Levoketoconazole (Recorlev) Form

Levoketoconazle (Recorlev®) is a cortisol synthesis inhibitor. FDA Approved Indication(s) Recorlev is indicated for cortisol synthesis inhibitor indicated for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome (CS) for whom surgery is not an option or has not been curative. Limitation(s) of use: Recorlev is not approved for the treatment of fungal infections. 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 Recorlev is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Cushing’s Syndrome (must meet all):

1. Diagnosis of CS;
   2. Prescribed by or in consultation with an endocrinologist;
   3. Age ≥ 18 years;
   4. Member meets one of the following (a or b): a. Surgery has not been curative; b. Member is not eligible for surgery;
2. Failure of ketoconazole, unless contraindicated or clinically significant adverse effects are experienced;
3. Dose does not exceed 1,200 mg per day. Approval duration: 6 months B. Other diagnoses/indications (must meet 1 or 2):

4. 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 1 of 6

   CLINICAL POLICY Levoketoconazole 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

5. 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. Cushing’s Syndrome (must meet all):
6. 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 (see Appendix D);
   3. If request is for a dose increase, new dose does not exceed 1,200 mg per day. Approval duration: 12 months
      B. 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: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

9. 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 – Page 2 of 6

   CLINICAL POLICY Levoketoconazole 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: Abbreviation/Acronym Key CS: Cushing’s syndrome FDA: Food and Drug Administration UFC: urinary free cortisol 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 ketoconazole 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. 400 to 1,600 mg PO daily, administered BID or TID 1,600 mg/day Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Cirrhosis, acute liver disease or poorly controlled liver disease o Baseline aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 30 times the upper limit of normal o Recurrent symptomatic cholelithiasis o Prior history of drug induced liver injury due to ketoconazole or any azole antifungal therapy o Taking drugs that cause QT prolongation associated with ventricular arrhythmias • Boxed warning(s): hepatotoxicity, QT prolongation Appendix D: General Information • Positive treatment response for CS includes, but is not limited to, normalization of cortisol levels or action at its receptors to eliminate signs and symptoms of the disease. A 24-hour urinary free cortisol (UFC) level may be used to assess normalization of cortisol levels. The American Association of Neurological Surgeons notes that UFC levels higher than 50-100 mcg/24 h in adults suggest the presence of CS. Dexamethasone suppression test or late night salivary cortisol concentrations may also be used to assess normalization of cortisol levels. • The use of ketoconazole for the treatment of CS is considered off-label. However, ketoconazole is known to block multiple adrenal enzymes which is its understood mechanism in the treatment of CS. Ketoconazole is recommended as a second-line treatment by the 2015 Endocrine Society Clinical Practice Guidelines with moderate quality of evidence as a steroidogenesis inhibitor, and is also endorsed by the 2021 Pituitary Society Guideline Update. Page 3 of 6

   CLINICAL POLICY Levoketoconazole V. Dosage and Administration
   Indication Dosing Regimen CS Starting dose is 150 mg PO BID. May increase by 150 mg daily, no more frequently than 2-3 weeks based on 24-hour urine free cortisol levels and patient tolerability Maximum Dose 1,200 mg/day, administered as 600 mg BID VI. Product Availability
   Tablet: 150 mg VII.