MAKENA, Hydroxyprogesterone Caproate HYDROXYPROGESTERONE CAPROATE, Hydroxyprogesterone Caproate Form

Hydroxyprogesterone caproate (Makena®/compound) is a progestin. FDA Approved Indication(s) 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. The effectiveness of Makena is based on improvement in the proportion of women who delivered < 37 weeks of gestation. There are no controlled trials demonstrating a direct clinical benefit, such as improvement in neonatal mortality and morbidity. Limitation(s) of use: While there are many risk factors for preterm birth, safety and efficacy of Makena has been demonstrated only in women with a prior spontaneous singleton preterm birth. It is not intended for use in women with multiple gestations or other risk factors for preterm birth. ____ The FDA withdrew its approval of Makena and its generics. Makena and its generics are no longer approved and cannot lawfully be distributed in interstate commerce (see Appendix D). Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. It is the policy of health plans affiliated with Centene Corporation® that Makena/compounded hydroxyprogesterone caproate is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Prevention of Preterm Birth (must meet all):CP.PMN.22/HNCA.CP.PMN.22 Brand Name Override policy does not apply

1. Provider attestation acknowledging FDA’s withdrawal of Makena and its generics as a result of failure to demonstrate clinical benefit in the confirmatory PROLONG trial;
   2. Request is for compounded hydroxyprogesterone caproate;
2. Current singleton pregnancy;
3. History of singleton spontaneous preterm birth (delivery at < 37 weeks of gestation following spontaneous preterm labor or premature rupture of membranes);
4. Hydroxyprogesterone caproate is not prescribed concurrently with Crinone® or Endometrin®;
   
   6. Therapy to begin between 16 weeks, 0 days and 27 weeks, 6 days of gestation;

5. Dose does not exceed 250 mg (1 mL) IM or 275 mg (1.1 mL) SC once weekly. Page 1 of 8

   CLINICAL POLICY Hydroxyprogesterone Caproate Approval duration: Up to a total of 21 doses to reach week 37 (through 36 weeks, 6 days) of gestation or delivery, whichever occurs first B. Other diagnoses/indications (must meet 1 or 2):

   1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
   2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
      II. Continued Therapy A. Prevention of Preterm Birth (must meet all):CP.PMN.22/HNCA.CP.PMN.22 Brand Name Override policy does not apply
6. Provider attestation acknowledging FDA’s withdrawal of Makena and its generics as a result of failure to demonstrate clinical benefit in the confirmatory PROLONG trial;
   2. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
7. Member is responding positively to therapy;
8. Member has not received more than 21 total doses for the current pregnancy;
9. Member has not reached week 37 of gestation;

10. If request is for a dose increase, new dose does not exceed 250 mg (1 mL) IM or 275 mg (1.1 mL) SC once weekly. Approval duration: Up to a total of 21 doses to reach week 37 (through 36 weeks, 6 days) of gestation or delivery, whichever occurs first B. Other diagnoses/indications (must meet 1 or 2):

    1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: Page 2 of 8

    CLINICAL POLICY Hydroxyprogesterone Caproate CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

    2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
       III. Diagnoses/Indications for which coverage is NOT authorized:
       A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents; B. Use in women with multiple gestations. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key FDA: Food and Drug Administration Appendix B: Therapeutic Alternatives
       Not applicable Appendix C: Contraindications/Boxed Warnings • Contraindication(s):
       o Current or history of thrombosis or thromboembolic disorders o Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions o Undiagnosed abnormal vaginal bleeding unrelated to pregnancy o Cholestatic jaundice of pregnancy o Liver tumors, benign or malignant, or active liver disease o Uncontrolled hypertension • Boxed warning(s): none reported Appendix D: General Information • Data are inconclusive on the benefits of initiating hydroxyprogesterone therapy after 20 weeks, 6 days of gestation. However, a prospective cohort study by Centene Corporate evaluated whether providing 17 alpha-hydroxyprogesterone caproate (17P) to high-risk pregnant women (n = 193) who have a history of pre-term delivery in a Medicaid managed care population reduces the rate of recurrent preterm delivery and neonatal intensive care unit (NICU) admissions. The findings were that offering 17P as a benefit does have a statistically significantly different, positive effect on reducing the rate of recurrent pre-term delivery and rate of NICU admission in a managed Medicaid Page 3 of 8

    CLINICAL POLICY Hydroxyprogesterone Caproate • population. There was no decrease in effectiveness with delay in initiation of 17P as long as it was started by 28 weeks of gestation. In response to the 2019 PROLONG confirmatory trial showing 17-alpha- hydroxyprogesterone caproate provided no benefit in preventing preterm birth, the American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine advise more research is needed before substantively changing practice guidance.
    • The American College of Obstetricians and Gynecologists. Practice Bulletin No. 234 states that patients with a singleton pregnancy and a prior spontaneous preterm birth should be offered progesterone supplementation (either vaginal or intramuscular) in the context of a shared decision-making process incorporating the available evidence and the patient’s preferences. • On October 19, 2022 the FDA’s Obstetrics, Reproductive, and Urologic Drugs Advisory Committee (ORUDAC) voted 14 to 1 to recommend the withdrawal of Makena from the market. The committee concluded that the PROLONG trial failed to verify the clinical benefit of Makena and the drug has not been shown to be effective on neonatal outcomes or in preventing preterm birth, nor did it show any treatment effect in different subgroups, including those with known risk factors for preterm birth. The FDA announced the final decision to withdraw approval of Makena on April 6, 2023. Makena and its generics are no longer approved and cannot lawfully be distributed in interstate commerce.
    V. Dosage and Administration
    Indication Prevention of preterm birth Dosing Regimen Inject 250 mg (1 mL) IM or 275 mg (1.1 mL) SC once weekly (every 7 days) until week 37 of gestation or delivery, whichever occurs first. Maximum Dose IM: 250 mg/week, SC: 275 mg/week, until week 37 of gestation or delivery, whichever occurs first Begin treatment between 16 weeks, 0 days and 27 weeks, 6 days of gestation. Dose should be administered by a healthcare professional. VI. Product Availability
    Drug Name Makena Hydroxyprogesterone caproate Availability Multi-dose vial: 250 mg/mL
    Single-dose vial (preservative free): 250 mg/mL
    Prefilled syringe (preservative free): 250 mg/mL Multi-dose vial: 250 mg/mL
    Single-dose vial (preservative free): 250 mg/mL VII.