Important Safety Information

Treatment with SIGNIFOR may lead to bradycardia and QT prolongation. Use with caution in at-risk-patients. ECG testing is recommended prior to dosing and during treatment.

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Indication

SIGNIFOR® (pasireotide) Injection is indicated for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.

Disease Information

Method of Disease

CUSHING'S DISEASE IS CAUSED BY AN ACTH-SECRETING PITUITARY ADENOMA1,2

In patients with Cushing's disease, the hypothalamic-pituitary-adrenal (HPA) feedback loop is dysregulated,3 causing the inhibition normally exerted by cortisol on corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) production to cease to have an effect.4

  • Pituitary corticotroph adenomas secrete excess ACTH, which induces the overproduction of cortisol from the adrenal glands2,4
    • — Approximately 5% to 10% of pituitary adenomas are ACTH secreting5
  • Pituitary adenomas express somatostatin receptors (ssts), with sst5 being the most predominant6

Cushing's disease, for which SIGNIFOR is indicated, is a specific form of Cushing's syndrome, accounting for about 70% of observed cases in adults.4,7

References:

  1. Koch CA, Chrousos GP. Cushing's disease. In: Powell MP, Lightman SL, Laws ER Jr, eds. Management of Pituitary Tumors: The Clinician's Practical Guide. 2nd ed. Totowa, NJ: Humana Press; 2003:51-75.
  2. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2003;88(12):5593-5602.
  3. Biller BMK, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2008;93(7):2454-2462.
  4. National Institute of Health (NIH). What causes Cushings's syndrome? https://www.nichd.nih.gov/health/topics/cushing/conditioninfo/Pages/causes.aspx. Updated November, 30, 2012. Accessed June 1, 2013.
  5. American Cancer Society. What are pituitary tumors? http://www.cancer.org/cancer/pituitarytumors/detailedguide/pituitary-tumors-what-is-pituitary-tumor. Updated August 5, 2014. Accessed May 30, 2015.
  6. de Bruin C, Pereira AM, Feelders RA, et al. Coexpression of dopamine and somatostatin receptor subtypes in corticotroph adenomas. J Clin Endocrinol Metab. 2009;94(4):1118-1124.
  7. SIGNIFOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.

Video: An Overview of the Mechanism of Cushing's Disease

 

Learn how pituitary adenomas dysregulate the HPA-feedback loop, resulting in an excess of ACTH secretion.

Diagnosis

DIAGNOSIS OF CUSHING'S DISEASE IS CHALLENGING

A phased approach to diagnosing Cushing's disease, for which SIGNIFOR® (pasireotide) Injection is indicated, is necessary due to the multiple tests required to diagnose the disease.1,2 On average, it can take 6 years from the time symptoms are noticed before a person is diagnosed with Cushing's disease.3

PHASE I: EVALUATE SIGNS AND SYMPTOMS OF HYPERCORTISOLISM

Due to the commonality of the clinical signs of Cushing's syndrome and common health conditions found in the general population, any combination of the signs and symptoms of hypercortisolism warrants further investigation. Cushing's syndrome must be diagnosed prior to diagnosing a patient with Cushing's disease. Cushing's syndrome should be considered in patients with1:

  • Unusual features for their age
  • Multiple and progressive features
  • Incidentally discovered adrenal tumors
  • No recent exogenous glucocorticoid exposure

An initial drug history and physical exam can help determine whether symptoms are caused by hypercortisolism.

View the Diagnostic Algorithm1.7

PHASE II: DIAGNOSE CUSHING'S SYNDROME

Exogenous hypercortisolism should first be ruled out as the cause of symptoms associated with Cushing's syndrome.2,5 Once exogenous glucocorticoid use is excluded, at least 2 of the following biochemical tests for hypercortisolism can be used to diagnose endogenous Cushing's syndrome1:

Cortisol testLevel suggesting Cushing's syndrome
24-hour UFC (≥2 measurements) >Upper limit of normal for the assay1
Late-night salivary cortisol (≥2 measurements) >4 nmol/L (145 ng/dL) assay1
Dexamethasone suppression test (1 mg overnight or 2 mg for 48 hours) >50 nmol/L2
Midnight serum cortisol >50 nmol/L (sleeping); >207 nmol/L (awake)2
Dexamethasone-CRH >38.6 nmol/L4

PHASE III: CONFIRM CUSHING'S DISEASE

Once the diagnosis of Cushing's syndrome is confirmed, the next step is to identify the cause of excess cortisol secretion. The following tests are typically used to identify and/or locate the ACTH-secreting pituitary tumor.

