Version May 2024
Effective April 6, 2023, the FDA has withdrawn approval for Makena (hydroxyprogesterone caproate) and generic versions of Makena which had been approved to reduce the risk of preterm birth in patients with a singleton pregnancy who have a history of singleton spontaneous preterm birth. These drugs are no longer shown to be effective, and benefits do not outweigh the risks for the indication for which they were approved. Patients currently receiving treatment should talk to their health care provider. The FDA recognizes that a limited supply of these drugs has already been distributed and acknowledges that some health care providers might continue to prescribe or administer them. However, the FDA recommends health care providers consider its conclusion that these drug products are not shown to be effective for the indication for which they were approved and do not have benefits that outweigh their risks to patients.
Further information may be found at https://www.fda.gov/news-events/press-announcements/fda-commissioner-and-chief-scientist-announce-decision-withdraw-approval-makena and https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/makena-hydroxyprogesterone-caproate-injection-information.
Pregnancy indications:
Preterm birth (Makena):
Note: Effective April 6, 2023, the FDA has withdrawn approval for Makena and generic versions of Makena which had been approved to reduce the risk of preterm birth in patients with a singleton pregnancy who have a history of singleton spontaneous preterm birth.
Note: Treatment may begin between 16 weeks 0 days and 20 weeks 6 days of gestation. Continue once 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).
Nonpregnancy indications (generic product):
Amenorrhea, primary and secondary, or abnormal uterine bleeding due to hormonal imbalance:
Single dose therapy: IM: 375 mg as a single dose; begin at any time or
Cyclic therapy schedule: IM: 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:
Patients not on estrogen therapy: Cyclic therapy schedule: IM: 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: IM: 375 mg as a single dose; begin at any time or
Cyclic therapy schedule: IM: 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 or after 12 weeks with no objective response.
Note: Dosing in the prescribing information may not reflect current clinical practice. While approved for the treatment of advanced adenocarcinoma (stage III or IV) of the uterine corpus, other contemporary therapies 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 (United States: Withdrawn from market): Pediatric drug information")
Preterm birth, prevention: Note: Effective April 6, 2023, the FDA has withdrawn approval for Makena and generic versions of Makena which had been approved to reduce the risk of preterm birth in patients with a singleton pregnancy who have a history of singleton spontaneous preterm birth. These drugs are no longer shown to be effective, and benefits do not outweigh the risks for the indication for which they were approved.
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.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Dermatologic: Urticaria (12%)
Genitourinary: Premature labor (16%)
Local: Pain at injection site (35%), swelling at injection site (17%)
1% to 10%:
Dermatologic: Pruritus (8%)
Endocrine & metabolic: Gestational diabetes (6%)
Gastrointestinal: Diarrhea (2%), nausea (6%)
Genitourinary: Oligohydramnios (4%), preeclampsia (≤9%, including gestational hypertension)
Local: Injection-site nodule (5%), injection-site pruritus (6%)
<1%:
Cardiovascular: Pulmonary embolism
Local: Cellulitis at injection site
Postmarketing:
Cardiovascular: Chest discomfort
Dermatologic: Skin rash
Endocrine & metabolic: Hot flash
Gastrointestinal: Vomiting
Genitourinary: Cervical changes (cervical incompetency), cervical dilation, cervical shortening, premature rupture of membranes, urinary tract infection
Local: Injection-site reaction (including erythema at injection site, hypersensitivity reaction at injection site, irritation at injection site, rash at injection site, urticaria at injection site, warm sensation at injection site)
Nervous system: Dizziness, fatigue, headache
Respiratory: Dyspnea
Miscellaneous: Fever
Pregnancy indications (preterm birth): 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; uncontrolled hypertension
Nonpregnancy indications: 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; liver dysfunction or disease; missed abortion; as a diagnostic test for pregnancy.
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.
Disease related concerns:
• Depression: Use with caution in patients with depression; discontinue if depression recurs.
• Diabetes: May decrease glucose tolerance; use caution in patients with prediabetes and diabetes.
• 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.
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. Consider discontinuing if allergic reactions (eg, urticaria, pruritus, angioedema) occur.
