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Recorlev (levoketoconazole) Prior Authorization with Quantity Limit Program Summary
Policy Number: PH-1176
This program 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# |
Recorlev® (levoketoconazole) Tablet |
Treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative
Limitations of use: Recorlev is not approved for the treatment of fungal infections |
|
|
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.(2)
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.(2)
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.(3)
Clinical considerations and recommendations for Cushing’s syndrome diagnosis and monitoring of Cushing’s disease recurrence:(3)
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.(3)
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.(3)
Medications used for the treatment of Cushing’s disease target adrenal steroidogenesis, somatostatin, and dopamine receptors in the pituitary gland, and glucocorticoid receptors.(3)
There are several factors helpful in selection of medical therapy:(3)
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.(3)
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).(3)
Radiotherapy is primarily used as adjuvant therapy for patients with persistent or recurrent disease after transsphenoidal surgery or for aggressive tumor growth.(3)
|
Efficacy(1) |
Recorlev (levoketoconazole) contains the 2S,4R-enantiomer derived from racemic ketoconazole and is a cortisol synthesis inhibitor.
The effectiveness of Recorlev in patients with Cushing’s syndrome was evaluated in two studies (labeled Study 1 and Study 2).
Study 1 (NCT03277690) consisted of an open-label dose titration and maintenance phase of up to 19 weeks duration, followed by an 8-week double blind, placebo-controlled, randomized withdrawal phase. Persistence or recurrence of Cushing’s syndrome was evidenced by the mean of three 24-hour UFC levels greater than or equal to 1.5 X upper limit of normal.
The key secondary efficacy endpoint was the proportion of patients with mean UFC normalization, defined as a patient with mean UFC at or below the ULN at the end of the randomized withdrawal phase without meeting a requirement for early rescue during the randomized withdrawal phase.
The percent of patients who had normal mean UFC at the end of the randomized withdrawal phase was 52.4% in the Recorlev group and 5.6% in the placebo group, and the treatment difference (CI) was 46.8%.
Supportive evidence of efficacy was obtained from Study 2 (NCT01838551) which was a multicenter, single-arm, open-label study that consisted of three study phases (dose titration, maintenance, and extended evaluation) for a total of estimated treatment duration of up to 73 weeks. The primary efficacy endpoint of the study was the proportion of patients with normalization of mean UFC at or below the upper limit of normal based on central laboratory result without requiring a dose increase during maintenance phase. At the end of the maintenance phase, 30.9% of patients (95% exact confidence interval) met the primary endpoint. |
Safety(1) |
|
REFERENCES
Number |
Reference |
1 |
Recorlev Prescribing Information. Xeris Pharmaceuticals, Inc. December 2021. |
2 |
Endocrine Society. Cushing’s disease. Accessed at: https://www.hormone.org/diseases-and-conditions/cushings-disease |
3 |
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 |
|
||||||
Recorlev |
Levoketoconazole Tab |
150 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 |
|
|||||||||
Recorlev |
Levoketoconazole Tab |
150 MG |
240 |
Tablets |
30 |
DAYS |
|
|
|
CLIENT SUMMARY – PRIOR AUTHORIZATION
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
Client Formulary |
Recorlev |
Levoketoconazole Tab |
150 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 |
Recorlev |
Levoketoconazole Tab |
150 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(s) 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 see Quantity Limit Criteria |
QUANTITY LIMIT CLINICAL CRITERIA FOR APPROVAL
Module |
Clinical Criteria for Approval |
PA QL |
Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:
Length of Approval: Initial requests 6 months Renewal requests 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 _ Recorlev (levoketoconazole) _PAQL _ProgSum_ 1/1/2024