examination if migraine, loss of vision, proptosis, diplopia, or other visual disturbances occur; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.
- Thromboembolism: Discontinue if arterial thrombosis, DVT, or thromboembolic events occur. Use is contraindicated with current or history of thrombosis or thromboembolic disorders.
Disease related concerns:
- Carbohydrate intolerance: May have adverse effects on glucose tolerance; use caution in women with prediabetes and diabetes.
- Depression: Use with caution in patients with depression; discontinue if depression occurs.
- Diseases exacerbated by fluid retention: Use with caution in patients with diseases that may be exacerbated by fluid retention, including asthma, epilepsy, preeclampsia, cardiac or renal dysfunction.
- Hepatic impairment: Specific studies have not been conducted; elimination may be decreased. Use is contraindicated with hepatic impairment.
- Hypertension: Monitor women who develop hypertension during therapy; consider risk versus benefit of continuation. Use is contraindicated with uncontrolled hypertension.
- Jaundice: Monitor women who develop jaundice during therapy; consider risk versus benefit of continuation. Use is contraindicated in women with cholestatic jaundice of pregnancy.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Dosage form specific issues:
- Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
- Castor oil: Some formulations contain castor oil. Discontinue if allergic reactions (eg urticaria, pruritus, angioedema) occur.
Other warnings/precautions:
- Appropriate use: Preterm birth: The effectiveness of hydroxyprogesterone is based on improvement in the proportion of women who delivered at less than 37 weeks of gestation. Clinical benefits related to improved neonatal mortality or morbidity following maternal use have not been demonstrated. Not intended to stop active preterm labor.
- Appropriate use: Uterine adenocarcinoma: While the intramuscular solution is approved for the treatment of stage III or IV adenocarcinoma of the uterine corpus, chemotherapy may be preferable to progestin therapy in the management of advanced disease. Based on a systematic review, response to hormonal therapy is inversely proportional to tumor grade (Decruze 2007).
- Laboratory changes: Use may change the results of some laboratory tests (eg, coagulation factors, tests of hepatic or thyroid function).
- Product selection: Hydroxyprogesterone caproate is available in multiple dosage forms. The Makena brand and the generic product (generic for Delautin) have different indications (Makena pregnancy indications; the generic product has non-pregnancy indications); products are not interchangeable.
Monitoring Parameters
Glucose (in patients with prediabetes or diabetes); blood pressure; signs/symptoms of depression, fluid retention, jaundice, and/or thromboembolic disorders.
Non-pregnancy uses: Papanicolaou smear, pelvic organ and breast exam prior to therapy
Pregnancy
Pregnancy Considerations
Adverse events were not observed in human studies following second or third trimester exposure; use not studied during first trimester.
Following use of Makena, maternal serum concentrations of hydroxyprogesterone caproate are widely variable and may be decreased in women with increased BMI. Hydroxyprogesterone is metabolized by the placenta and reaches the fetal circulation. In one study, the cord:maternal concentration ratio averaged 0.2. Hydroxyprogesterone caproate was detected in cord blood when delivery occurred ≥44 days after the last injection (Caritis 2012; Hemauer 2008).
Patient Education
What is this drug used for?
- It delays a baby's birth when it is too early.
- It is used to treat some uterine cancers.
- It is used to treat abnormal period (menstrual) cycles.
- It may be given to you for other reasons. Talk with the doctor.
Frequently reported side effects of this drug
- Injection site pain
- Nausea
- Vomiting
- Diarrhea
- Abdominal cramps
- Bloating
- Breast soreness
- Weight gain
- Weight loss
- Hair loss
- Decreased sex drive
- Increased sex drive
- Lack of appetite
- Increased appetite
- Loss of strength and energy
- Back pain
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.
- Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood.
- Vision changes
- Severe headache
- Severe dizziness
- Passing out
- Depression
- Shortness of breath
- Excessive weight gain
- Swelling of arms or legs
- No menstrual periods
- Severe injection site swelling, oozing of blood, or irritation
- Virilization like in females a deep voice, facial hair, acne, or menstrual changes.
- Abnormal vaginal bleeding
- Yellow skin
- Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