Other warnings/precautions:
• Product selection: Hydroxyprogesterone caproate is available in multiple dosage forms. The Makena brand and approved generics have pregnancy-related indications; the generic products (generic for Delautin) have nonpregnancy 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).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Oil, Intramuscular:
Makena: 250 mg/mL (5 mL [DSC]) [contains benzyl alcohol, benzyl benzoate, castor oil (ricine oil)]
Makena: 250 mg/mL (1 mL [DSC]) [contains benzyl benzoate, castor oil (ricine oil)]
Generic: 250 mg/mL (1 mL [DSC], 5 mL [DSC])
Oil, Intramuscular [preservative free]:
Generic: 250 mg/mL (1 mL [DSC])
Solution, Intramuscular:
Generic: 1.25 g/5 mL (5 mL [DSC])
Solution Auto-injector, Subcutaneous [preservative free]:
Makena: 275 mg/1.1 mL (1.1 mL [DSC]) [contains benzyl benzoate, castor oil (ricine oil)]
May be product dependent
Solution (HYDROXYprogesterone Caproate Intramuscular)
1.25 g/5 mL (per mL): $462.14
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
IM:
Generic product (nonpregnancy indications): For IM use only. Administer deep 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 contains visible particles or crystals. 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, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020). Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Pregnancy indications: Preterm birth (Makena): Note: Effective April 6, 2023, the FDA has withdrawn approval for Makena and generic versions of Makena which had been approved to reduce the risk of preterm birth in patients with a singleton pregnancy who have a history of singleton spontaneous preterm birth. These drugs are no longer shown to be effective, and benefits do not outweigh the risks for the indication for which they were approved.
Non pregnancy indications (generic product):
Amenorrhea and abnormal uterine bleeding due to hormonal imbalance: Management of amenorrhea (primary and secondary) and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology (eg, submucous fibroids, uterine cancer) in nonpregnant patients.
Production of secretory endometrium and desquamation: For the production of secretory endometrium and desquamation in nonpregnant patients.
Test for endogenous estrogen production: As a test for endogenous estrogen production in nonpregnant patients.
Uterine adenocarcinoma, advanced: Treatment of advanced (stage III or IV) uterine adenocarcinoma in nonpregnant patients. Note: While the IM solution is approved for the treatment of stage III or IV adenocarcinoma of the uterine corpus, other contemporary therapies 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).
HYDROXYprogesterone caproate may be confused with medroxyPROGESTERone
Substrate of CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Chlorprothixene: Progestins may enhance the adverse/toxic effect of Chlorprothixene. Progestins may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy
MetyraPONE: Progestins may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking progestins. Risk D: Consider therapy modification
Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Risk X: Avoid combination
Hydroxyprogesterone caproate 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).
Following maternal use of hydroxyprogesterone caproate in the second or third trimester for the prevention of preterm birth, adverse outcomes were not observed in children evaluated at ~48 months of age. Children were evaluated for communication skills, gross motor, fine motor, problem solving, and personal/social parameters. Outcomes were similar to children in the placebo group (Northen 2007). Outcome data following first trimester exposure is limited; long-term outcomes are under study (Dudás 2006; Heinonen 1977; Murphy 2022; Simons 2021; SMFM 2020).
The pharmacokinetic properties of hydroxyprogesterone caproate are altered during pregnancy. Serum concentrations are widely variable following IM injection. The half-life varies between patients with singleton and multifetal pregnancies. Increasing maternal BMI increases hydroxyprogesterone clearance; GA may also influence the pharmacokinetics of hydroxyprogesterone caproate (Boggess 2018; Caritis 2011; Caritis 2012; Caritis 2014; Della Torre 2019).
Hydroxyprogesterone caproate IM may be offered to patients with a singleton pregnancy and prior spontaneous preterm birth as part of a shared decision-making process, considering the available efficacy data and patient preference (ACOG 2021; SMFM 2020). Treatment may begin between 16 weeks 0 days and 20 weeks 6 days of gestation; however, treatment may be more effective if started earlier in this gestation period than later. Clinical data following SUBQ administration are lacking (ACOG 2021). When used for the prevention of preterm birth, the effectiveness of hydroxyprogesterone is based on improvement in the proportion of patients who delivered at less than 37 weeks' gestation. Clinical benefits related to improved neonatal mortality or morbidity following maternal use have not been demonstrated.
Progestins are present in breast milk.
Maternal progestin use has not been found to adversely affect breastfeeding, health, growth, or development of the infant. Use of Makena is not indicated following delivery.
Monitor blood glucose (in patients with prediabetes or diabetes). Monitor BP. Monitor for signs/symptoms of hypersensitivity, depression, fluid retention, jaundice, vision changes (obtain ophthalmic exam for sudden vision changes), and/or thromboembolic disorders. Consider risk versus benefit of continuing therapy if hypertension or jaundice occur.
Nonpregnancy uses: Papanicolaou smear, pelvic organ and breast exam prior to therapy; evaluate irregular bleeding that does not respond 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 patients (singleton pregnancies): 16.4 ± 3.6 days.
Time to peak, serum: IM: Nonpregnant females: 3 to 7 days; Pregnant patients (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.
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