WHA

ISTURISA (osilodrostat)

SELF-ADMINISTRATION - Oral

Indication for Prior Authorization:
  • Indicated for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative
Patients must meet the following criteria for the indication(s) above:
  • Patient is 18 years of age or older, AND
  • Prescribed by or in consultation with an endocrinologist, AND
  • Diagnosis of Cushing's disease, AND
  • Chart note documentation confirms one of the following:
    • Patient is not a candidate for pituitary surgery, OR
    • Pituitary surgery or repeat surgeries, with or without radiation therapy, has not been curative for the patient, and the patient still requires a cortisol synthesis inhibitor, AND
  • Patient has tried and failed at least one of the following cortisol synthesis inhibitors: ketoconazole or Lysodren® (mitotane), AND
  • Baseline ECG is obtained/monitored periodically, and if indicated hypokalemia and/or hypomagnesemia is corrected prior to Isturisa® initiation and monitored periodically during treatment with Isturisa®.  Consider temporary discontinuation of Isturisa® in the case of an increase in QTc interval > 480 ms
Reauthorization criteria:
  • Chart note documentation confirms a positive clinical response to therapy (e.g. a clinically meaningful reduction in 24-hour urinary free cortisol levels, improvement in signs or symptoms of the disease)
Dosing:
  • 2 mg orally twice daily
  • 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 patient tolerates 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 in maintained.
  • Maintenance dosage varied between 2 mg and 7 mg twice daily in clinical trials.  The maximum recommended maintenance dosage is 30 mg twice daily.
  • Once maintenance dosage is achieved, monitor cortisol levels at least every 1-2 months or as indicated.
  • Starting dose is reduced for patients with moderate hepatic impairment (Child-Pugh B) and severe hepatic impairment (Child-Pugh C).
Approval:
  • 1 year
Review History:
  • October 20, 2020 - Original Review
References: 

• Baudry C, Coste J, Khalil RB, et al. Efficiency and tolerance of mitotane in Cushing’s disease in 76 patients from a single center. Eur J Endocrinol. 2012;167:473-481.
• Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing's disease: is it worth a try? J Endrocrin Metab. 2014;99(5):1623-1630.
• Clinical Pharmacology Web site. http://clinicalpharmacology-ip.com/. Accessed April 23, 2020.
• Creemers SG, Hofland LJ, Lamberts SWJ, Feelders RA. Cushing’s syndrome: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother. 2015;16(12):1829-1844.
• Cuevas-Ramos D, Lim DST, Fleseriu M. Update on Medical Treatment for Cushing's Disease. Clin Diabetes Endocrinol. 2016;2:16. doi 10.1186/s40842-016-0033-9.
• Cushing’s Disease News. Isturisa shows sustained responses in Cushing’s disease patients in LINC-4 trial https://cushingsdiseasenews.com/2020/06/24/isturisa-shows-sustained-responses-cushings-disease-linc-4-trial/. Accessed July 13, 2020.
• Daniel E, Aylwin S, Mustafa O, et al. Effectiveness of metyrapone in treating Cushing’s syndrome: a retrospective multicenter study in 195 patients. J Clin Endocrinol Metab. 2015;100(11):4146-4154.
• Duggan S. Osilodrostat: first approval. Drugs. 2020;80:495-500.
• Endocrine Society.org. Methodology. https://www.endocrine.org/clinical-practice-guidelines/methodology. Accessed April 20, 2020.
• Feelders RA, Newell-Price J, Pivonello R, Nieman LK, Hofland LJ, Lacroix A. Advances in the medical treatment of Cushing’s syndrome. Lancet Diabetes Endocrinol. 2019;7:300-312.
• Food and Drug Administration/Center for Drug Evaluation and Research. FDA approved drug products. Food and Drug Administration Web site. https://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed April 22, 2020.
• Food and Drug Administration. Isturisa clinical review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000MedR.pdf. January 14, 2020. Accessed April 8, 2020.
• Godbout A, Manavela M, Danilowicz K, Beauregard H, Bruno OD, Lacroix A. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol. 2010;163(5):709-716.
• Isturisa [formulary dossier], Lebanon, NJ: Recordati Rare Diseases Inc.; April 2020.
• Isturisa [package insert], Lebanon, NJ: Recordati Rare Diseases Inc.; March 2020.
• Ketoconazole tablets [package insert], Richland, MS: Burel Pharmaceuticals, Inc.; February 2020.
• Lexicomp Web site. http://online.lexi.com/lco/action/home. Accessed June 12, 2020.
• Molitch ME. Diagnosis and treatment of pituitary adenomas. A review. JAMA.2017;317(5):516-524.
• Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100: 2807-2831.
• Nieman LK. Epidemiology and clinical manifestations of Cushing’s syndrome. UpToDate Web site. Updated February 4, 2019[a]. www.uptodate.com. Accessed April 14, 2020.
• Nieman LK. Causes and pathophysiology of Cushing’s syndrome. UpToDate Web site. Updated November 12, 2019[b]. www.uptodate.com. Accessed April 14, 2020.
• Nieman LK. Overview of the treatment Cushing’s syndrome. UpToDate Web site. Updated October 30, 2019[c]. www.uptodate.com. Accessed May 26, 2020.
• Nieman LK. Medical therapy of hypercortisolism (Cushing's syndrome). UpToDate Web site. Updated October 30, 2018[d]. www.uptodate.com. Accessed June 12, 2020.
• Pivonello R, De Martino MC, Cappabianca P, et al. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab. 2009;94(1):223-230.
• Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BMK, Colao A. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4:611-629.
• Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomized withdrawal phase. Lancet Diabetes Endocrinol. 2020;https://doi.org/10.1016/S2213-8587(20)30240-0. 
 

Last review date: October 20, 2020