Progesterone (Crinone, Endometrin, Milprosa) Form

The following are progesterone products requiring prior authorization: progesterone gel (Crinone® 4%, Crinone® 8%), progesterone vaginal insert (Endometrin®), and progesterone vaginal system (Milprosa™). _ *Sections I.A., I.B., II.A., II.B. Infertility/Fertility Preservation Treatment All lines of business: pharmacy benefit coverage is required. HIM line of business - pharmacy benefit coverage restrictions by state: States without pharmacy benefit restriction: AR, FL, IL, IN, KS, NC, NV, SC, TN, WA
(Policy may be used for formulary and non-formulary drugs.)
States with pharmacy benefit restriction: AZ, GA, MO, MS, NH, OH, PA, TX (Policy may be used for formulary drugs only; non-formulary drugs are a pharmacy benefit exclusion.) FDA Approved Indication(s) Crinone 4% is indicated for the treatment of secondary amenorrhea. Crinone 8% is indicated: • For progesterone supplementation or replacement as part of an Assisted Reproductive Technology (ART) treatment for infertile women with progesterone deficiency.
• For the treatment of secondary amenorrhea in women who have failed to respond to treatment with Crinone 4%. Endometrin is indicated to support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of an ART treatment program for infertile women. Milprosa is indicated to support embryo implantation and early pregnancy (up to 10 weeks post- embryo transfer) by supplementation of corpus luteal function as part of an ART treatment program for infertile women up to and including 34 years of age.
• Limitation of use: Efficacy in women 35 years of age and older has not been established. 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 Crinone, Endometrin, and Milprosa are medically necessary when the following criteria are met:

CLINICAL POLICY
Progesterone I. Initial Approval Criteria
A. Assisted Reproductive Technology (ART) Treatment (must meet all):

1. Member must have infertility coverage (optional pharmacy benefit);
2. Age ≥ 18 years;
3. Request is for Crinone 8%, Endometrin, or Milprosa;
4. Prescribed as supplementation or replacement of progesterone as part of ART treatment for infertile women;
   5. Request meets one of the following (a, b, or c): a. Crinone 8%: Dose does not exceed 180 mg per day for up to 12 weeks; b. Endometrin: Dose does not exceed 300 mg per day for up to 10 weeks; c. Milprosa: Dose does not exceed one vaginal system per week for up to 10 weeks. Approval duration: 6 months B. Secondary Amenorrhea (must meet all):
5. Diagnosis of secondary amenorrhea;
6. Age ≥ 18 years;
7. Request is for Crinone 4% or 8%;
8. Failure of a progestin product (e.g., medroxyprogesterone, norethindrone), unless contraindicated or clinically significant adverse effects are experienced;
   5. Dose does not exceed 45 mg Crinone 4% or 90 mg Crinone 8% every other day for up to 6 doses. Approval duration: 4 weeks C. Prevention of Preterm Birth (off-label) (must meet all):
   6. Prescribed for prevention of preterm birth;
9. Age ≥ 18 years;
10. Request is for Crinone 8% or Endometrin;
11. Gestational age is ≥ 16 weeks;
12. The requested agent is not prescribed concurrently with Makena®;

13. Documentation of one of the following (a or b): a. Short cervix; b. Singleton pregnancy and history of spontaneous preterm birth;

    7. Dose does not exceed 90 mg per day Crinone 8% or 200 mg per day Endometrin. Approval duration: 6 months D. Other diagnoses/indications (must meet 1 or 2):
    8. 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: Page 2 of 9

    CLINICAL POLICY
    Progesterone 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. All Indications in Section I (must meet all):
    3. 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);
14. Member is responding positively to therapy;

15. Member meets one of the following (a, b, or c): a. If request is for ART treatment, both (i and ii): i. Member must have infertility coverage (optional pharmacy benefit); ii. Member has not yet received more than 12 weeks of therapy (Crinone 8%) or 10 weeks of therapy (Endometrin and Milprosa); b. If request is for secondary amenorrhea, member has not yet received 6 doses of Crinone 4% or 8%; c. If request is for prevention of preterm birth, week 37 (through 36 weeks, 6 days) of gestation or delivery has not yet been reached;

    4. If request is for a dose increase, request meets one of the following (a, b, or c): a. ART treatment (i, ii, or iii):
       i. Crinone 8%: New dose does not exceed 180 mg per day for up to 12 weeks; ii. Endometrin: New dose does not exceed 300 mg per day for up to 10 weeks; iii. Milprosa: New dose does not exceed one vaginal system per week for up to 10 weeks; b. Secondary amenorrhea: New dose does not exceed 45 mg Crinone 4% or 90 mg Crinone 8% every other day for up to 6 doses; c. Prevention of preterm birth: New dose does not exceed 90 mg per day Crinone 8% or 200 mg per day Endometrin. Approval duration:
       Secondary amenorrhea: 4 weeks total ART treatment: 6 months total Prevention of preterm birth: 6 months total B. Other diagnoses/indications (must meet 1 or 2):
    5. 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): Page 3 of 9

