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.
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
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
Learn how pituitary adenomas dysregulate the HPA-feedback loop, resulting in an excess of ACTH secretion.
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:
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 test||Level 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|
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.
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
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
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
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:
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
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
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
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 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
SIGNIFOR® (pasireotide) Injection, for subcutaneous use
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:
The most common adverse reactions (frequency ≥20% in either group) occurring in patients receiving SIGNIFOR in clinical trials were:
Please see full Prescribing Information.