Important Safety Information

Liver test elevations are associated with SIGNIFOR use. Liver tests are recommended prior to and during treatment with SIGNIFOR.

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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.

Dosing & Administration

Dosing & Administration

THE RECOMMENDED INITIAL DOSE IS EITHER 0.6 mg OR 0.9 mg TWICE A DAY1

  • The recommended dosage range of SIGNIFOR is 0.3 to 0.9 mg by subcutaneous injection twice a day. Titrate dose based on response and tolerability
  • Patients should be evaluated for a treatment response (clinically meaningful reduction in 24-hour urinary-free cortisol (UFC) levels and/or improvement in signs or symptoms of the disease) and should continue receiving therapy with SIGNIFOR as long as benefit is derived
    • — Maximum UFC reduction is typically seen by 2 months of treatment
  • For patients who are started on 0.6 mg twice a day, a dosage increase to 0.9 mg twice a day may be considered based on response to treatment, as long as the 0.6 mg dosage is well tolerated by the patient

References:

  1. SIGNIFOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.

Dose Adjustments

IMPORTANT SAFETY INFORMATION PRIOR TO DOSING1

  • Prior to the start of SIGNIFOR, patients should have baseline levels of fasting plasma glucose, hemoglobin A1c, liver tests, baseline electrocardiogram, and gallbladder ultrasound. Patients should also have baseline potassium and magnesium levels checked
  • Treatment of patients with poorly controlled diabetes mellitus should be intensively optimized with anti-diabetic therapy prior to starting SIGNIFOR

DOSE REDUCTION RECOMMENDATIONS1

  • Management of suspected adverse reactions may require temporary dose reduction of SIGNIFOR
    • — Dose reduction by 0.3 mg bid decrements per injection is suggested

TREATMENT CONSIDERATIONS1

  • The recommended initial dosage for patients with moderate hepatic impairment (Child-Pugh B) is 0.3 mg twice a day, and maximum dosage is 0.6 mg twice a day
  • SIGNIFOR should not be used in patients with severe hepatic impairment (Child-Pugh C)

References:

  1. SIGNIFOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.

Dosing & Administration Video

SIGNIFOR Dosing and Administration for Cushing's Disease Video

 

SIGNIFOR is administered subcutaneously by self-injection into the top of the thigh or abdomen.

SIGNIFOR should be clear and colorless. Prior to injection, patients should visually inspect the product for particulate matter and discoloration.

The successful preparation and administration of SIGNIFOR is dependent on utilizing the proper techniques throughout the process.

Following each step shown in this video will ensure the correct administration.

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.

See additional safety highlights below

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.