Important Safety Information

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...

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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.

Efficacy

Trial Design

THE LARGEST PHASE III TRIAL ADDRESSES AN UNMET MEDICAL NEED IN THE TREATMENT OF CUSHING'S DISEASE

OBJECTIVE

  • A Phase III, multicenter, randomized study was conducted to evaluate the safety and efficacy of 2 dose 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 who had refused surgery1,2

STUDY DESIGN2

aAfter 3 months of treatment, patients with a mean 24-hour urinary free cortisol (UFC) ≤2.0 x the upper limit of normal (ULN) and below or equal to their baseline values continued blinded treatment at the randomized dose until Month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3 mg bid.2

  • Patients with a baseline 24-hour UFC >1.5 x ULN were randomized to receive a SIGNIFOR dosage of either 0.6 mg sc bid or 0.9 mg sc bid2
  • The majority of patients were female (78%) and had persistent or recurrent Cushing's disease despite pituitary surgery (83%) with a mean age of 40 years2
  • Mean baseline 24-hour UFC was higher in the 0.6 mg arm; 868 nmol/24 h for the 0.6 mg arm and 750 nmol/24 h for the 0.9 mg arm2

References:

  1. Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3  study of pasireotide in Cushing's disease. N Engl J Med. 2012;366(10):914-924.
  2. SIGNIFOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.

See additional safety highlights below

Primary Efficacy End Point

The proportion of patients who achieved normalization of mean 24-hour urinary free cortisol (UFC) levels (UFC ≤ULN) after 6 months of treatment without a dose increase1

SIGNIFOR: UFC NORMALIZATION IN PATIENTS WITH CUSHING'S DISEASE1

The percentages of patients with mean urinary free cortisol (mUFC) ≤ the upper limit of normal or ≥50% reduction from baseline, a less stringent end point than the primary end point, were 34% in the 0.6 mg bid and 41% in the 0.9 mg bid groups.1

OTHER CLINICAL END POINTS

DECREASES OBSERVED IN BLOOD PRESSURE1,2

Because the study allowed initiation of antihypertensive medication and dose increases in patients already receiving such medications, the individual contribution of SIGNIFOR or of antihypertensive medication adjustments cannot be clearly established.1

DECREASES OBSERVED IN WEIGHT, BODY MASS INDEX (BMI), AND WAIST CIRCUMFERENCE1

Individual patients showed varying degrees of improvement in Cushing's disease manifestations, but because of the variability in response and the absence of a control group in this trial, it is uncertain whether these changes could be ascribed to the effects of SIGNIFOR.1

References:

  1. SIGNIFOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.
  2. Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med.2012;366(10):914-924.

See additional safety highlights below

Urinary Free Cortisol Reductions

SIGNIFOR: DECREASES OBSERVED IN MEAN URINARY FREE CORTISOL (UFC)1

aOnly patients who completed 6 months of treatment are included in this analysis (n=110).1

References:

  1. SIGNIFOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.
  2. Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med.2012;366(10):914-924.

See additional safety highlights below

Changes in Urinary Free Cortisol

SIGNIFOR: UFC REDUCED IN THE MAJORITY OF PATIENTS IN BOTH DOSE GROUPS1

aChange in urinary free cortisol (UFC) at Month 6 of 103 patients with baseline and Month 6 UFC measurements, sorted by baseline UFC level. 103 out of 162 patients were in the study at Month 6. Reference line is the upper limit of normal (ULN) for UFC, which is 145 nmol/24 h.1

The percentages of patients with mUFC ≤ULN or ≥50% reduction from baseline, a less stringent end point than the primary end point, were 34% in the 0.6 mg bid group and 41% in the 0.9 mg bid groups.2

References:

  1. Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med. 2012;366(10):914-924.
  2. SIGNIFOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.

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.