Effective Date

Date of Origin 

1/1/2023

Signifor^®

(pasireotide)

Subcutaneous injection

Adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative

1

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's 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.(3)

The Endocrine Society indicates the following recommendations for the diagnosis of Cushing’s syndrome:(2,3)

• Excessive exogenous glucocorticoid exposure needs to be ruled out as the underlying cause of Cushing’s syndrome signs/symptoms prior to conducting biochemical testing
• The following groups are recommended for biochemical testing for Cushing’s syndrome:
  • Patients with unusual features for age (e.g., osteoporosis, hypertension)
  • Patients with multiple and progressive features, particularly those who are more predictive of Cushing’s syndrome
  • Children with decreasing height percentile and increasing weight
  • Patients with adrenal incidentaloma compatible with adenoma
• The following tests are recommended as initial testing, based on suitability for the patient:
  • Urine free cortisol (UFC; at least two measurements) greater than the normal range for the assay
  • Late-night salivary cortisol (two measurements) greater than 145 ng/dL
  • 1 mg overnight dexamethasone suppression test (DST) with a serum cortisol greater than 1.8 mcg/dL
  • Longer low dose DST (2 mg/d for 48 hours) with a serum cortisol greater than 1.8 mcg/dL
• Exclude physiologic causes of hypercortisolism (e.g., pregnancy, depression and other psychiatric conditions, alcohol dependence, glucocorticoid resistance, morbid obesity, poorly controlled diabetes)
• Patients should be seen by an endocrinologist for repeat biochemical testing and diagnosis

The goal of treatment for Cushing’s syndrome is to normalize cortisol levels or normalizing the action at cortisol receptors to reduce or eliminate the signs and symptoms of Cushing’s syndrome and treat comorbidities associated with hypercortisolism. The Endocrine Society recommends the use of a multidisciplinary team, including an endocrinologist, for the diagnosis and management of Cushing’s disease.(3,4)

First line treatment is surgical resection of the primary lesion(s) unless surgery is not possible or is unlikely to significantly reduce glucocorticoid excess. In patients that underwent noncurative surgery or those for whom surgery was not an option, the Endocrine Society guidelines and Pituitary Society guidelines recommend the following second-line treatment options:(2,3)

• Bilateral adrenalectomy for those with severe ACTH-dependent disease who cannot be controlled with medical therapy
• Radiation therapy or radiosurgery
• Medical treatment:
  • Steroidogenesis inhibitors recommended as second line therapy include: ketoconazole (400-1600 mg/day, every 6 to 8 hours dosing), metyrapone (500 mg to 6 g per day, every 6 to 8 hours dosing [FDA approved as a diagnostic agent in the US]), and mitotane (500 mg to 8 g per day)
  • Pituitary directed agents include: cabergoline (1-7 mg/week) and pasireotide (600-900 mcg twice daily)
  • Glucocorticoid receptor-directed agents include: mifepristone (300-1200 mg once daily)

Efficacy(1)

A Phase III multicenter, randomized study was conducted to evaluate the safety and efficacy of two dosage levels of Signifor over a 6-month treatment period in Cushing’s disease patients with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or had refused surgery.

Patients with a baseline 24-hour urine free cortisol (UFC) greater than 1.5 X the upper limit of normal were randomized to receive a Signifor dosage of either 0.6 mg subcutaneous twice daily or 0.9 mg subcutaneous twice daily. After the initial six months in the study, patients entered an additional 6-month open-label treatment period. The primary efficacy endpoint was the proportion of patients who achieved normalization of mean 24-hour UFC levels after six months of treatment and did not dose increase during this period.

At month 6, the percentages of responders for the primary endpoint were 15% and 26% in the 0.6 mg twice daily and 0.9 mg twice daily groups respectively. The percentages of patients with mean UFC less than or equal to ULN or greater than or equal to 50% reduction from baseline, a less stringent endpoint than the primary endpoint, were 34% in the 0.6 mg twice daily and 41% in the 0.9 mg twice daily groups.

Safety(1)

Signifor (pasireotide) has no FDA labeled contraindications.

1

Signifor prescribing information. Novartis Pharmaceuticals Corporation. January 2020.

2

Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015 Aug;100(8):2807–2831.

3

Fleseriu M, Auchus R, Bancos I, et al. Pituitary Society Consensus on Diagnosis and Management of Cushing's Disease: A Guideline Update. Lancet Diabetes Endocrinol. 2021;9(12):847-875.

4

Nieman LK, Biller BMK, Findling JW, et al. The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008 May;93(5):1526–1540.

SIGNIFOR*pasireotide diaspartate inj

0.3 MG/ML ; 0.6 MG/ML ; 0.9 MG/ML

M ; N ; O ; Y

N

3017007520

SIGNIFOR*pasireotide diaspartate inj

0.3 MG/ML ; 0.6 MG/ML ; 0.9 MG/ML

60.0

AMPULS

30

Days

SIGNIFOR*pasireotide diaspartate inj

0.3 MG/ML ; 0.6 MG/ML ; 0.9 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

SIGNIFOR*pasireotide diaspartate inj

0.3 MG/ML ; 0.6 MG/ML ; 0.9 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met: 

1. ONE of the following:
   1. The patient has a diagnosis of Cushing’s disease AND BOTH of the following:
      1. The patient has urinary free cortisol levels greater than 1.5 times the upper limit of normal AND
      2. ONE of the following:
         1. The patient has had an inadequate response to pituitary surgical resection OR
         2. The patient is not a candidate for pituitary surgical resection OR
   2. The patient has another FDA approved indication for the requested agent AND
2. ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. The prescriber has provided information in support of using the requested agent for the patient’s age for the requested indication AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., endocrinologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient will NOT be using the requested agent in combination with Signifor LAR (pasireotide LAR) AND
5. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: Cushing’s Disease – 6 months

                                All other FDA approved diagnoses – 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met: 

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process AND
2. The patient has had clinical benefit with the requested agent AND
3. The patient has urinary free cortisol levels less than or equal to the upper limit of normal AND
4. The patient has had improvements or stabilization from baseline (prior to therapy with the requested agent) as indicated by ONE of the following:
   1. Fasting plasma glucose OR
   2. Hemoglobin A1c OR
   3. Hypertension OR
   4. Weight AND
5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., endocrinologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
6. The patient will NOT be using the requested agent in combination with Signifor LAR (pasireotide LAR) AND
7. The patient does NOT have an FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

QL with PA

Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. ALL of the following:
   1. The requested quantity (dose) is greater than the program quantity limit AND
   2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
   3. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does not exceed the program quantity limit

Length of Approval: Initial: Cushing’s Disease – 6 months, All other FDA approved diagnosis – 12 months; Renewal: 12 months