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.

Safety Profile

Warnings and Precautions

  • Treatment with SIGNIFOR may lead to decreases in circulating levels of cortisol resulting in biochemical and/or clinical hypocortisolism. SIGNIFOR dose reduction or interruption and/or adding low-dose short-term glucocorticoid therapy may be necessary.
  • Hyperglycemia and diabetes occurs with initiation of SIGNIFOR therapy; intensive glucose monitoring is recommended and may require initiation or adjustment of anti-diabetic treatment per standard of care.
  • 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.
  • Liver test elevations are associated with SIGNIFOR use. Liver tests are recommended prior to and during treatment with SIGNIFOR.
  • Cholelithiasis is associated with SIGNIFOR use. Perform gallbladder ultrasounds before and at 6- and 12- month intervals.
  • Inhibition of pituitary hormones may occur with SIGNIFOR treatment. Monitoring of pituitary function should occur prior to initiation of therapy and periodically during treatment with SIGNIFOR.

See additional safety highlights below

Phase III Study Safety Profile

  • In the Phase III trial, adverse reactions were reported in 98% of patients1
    • — Serious adverse events were reported in 25% of patients
  • The most common adverse reactions (frequency ≥20% in either group) were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes mellitus1
  • There were no deaths during the study1
  • Adverse events leading to study discontinuation were reported in 17% of patients1

ADVERSE REACTIONS (FREQUENCY ≥20%)1

 SIGNIFOR
0.6 mg bid
n=82
SIGNIFOR
0.9 mg bid
n=80
Overall
N=162
Diarrhea 48 (59) 46 (58) 94 (58)
Nausea 38 (46) 46 (58) 84 (52)
Hyperglycemia 31 (38) 34 (43) 65 (40)
Cholelithiasis 25 (30) 24 (30) 49 (30)
Headache 23 (28) 23 (29) 46 (28)
Abdominal pain 19 (23) 20 (25) 39 (24)
Fatigue 12 (15) 19 (24) 31 (19)
Diabetes mellitus 13 (16) 16 (20) 29 (18)

See full adverse reactions table in full Prescribing Information.

References:

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

Hyperglycemia

Signs and symptoms of hyperglycemia include1:

  • Excessive thirst
  • High urine output
  • Increased appetite with weight loss
  • Tiredness

During treatment as recommended:

  • Self-monitoring of blood glucose should be done before and during SIGNIFOR® (pasireotide) Injection treatment
  • Start the patient on or adjust anti-diabetic medication if an elevation in blood sugar levels occurs
  • Consider dose reduction or discontinue SIGNIFOR treatment if hyperglycemia cannot be controlled despite medical management2
  • Offer nutrition and lifestyle counselling as part of overall treatment regimen1

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.

References:

  1. National Institute of Diabetes and Digestive and Kidney Diseases. National Digestive Diseases Information Clearinghouse [NDDIC]: Your Guide to Diabetes: Type 1 and Type 2 Dec 2013. Available at http://diabetes.niddk.nih.gov/dm/pubs/type1and2/YourGuide2Diabetes_508.pdf.
  2. 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.