DARAPRIM, Pyrimethamine Form

Pyrimethamine (Daraprim®) is a folic acid antagonist. FDA Approved Indication(s) Daraprim is indicated for the treatment of toxoplasmosis when used conjointly with a sulfonamide. 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 Daraprim is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Initial Therapy for Toxoplasmosis Infection – Active Disease (must meet all):

1. Diagnosis of toxoplasmosis;
   2. Prescribed by or in consultation with an infectious disease or HIV specialist;
   3. Member meets one of the following (a or b): a. Age < 18 years;
      b. Failure of ≥ 10 days, or radiological deterioration within 7 days, of trimethoprim/sulfamethoxazole (TMP/SMX) at maximum indicated doses, unless contraindicated or clinically significant adverse effects are experienced;
2. Daraprim is prescribed with sulfadiazine or clindamycin, and leucovorin;
   5. If request is for the brand product, member must use the generic product, unless contraindicated or clinically significant adverse effects are experienced;

3. Request meets one of the following (a, b, or c):
   a. b. Immunocompromised member: Dose does not exceed an initial loading dose of 200 mg, followed by ≤ 75 mg per day for treatment duration; Immunocompetent member: Dose does not exceed initial loading dose of 100 mg, followed by ≤ 50 mg per day for treatment duration; c. Dose is supported by practice guidelines or peer-reviewed literature for the relevant use (prescriber must submit supporting evidence). Approval duration:
   Congenital toxoplasmosis in newborns – 12 months All other requests – Duration of request or 8 weeks (whichever is less) Page 1 of 9

   CLINICAL POLICY Pyrimethamine B. Primary Prophylaxis for Toxoplasmosis – Preventing 1st Episode (off-label) (must meet all):

   1. Diagnosis of HIV infection;
   2. Prescribed by or in consultation with an infectious disease or HIV specialist;
   3. Request is for prevention for toxoplasmosis;
   4. One of the following (a or b): a. Age ≥ 6 years: CD4 count < 100 cells/mm3; b. Age < 6 years: CD4 cell percentage < 15%;
4. Seropositive for Toxoplasma gondii IgG;
   6. Member is contraindicated or has experienced clinically significant adverse effects to TMP/SMX;
5. Daraprim is prescribed with leucovorin and dapsone;
   8. If request is for the brand product, member must use the generic product, unless contraindicated or clinically significant adverse effects are experienced;
6. Dose does not exceed 75 mg per week.
   Approval duration: 6 months
   C. Other diagnoses/indications (must meet 1 or 2):
7. 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
8. 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. Chronic Maintenance – Following Initial Therapy for Active Disease (off-label) (must meet all):
   1. 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);

9. Member is HIV-infected with one of the following (a or b): a. Age ≥ 6 years: CD4 count ≤ 200 cells/mm3 at any time in the previous 6 months; Page 2 of 9

   CLINICAL POLICY Pyrimethamine b. Age < 6 years: CD4 percentage has risen < 15% from baseline at any time in the previous 6 months;

10. Adherence to antiretroviral therapy as evidenced by pharmacy claims history or office notes;
11. If request is for the brand product, member must use the generic product, unless contraindicated or clinically significant adverse effects are experienced;
12. Request meets one of the following (a or b): a. Dose does not exceed 50 mg per day; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant use (prescriber must submit supporting evidence). Approval duration: 6 months B. Primary Prophylaxis for Toxoplasmosis – Preventing 1st Episode (off-label) (must meet all):
    1. 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);
13. Member is HIV-infected with one of the following (a or b): a. Age ≥ 6 years: CD4 count ≤ 200 cells/mm3 at any time in the previous 3 months; b. Age < 6 years: CD4 percentage has risen < 15% from baseline at any time in the previous 3 months;
14. Adherence to antiretroviral therapy as evidenced by pharmacy claims history or office notes;
15. If request is for the brand product, member must use the generic product, unless contraindicated or clinically significant adverse effects are experienced;
16. Dose does not exceed 75 mg per week.
    Approval duration: 3 months C. Other diagnoses/indications (must meet 1 or 2):
17. 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

