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).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). However, hydroxyprogesterone caproate is extensively metabolized and hepatic impairment may reduce its elimination; use is contraindicated in patients with active liver disease.
(For additional information see "Hydroxyprogesterone caproate: Pediatric drug information")
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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). However, hydroxyprogesterone caproate is extensively metabolized and hepatic impairment may reduce its elimination.
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)]
May be product dependent
The Makena Care Connection is a comprehensive program for patients and health care providers which provides administrative support (including insurance benefit investigation and prescription fulfillment); financial and co-pay assistance for eligible patients; and treatment support (including educational information, home health care service and scheduled treatment reminders). The Makena Care Connection is available by calling 1-800-847-3418; or visit http://www.makenahcp.com/makena-care-connection for additional information.
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.
IM: Administer into the upper outer quadrant of the gluteus maximus.
Generic products: Use of wet needle or syringe may cause solution to become cloudy; potency is not affected.
Makena: Withdraw dose using an 18-gauge needle; inject dose using a 21-gauge 1 1/2-inch needle. Administer by slow injection (≥1 minute). 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.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.
NIOSH recommends double gloving, a protective gown, and ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator) for preparation. Double gloving and a protective gown are required during IM administration (NIOSH 2016).
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.
HYDROXYprogesterone caproate may be confused with medroxyPROGESTERone
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>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
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.
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.
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.
Clinical benefits related to neonatal mortality and morbidity following use have not been demonstrated. Long-term effects of hydroxyprogesterone in utero exposure were evaluated in a follow-up safety study of 278 children (mean age: 48 months) whose mothers were part of an earlier hydroxyprogesterone-placebo efficacy trial; no significant differences in physical development, neurodevelopment, and health status were reported between the treatment and placebo groups (Northen 2007).
Substrate of CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Risk X: Avoid combination
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).
Progestins are present in milk following maternal use and have not been found to adversely affect breastfeeding, health, growth, or development of the infant. Use of Makena is not indicated following delivery.
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
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.
Distribution: Extensively bound to plasma proteins including albumin and corticosteroid-binding globulins
Metabolism: Hepatic via CYP3A4 and 3A5; forms metabolites
Half-life elimination: Nonpregnant females: ~8 days; Pregnant females (singleton pregnancies): 16.4 ± 3.6 days
Time to peak, serum: IM: Nonpregnant females: 3 to 7 days; Pregnant females (singleton pregnancies): 1 to 7 days
Excretion: Urine (~30%) and feces (~50%); primarily as metabolites
Hepatic function impairment: Extensively metabolized; hepatic impairment may reduce the elimination of hydroxyprogesterone.
Oil (HYDROXYprogesterone Caproate Intramuscular)
250 mg/mL (per mL): $342.00 - $1,023.80
Oil (Makena Intramuscular)
250 mg/mL (per mL): $963.60
Solution (HYDROXYprogesterone Caproate Intramuscular)
1.25 g/5 mL (per mL): $462.14
Solution Auto-injector (Makena Subcutaneous)
275MG/1.1ML (per mL): $876.00
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