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Isturisa (osilodrostat) Prior Authorization with Quantity Limit Program Summary
Policy Number: PH-1133
This prior authorization applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx and Health Insurance Marketplace formularies.
POLICY REVIEW CYCLE
Effective Date |
Date of Origin |
1/1/2024 |
|
FDA APPROVED INDICATIONS AND DOSAGE
Agent(s) |
FDA Indication(s) |
Notes |
Ref# |
Isturisa® (osilodrostat) Tablets |
Treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative
|
|
1 |
See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm
CLINICAL RATIONALE
Cushing's Syndrome |
Cushing's syndrome denotes pathologic hypercortisolism as a result of excessive adrenocorticotropic hormone (ACTH) production, or autonomous adrenal production of cortisol. This potentially lethal disorder is associated with significant comorbidities, including hypertension, diabetes, coagulopathy, cardiovascular disease, infections, and fractures. As a result, even after cure of hypercortisolism, mortality rates may be increased. Because of this it is important to make the diagnosis as early in the disease course as possible, to prevent additional morbidity and residual disease. Signs and symptoms of Cushing’s syndrome are broad and often common among the general population, such as obesity, depression, diabetes, hypertension, or menstrual irregularities. Some features are more discriminatory and unique to Cushing’s syndrome, such as reddish-purple striae, plethora, proximal muscle weakness, bruising with no obvious trauma, and unexplained osteoporosis.(5) Cushing’s disease is a form of Cushing syndrome. Cushing’s disease occurs when a benign tumor in the pituitary gland causes the pituitary gland to produce too much ACTH. Cushing's disease can also occur with diffuse growth of the pituitary gland (pituitary hyperplasia). Pituitary hyperplasia can lead to the release of too much ACTH, which then leads to over-production of cortisol by the adrenal glands.(5) Diagnosis of Cushing’s syndrome is often delayed for years, partly because of lack of awareness of the insidious progressive disease process and testing complexity. Screening and diagnostic tests for Cushing’s syndrome assess cortisol secretory status: abnormal circadian rhythm with late-night salivary cortisol (LNSC), impaired glucocorticoid feedback with overnight 1 mg dexamethasone suppression test (DST) or low-dose 2-day dexamethasone test (LDDT), and increased bioavailable cortisol with 24-hour urinary free cortisol (UFC). The sensitivity of all tests is higher than 90%; the highest sensitivity rates are obtained with DST and LNSC and the lowest with UFC. Specificity is somewhat lower than sensitivity, with LNSC being the most specific and DST and UFC the least specific. LNSC should not be used in patients with disruption of normal day and night cycle, such as night-shift workers.(6) Clinical considerations and recommendations for Cushing’s syndrome diagnosis and monitoring of Cushing’s disease recurrence:(6)
Transsphenoidal surgery is recommended as first-line therapy for patients with Cushing’s disease. Remission, typically defined as postoperative serum cortisol concentrations lower than 2 mcg/dL, is seen in approximately 80% of patients with microadenomas and 60% with macroadenomas if the procedure is performed by an experienced surgeon. Patients in remission require glucocorticoid replacement until HPA axis recovery. As remission could be delayed, monitoring until postoperative cortisol nadir can usually identify such cases.(6) Recurrence after successful pituitary surgery is characterized as the reappearance of clinical and biochemical features of hypercortisolism after initial remission. Published recurrence rates vary between 5% and 35% with half of recurrences appearing within the first 5 years after surgery and half after up to 10 years or more. Compared with use in the initial diagnosis of Cushing’s syndrome, LNSC, DST, UFC, and desmopressin tests have a lower sensitivity for recurrence, but specificity is high. Repeat transsphenoidal surgery can be considered in patients with biochemical evidence of recurrent Cushing’s disease with visible tumor on MRI.(6)
Medications used for the treatment of Cushing’s disease target adrenal steroidogenesis, somatostatin, and dopamine receptors in the pituitary gland, and glucocorticoid receptors.(6)
There are several factors helpful in selection of medical therapy:(6)
Adrenal steroidogenesis inhibitors are usually used first given their reliable effectiveness. For patient with mild disease and no visible tumor on MRI, ketoconazole, osilodrostat, or metyrapone are typically preferred. For patients with mild-to-moderate disease and some residual tumor, there might be a preference for cabergoline or pasireotide because of the potential for tumor shrinkage. For patients with severe disease, rapid normalization of cortisol is the most important goal. With osilodrostat and metyrapone, response will typically be seen within hours, and with ketoconazole within a few days.(6)
Change in treatment should be considered if cortisol levels are persistently elevated after 2-3 months on maximum tolerated doses. If cortisol does not normalize but is reduced or there is some clinical improvement, combination therapy can be considered (low quality, discretionary recommendation). Many experts consider combining ketoconazole with metyrapone or potentially ketoconazole with osilodrostat to maximize adrenal blockade when monotherapy is not effective, or to allow lower doses of both drugs (low quality, discretionary recommendation). Ketoconazole plus cabergoline or pasireotide, and pasireotide plus cabergoline could be rational combinations if there is visible tumor present (low quality, discretionary recommendation). Other combinations that can be used include triplets of cabergoline, pasireotide, plus ketoconazole, and ketoconazole, metyrapone, plus mitotane (low quality, discretionary recommendation).(6)
Radiotherapy is primarily used as adjuvant therapy for patients with persistent or recurrent disease after transsphenoidal surgery or for aggressive tumor growth.(6)
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Efficacy |
Isturisa is a cortisol synthesis inhibitor, by blocking the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland. The safety and efficacy of Isturisa were established in a 48-week, multicenter study that consisted of four study periods.(1)
The trial enrolled Cushing’s disease patients with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery. Inclusion criteria included the following(4):
The primary endpoint of the study was to compare the percentage of complete responders at the end of the 8 week randomized withdrawal period (Period 3) between patients randomized to continue Isturisa versus the patients switched to placebo. A complete responder for the primary endpoint was defined as a patient who had mUFC less than or equal to ULN based on central laboratory result at the end of Period 3 (week 34), and who neither discontinued randomized treatment or the study nor had any dose increase above their week 26 dose. The key secondary endpoint was to assess the complete responder rate at the end of Period 2 (week 24). A complete responder for the key secondary endpoint was defined as a patient with mUFC less than or equal to ULN at week 24 who did not require an increase in dose above the level established at the end of Period 1 (week 12). Patients who were missing mUFC assessment at week 24 were counted as non-responders for the key secondary endpoint.(1)
At the end of Period 3, the percentage of complete responders for the primary endpoint was 86% and 29% in the Isturisa and placebo groups, respectively (Table 3). The difference in percentage of complete responders between Isturisa and placebo groups was 57%, with 95% two-sided CI of (38, 76). The 95% CI were not presented by individual strata due to the small sample sizes of some of these strata.