    CLINICAL POLICY
    Progesterone 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.
       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. IV. Appendices/General Information Appendix A: Abbreviations ACOG: American College of Obstetrics and Gynecologists ART: Assisted Reproductive Technology FDA: Food and Drug Administration
       Appendix B: Therapeutic Alternatives This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization. Drug
       Dosing Regimen Dose Limit/ Maximum Dose 10 mg/day x 10 days medroxyprogesterone
       (e.g., Provera) norethindrone acetate (Aygestin) Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Secondary amenorrhea: 5 to 10 mg PO QD for 5 to 10 days Secondary amenorrhea: 2.5 to 10 mg PO QD for 5 to10 days
       10 mg/day x 10 days Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Crinone, Endometrin, Milprosa:
        Known sensitivity to progesterone or any other ingredients in Crinone, Endometrin, or Milprosa.  Active thrombophlebitis or thromboembolic disorders, or a history of hormone- associated thrombophlebitis or thromboembolic disorders. Page 4 of 9

    CLINICAL POLICY
    Progesterone  Known of suspected malignancy of the breast o Crinone, Endometrin  Missed abortion or ectopic pregnancy
     Liver dysfunction or disease
     Known or suspected malignancy of the genital organs
    o Crinone, Milprosa:
     Undiagnosed vaginal bleeding o Milprosa  Severe hepatic impairment or disease • Boxed warning(s): none reported Appendix D: General Information • Micromedex recommendation IIa for the use of progesterone as prophylaxis for premature birth of newborn in women with short cervix. Studies cited used the following progesterone products: progesterone 90 mg vaginal gel once daily in women who had a singleton pregnancy and short cervix (with or without a history of early preterm delivery); or micronized progesterone 200 mg intravaginally at bedtime. In the micronized progesterone group women with a cervical length of 15 mm or less, with singleton or twin pregnancies, without regard to past early preterm delivery, were randomized to receive either placebo (n = 125) or micronized progesterone 200 mg intravaginally at bedtime (n = 125). Women with a history of ruptured membranes or cervical cerclage were excluded. In clinical trials, less than 25 mm is the length most frequently used to define short cervix measured mid-pregnancy (prior to 24 weeks gestation). American College of Obstetrics and Gynecologists (ACOG) recommends vaginal progesterone supplementation if cervical length is 20 mm or less before or at 24 weeks of gestation in women with singleton gestation and no prior spontaneous preterm birth. • • According to ACOG, current evidence does not support the routine use of progesterone in women with multiple gestations. • The dosage increase from the Crinone 4% gel can only be accomplished by using the 8% gel. Increasing the volume of gel administered does not increase the amount of progesterone absorbed. V. Dosage and Administration Drug Name Progesterone gel (Crinone 4% and Crinone 8%) Dosing Regimen 8% (90 mg) vaginally QD 90 mg/day Maximum Dose 8% (90 mg) vaginally BID 180 mg/day Indication Progesterone supplementation in ART Partial or complete ovarian failure requiring progesterone replacement in ART Secondary amenorrhea 4% (45 mg) vaginally QOD up to a total of 6 doses 4%: 45 mg/day 8%: 90 mg/day Page 5 of 9

    CLINICAL POLICY
    Progesterone Drug Name Indication Prophylaxis of premature birth (off- label) Progesterone vaginal insert (Endometrin) Progesterone supplementation in ART Dosing Regimen If 4% fails, 8% (90 mg) vaginally QOD up to a total of 6 doses. 90 mg vaginally QD Starting 16 to 24 weeks gestation and continuing through 34 weeks gestation; some studies extend through week 36 (Clinical Pharmacology, ACOG) 100 mg vaginally BID or TID Maximum Dose 90 mg/day 300 mg/day Prophylaxis of premature birth (off- label) 200 mg vaginally at bedtime 200 mg/day Progesterone vaginal system (Milprosa) Progesterone supplementation in ART Starting 16 to 24 weeks gestation and continuing through 34 weeks gestation; some studies extend through week 36 (Clinical Pharmacology, ACOG) One vaginal system inserted vaginally initially on the day after oocyte retrieval and then replaced weekly, continuing for up to 10 weeks total duration. 11 mg/day VI. Product Availability Drug Name Progesterone gel (Crinone 4% and Crinone 8%) Progesterone vaginal insert (Endometrin) Progesterone vaginal system (Milprosa) Availability Gel: 4% (45 mg of progesterone, 6 single-use applicators) Gel: 8% (90 mg of progesterone, 15 single-use applicators)
    Vaginal insert: 100 mg (21 inserts and disposable applicators) Vaginal system: silicone ring containing 1.78 grams of progesterone and releases an average of 11 mg/day of progesterone over a 7-day period of use. Page 6 of 9

    CLINICAL POLICY
    Progesterone VII.