 
ACTH test
 

Measures plasma adrenocorticotropic hormone (ACTH) by immunoradiometric assay. Higher levels of plasma ACTH (>10 pg/mL) in a patient with Cushing's syndrome suggest an ACTH-secreting tumor. ACTH is usually low or undetectable (<10 pg/mL) in patients with an adrenal cortisol-secreting tumor.5

 
Magnetic resonance imagining (MRI)
 

In a patient with high levels of cortisol and detectable adrenocorticotropic hormone (ACTH), T1-weighted MRI of the pituitary should be performed in the coronal plane with diminished gadolinium enhancement. This procedure has ~70% sensitivity in detecting adenomas as small as 3 mm.5,6 Adenomas measuring <6 mm may require further testing and confirmation with inferior petrosal sinus sampling (IPSS). Adenomas detected on MRI may be nonsecreting; however, ACTH-secreting adenomas may go undetected. Further testing is required.2,5,7

 
Inferior petrosal sinus sampling (IPSS)
 

A positive inferior petrosal sinus sampling (IPSS) test confirms that the pituitary is the source of ACTH hypersecretion.5,8 For a reliable result, both sinuses should be catherized and sampling of sinuses and peripheral blood must be done simultaneously.9 A negative IPSS test suggests an ACTH-secreting tumor elsewhere in the body, eg, the lungs.5

References:

  1. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540.
  2. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing's syndrome. Lancet. 2006;367(9522):1605-1617.
  3. Psaras T, Milian M, Hattermann V, Freiman T, Gallwitz B, Honegger J. Demographic factors and the presence of comorbidities do not promote early detection of Cushing's disease and acromegaly. Exp Clin Endocrinol Diabetes. 2011;119(1):21-25.
  4. Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. The dexamethasone-suppressed corticotropin-releasing hormone stimulation test differentiates mild Cushing's disease from normal physiology. J Clin Endocrinol Metab. 1998;83(2):348-352.
  5. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2003;88(12):5593-5602.
  6. Koch CA, Chrousos GP. Cushing's disease. In: Powell MP, Lightman SL, Laws ER Jr, eds. Management of Pituitary Tumors: The Clinician's Practical Guide. 2nd ed. Totowa, NJ: Humana Press; 2003:51-75.
  7. Nieman LK, Ilias I. Evaluation and treatment of Cushing's syndrome. Am J Med. 2005;118(12):1340-1346.
  8. National Endocrine and Metabolic Diseases Information Service. Cushing's Syndrome. Bethesda, MD: National Institutes of Health. NIH Publication No. 08-3007. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.htm. Published July 2008. Accessed June 3, 2015.
  9. Bertagna X, Raux-Demay MC, Guilhaume B, Girard F, Luton JP. Cushing's disease. In: Melmed S, ed. The Pituitary. 2nd ed. Malden, MA: Blackwell Publishing; 2002:496-560.

Treatment

After confirmed diagnosis of Cushing's disease, it is important to quickly initiate treatment to avoid prolonged exposure to hypercortisolism.1 The goals of treatment in Cushing's disease include2:

  • Normalization of biochemistry (ie, cortisol levels)
  • Improvement of clinical features
  • Long-term control without recurrence

FIRST-LINE TRANSSPHENOIDAL SURGERY

Resection of the pituitary tumor by transsphenoidal surgery is the standard first-line option.1 Surgical skill and experience are among the most important factors for high success rates with transsphenoidal surgery.3 Most major centers quote high remission rates with first-line transsphenoidal surgery.1

SECOND-LINE TREATMENT OPTIONS

 
Repeat transsphenoidal surgery
 

If surgery fails or disease recurs, repeat pituitary surgery may be performed. However, the overall success rate is much lower than with first-line transsphenoidal surgery. Repeat surgery is only recommended when evidence of a remaining pituitary adenoma can be established.3

 
Radiotherapy
 

Fractionated external beam radiotherapy has been shown to achieve control of hypercortisolism. Long-term follow-up after radiotherapy is necessary because the risk of relapse and therapy-induced pituitary failure remains years after treatment.2,4

 
Radiosurgery
 

Stereotactic radiosurgery has been shown to achieve control of hypercortisolism. Long-term follow-up after radiosurgery is necessary because the risk of relapse and therapy-induced pituitary failure remain years after treatment.2

 
Bilateral adrenalectomy
 

Bilateral adrenalectomy involves complete removal of both adrenal glands and provides immediate control over hypercortisolism, but will result in permanent hypoadrenalism.2 Adrenalectomy is the only therapeutic option that offers an immediate control of hypercortisolism.5

SIGNIFOR is the first medical therapy that provides cortisol control in patients with Cushing’s disease.6

References:

  1. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2003;88(12):5593-5602.
  2. Biller BMK, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2008;93(7):2454-2462.
  3. Boscaro M, Barzon L, Fallo F, Sonino N. Cushing's syndrome. Lancet. 2001;357(9258):783-791.
  4. Buchfelder M, Schlaffer S. Surgical management and radiotherapy. In: Lamberts SWJ, ed. Handbook of Cushing's Disease. Bristol, UK: BioScientifica; 2011:64-81.
  5. Assié G, Bahurel H, Bertherat J, Kujas M, Legmann P, Bertagna X. The Nelson's syndrome...revisited. Pituitary. 2004;7(4):209-215.
  6. SIGNIFOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.

