Osilodrostat (Isturisa) Form

Osilodrostat (Isturisa®) is a cortisol synthesis inhibitor. FDA Approved Indication(s) Isturisa is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease (CD) for whom pituitary surgery is not an option or has not been curative. 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 Isturisa is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Cushing’s Disease (must meet all):

1. Diagnosis of CD;
   2. Prescribed by or in consultation with an endocrinologist;
   3. Age ≥ 18 years;
   4. Member meets one of the following (a or b): a. Pituitary surgery has not been curative; b. Member is not eligible for pituitary surgery;
2. Dose does not exceed 30 mg twice daily. Approval duration: 6 months B. Other diagnoses/indications (must meet 1 or 2):

3. 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 Page 1 of 6

   CLINICAL POLICY Osilodrostat

4. 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 Disease (must meet all):
5. 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);
6. Member is responding positively to therapy (see Appendix D);
   3. If request is for a dose increase, new dose does not exceed 30 mg twice daily. Approval duration: 12 months B. 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.
   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: Abbreviation/Acronym Key CD: Cushing’s disease FDA: Food and Drug Administration Page 2 of 6

   CLINICAL POLICY Osilodrostat UFC: urinary free cortisol Appendix B: Therapeutic Alternatives
   Not applicable Appendix C: Contraindications/Boxed Warnings None reported Appendix D: General Information • Treatment response for CD may be defined as reduction in 24-hour urinary free cortisol (UFC) levels and/or improvement in signs or symptoms of the disease. Maximum UFC reduction is typically seen by two months of treatment.
   • Across sampled U.S. laboratories (Mayo Clinic Laboratories, LabCorp, Quest Diagnostics), 24-hour UFC adult reference values range from 3 to 64 mcg/24 h. The American Association of Neurological Surgeons notes that UFC levels higher than 50- 100 mcg/24 h in adults suggest the presence of Cushing’s syndrome [inclusive of CD]. In this context, the Endocrine Society notes that 24-hour UFC levels may range from more than 5 times normal in severe cases to as low as 1.5 times normal in relatively mild cases.
   Maximum Dose 60 mg/day V. Dosage and Administration
   Indication Dosing Regimen CD • Recommended Dosage, Titration, and Monitoring • Initiate dosing at 2 mg orally twice daily, with or without food. Initially, titrate the dosage by 1 to 2 mg twice daily, no more frequently than every 2 weeks based on the rate of cortisol changes, individual tolerability and improvement in signs and symptoms of Cushing’s disease. If a patient tolerates Isturisa dosage of 10 mg twice daily and continues to have elevated 24-hour urine free cortisol (UFC) levels above upper normal limit, the dosage can be titrated further by 5 mg twice daily every 2 weeks. Monitor cortisol levels from at least two 24-hour urine free cortisol collections every 1-2 weeks until adequate clinical response is maintained. • The maintenance dosage of Isturisa is individualized and determined by titration based on cortisol levels and patient’s signs and symptoms. • The maintenance dosage varied between 2 mg and 7 mg twice daily in clinical trials. The maximum recommended maintenance dosage of Isturisa is 30 mg twice daily. • Once the maintenance dosage is achieved, monitor cortisol levels at least every 1-2 months or as indicated. Dosage Interruptions and Modifications Page 3 of 6

   CLINICAL POLICY Osilodrostat Indication Dosing Regimen Maximum Dose • Decrease or temporarily discontinue Isturisa if urine free cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, and/or patients report symptoms of hypocortisolism. If necessary, glucocorticoid replacement therapy should be initiated. • Stop Isturisa and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency. If treatment is interrupted, re-initiate Isturisa at a lower dose when cortisol levels are within target ranges and patient symptoms have been resolved. • VI. Product Availability
   Tablets: 1 mg, 5 mg, 10 mg VII.