18. 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 Page 3 of 9

    CLINICAL POLICY Pyrimethamine 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. Malaria. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key CDC: Centers for Disease Control and Prevention FDA: Food and Drug Administration HHS: Department of Health and Human Services HIV: human immunodeficiency virus TMP/SMX: trimethoprim/sulfamethoxazole
    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.
    Dosing Regimen Drug Name Dose Limit/ Maximum Dose See regimen trimethoprim/ sulfamethoxazole (Bactrim®, Bactrim® DS) Treatment: TMP 5 mg/kg and SMX 25 mg/kg IV or PO BID
    Primary prophylaxis: 1 DS PO QD (preferred) or 1 DS TIW or 1 SS QD Chronic maintenance: 1 DS PO QD or BID 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. Off-label uses; dosing recommendations per HHS guidelines Appendix C: Contraindications/Boxed Warnings • Contraindication(s): documented megaloblastic anemia due to folate deficiency, known hypersensitivity to pyrimethamine or to any component of the formulation • Boxed warning(s): none reported Appendix D: General Information
    • On June 21, 2017, Daraprim’s FDA labeling was updated to exclude the previously approved indications for treatment and chemoprophylaxis of malaria. These uses are not recommended per the CDC malaria treatment guidelines due to prevalent worldwide resistance to pyrimethamine. Page 4 of 9

    CLINICAL POLICY Pyrimethamine • For the treatment of toxoplasmosis, higher doses than what is recommended by the FDA, HHS, and CDC may be required for severe cases or cases affecting sequestered sites such as chorioretinitis. V. Dosage and Administration
    Indication Treatment of toxoplasmosis Dosing Regimen Administered PO in combination with a sulfonamide ± leucovorin; recommended dosing regimen varies per guideline referenced: Maximum Dose 300 mg/day FDA labeling Adults: 50-75 mg daily for 1-3 weeks depending on the response of the patient and tolerance to therapy, followed by one-half of the initial dose continued for an additional 4 to 5 weeks Pediatrics: 1 mg/kg/day divided into 2 equal daily doses for 2-4 days, followed by one-half of the initial dose continued for approximately 1 month HHS guidelines [HIV-infected patients] Initial loading dose of 200 mg, followed by 50 mg/day (if body weight ≤ 60 kg) or 75 mg/day (if body weight > 60 kg) for the remainder of treatment duration CDC guidelines
    [ocular toxoplasmosis] Adult: Initial loading dose of 100 mg, followed by 25-50 mg/day for the remainder of treatment duration (usually 4-6 weeks) Pediatric: Initial loading dose of 2 mg/kg, followed by 1 mg/kg/day for the remainder of treatment duration (usually 4-6 weeks) [congenital toxoplasmosis] Newborns: 2 mg/kg per day, divided twice per day for the first 2 days; then from day 3 to 2 months (or 6 months if symptomatic) 1 mg/kg per day, every day; then 1 mg/kg per day 3 times per week for a total of 12 months 50-75 mg/week PO in combination with a sulfonamide
    Recommended treatment regimen is Daraprim 50 mg per week plus dapsone 50 mg once daily plus leucovorin 25 mg per week or Daraprim 75 mg Page 5 of 9 75 mg/week Primary prophylaxis of toxoplasmosis*

    CLINICAL POLICY Pyrimethamine Indication Maximum Dose Dosing Regimen plus dapsone 200 mg plus plus leucovorin 25 mg weekly 25-50 mg/day PO in combination with a sulfonamide Chronic maintenance therapy (secondary prophylaxis of toxoplasmosis)Off-label uses recommended by the HHS guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents 50 mg/day VI. Product Availability
    Tablet: 25 mg VII.