SIGNIFOR® (pasireotide) Injection, for subcutaneous use

INDICATION

SIGNIFOR is indicated for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions:

  • Hypocortisolism: Treatment with SIGNIFOR leads to suppression of adrenocorticotropic hormone (ACTH) secretion in Cushing's disease. Suppression of ACTH may lead to a decrease in circulating levels of cortisol and potentially hypocortisolism. Monitor and instruct patients on the signs and symptoms associated with hypocortisolism (e.g., weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia or hypoglycemia). SIGNIFOR dose reduction or interruption and/or adding a low-dose, short-term glucocorticoid may be necessary.
  • Hyperglycemia and Diabetes: Elevations in blood glucose levels have been seen in healthy volunteers and patients receiving SIGNIFOR. Pre-diabetes and diabetes were observed in the Phase III trial, with nearly all subjects developing worsening glycemia in the first 2 weeks of treatment. Cushing's disease patients with poor glycemic control (as defined by hemoglobin A1c (HbA1c) values >8% while receiving anti-diabetic therapy) may be at a higher risk of developing severe hyperglycemia and associated complications, e.g., ketoacidosis. Intensive glucose monitoring is recommended and may require initiation or adjustment of anti-diabetic treatment per standard of care. Glycemic status should be assessed prior to starting therapy with SIGNIFOR. Self-monitoring of blood glucose and/or fasting plasma glucose (FPG) assessments should be done every week for the first 2 to 3 months and periodically thereafter, as clinically appropriate, as well as over the first 2 to 4 weeks after any dose increase. Patients who were initiated on anti-diabetic therapy as a result of SIGNIFOR may require closer monitoring after discontinuation of SIGNIFOR, especially if the anti-diabetic therapy has a risk of causing hypoglycemia. If uncontrolled hyperglycemia persists, despite appropriate medical management, the dose of SIGNIFOR should be reduced or discontinued.
  • Bradycardia and QT Prolongation: Bradycardia has been reported with the use of SIGNIFOR. Patients with cardiac disease and/or bradycardia or patients taking drugs associated with bradycardia should be carefully monitored. SIGNIFOR is associated with QT prolongation and should be used with caution in patients who are at significant risk of developing QT prolongation. A baseline ECG is recommended prior to initiating SIGNIFOR and monitoring for an effect on the QTc interval is advisable. Hypokalemia and hypomagnesemia must be corrected prior to SIGNIFOR administration and should be monitored periodically during therapy.
  • Liver Test Elevations: Elevations of ALT or AST >3X ULN were observed in 5% of patients in the Phase III trial. Evaluate liver tests prior to and during treatment with SIGNIFOR. Monitoring of liver tests should be done after 1 to 2 weeks on treatment, then monthly for 3 months, and every 6 months thereafter. If elevated liver test values are confirmed or rising, SIGNIFOR treatment should be interrupted. If resolution of abnormalities to normal or near normal occurs, resuming treatment with SIGNIFOR may be done cautiously, with close observation, and only if some other likely cause has been found.
  • Cholelithiasis: Cholelithiasis has been frequently reported in clinical studies with SIGNIFOR. Ultrasonic examination of the gallbladder before, and at 6- to 12-month intervals during treatment with SIGNIFOR is recommended.
  • Monitoring for Deficiency of Pituitary Hormones: The pharmacological activity of SIGNIFOR mimics that of somatostatin; therefore, inhibition of pituitary hormones other than ACTH may occur. Monitoring of pituitary function prior to initiation of SIGNIFOR and periodically during treatment should be considered. Patients who have undergone transsphenoidal surgery and pituitary irradiation are particularly at increased risk for deficiency of pituitary hormones.

Adverse Reactions:

The most common adverse reactions (frequency ≥20% in either group) occurring in patients receiving SIGNIFOR in clinical trials were:

  • Diarrhea (59%), nausea (58%), hyperglycemia (43%), cholelithiasis (30%), headache (29%), abdominal pain (25%), fatigue (24%), and diabetes mellitus (20%).

Drug Interactions:

  • Caution is required when co-administering SIGNIFOR with drugs that may prolong the QT interval.
  • The following drugs may require monitoring and possible dose adjustments when used with SIGNIFOR: cyclosporine, bromocriptine.

Please see full Prescribing Information.