The key secondary endpoint, complete responder rate after 24 weeks of treatment with Isturisa was achieved by 72/137 patients (52.6%) with 95% two-sided CI of (43.9, 61.1). The lower bound of this 95% CI exceeded 30%, the prespecified threshold for statistical significance and minimum threshold for clinical benefit. At week 48, 91/137 patients (66%) had normal mUFC levels. Variable decreases from baseline for blood pressure, glucose parameters, weight and weight circumference were observed at week 48. However, because the study allowed initiation of anti-hypertensive and anti-diabetic medications and dose increases in patients already receiving such medications and the absence of a control group, the individual contribution of Isturisa or of anti-hypertensive and anti-diabetic medication adjustments cannot be clearly established.(1) |
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Safety(1) |
Isturisa (osilodrostat) has no known FDA labeled contraindications. |
REFERENCES
Number |
Reference |
1 |
Isturisa prescribing information. Recordati Rare Disease, Inc. March 2020. |
2 |
|
3 |
|
4 |
Novartis Pharmaceuticals. A Phase III, Multi-center, Randomized, Double-blind, 48 Week Study With an Initial 12 Week Placebo-controlled Period to Evaluate the Safety and Efficacy of Osilodrostat in Patients With Cushing's Disease. Identification No. NCT02697734. Retrieved March 25, 2020 from https://clinicaltrials.gov/ct2/show/NCT02697734 |
5 |
Endocrine Society. Cushing’s disease. Accessed at: https://www.hormone.org/diseases-and-conditions/cushings-disease |
6 |
Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol December 2021;9 847-75. |
POLICY AGENT SUMMARY PRIOR AUTHORIZATION
Target Brand Agent(s) |
Target Generic Agent(s) |
Strength |
Targeted MSC |
Available MSC |
Final Age Limit |
Preferred Status |
|
||||||
Isturisa |
osilodrostat phosphate tab |
1 MG ; 10 MG ; 5 MG |
M ; N ; O ; Y |
N |
|
|
POLICY AGENT SUMMARY QUANTITY LIMIT
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
QL Amount |
Dose Form |
Day Supply |
Duration |
Addtl QL Info |
Allowed Exceptions |
Targeted NDCs When Exclusions Exist |
|
|||||||||
Isturisa |
Osilodrostat Phosphate Tab 1 MG |
1 MG |
240 |
Tablets |
30 |
DAYS |
|
|
|
Isturisa |
Osilodrostat Phosphate Tab 10 MG |
10 MG |
180 |
Tablets |
30 |
DAYS |
|
|
|
Isturisa |
Osilodrostat Phosphate Tab 5 MG |
5 MG |
300 |
Tablets |
30 |
DAYS |
|
|
|
CLIENT SUMMARY – PRIOR AUTHORIZATION
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
Client Formulary |
Isturisa |
osilodrostat phosphate tab |
1 MG ; 10 MG ; 5 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
CLIENT SUMMARY – QUANTITY LIMITS
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
Client Formulary |
Isturisa |
Osilodrostat Phosphate Tab 1 MG |
1 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Isturisa |
Osilodrostat Phosphate Tab 10 MG |
10 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
Isturisa |
Osilodrostat Phosphate Tab 5 MG |
5 MG |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL
Module |
Clinical Criteria for Approval |
|
Initial Evaluation Target Agent will be approved when ALL of the following are met:
Length of Approval: 6 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. *Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.
Renewal Evaluation Target Agent will be approved when ALL of the following are met:
Length of Approval: 12 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. |
QUANTITY LIMIT CLINICAL CRITERIA FOR APPROVAL
Module |
Clinical Criteria for Approval |
QL with PA |
Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:
Length of Approval: Initial: 6 months; Renewal: 12 months
|
This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.
Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment
BCBSAL _ Commercial _ CSReg _ Isturisa (osilodrostat) _PAQL _ProgSum_ 1/1/2024