IMPORTANT SAFETY INFORMATION

Warnings and Precautions: Hyperglycemia and Diabetes: SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. Patients with poor baseline glycemic control are at…+

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INDICATION: SIGNIFOR® LAR (pasireotide) for injectable suspension, for intramuscular use is a somatostatin analog indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.

Safety Profile

Warnings and Precautions Profile

  • Hyperglycemia and Diabetes: Sometimes severe. Monitor glucose levels periodically during therapy. Monitor glucose levels more frequently in the months that follow initiation or discontinuation of SIGNIFOR® LAR (pasireotide) therapy and following SIGNIFOR LAR dose adjustment. Use anti-diabetic treatment if indicated per standard of care.
  • Bradycardia and QT Prolongation: Use with caution in at-risk patients; Evaluate ECG and electrolytes prior to dosing and periodically while on treatment.
  • Liver Test Elevations: Evaluate liver enzyme tests prior to and during treatment.
  • Cholelithiasis: Monitor periodically.
  • Pituitary Hormone Deficiency(ies): Monitor for occurrence periodically and treat if clinically indicated.

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Adverse Reaction Profile

Adverse reactions occurring in ≥5% of patients exposed to SIGNIFOR® LAR (pasireotide) for injectable suspension in patients with acromegaly naive to drug therapy1:

Adverse Reaction TypeSIGNIFOR® LAR (40-60 mg)
(%)
N=178
Active Comparator (%) N=180
Hyperglycemia Related Adverse Reactions
Hyperglycemia 29 8
Diabetes mellitusa 26 4
Blood glucose increased 8 2
Glycosylated hemoglobin increased 6 2
Hypoglycemia 5 7
Gastrointestinal Related Adverse Reactions
Diarrhea 39 45
Abdominal pain 18 22
Nausea 14 22
Abdominal distension 12 12
Vomiting 8 7
Abdominal pain upper 6 8
Hepatobiliary Related Adverse Reactions
Cholelithiasis 26 36
Cardiac Related Adverse Reactions
Sinus bradycardiab 10 7
Hypertension 8 7
Nervous System Related Adverse Reactions
Headache 19 26
Dizziness 10 11
Skin Related Adverse Reactions
Alopecia 18 19
Infections Related Adverse Reactions
Nasopharyngitis 16 16
Influenza 8 4
Upper respiratory tract infection 7 3
Cough 5 8
Laboratory Related Adverse Reactions
Blood creatine phosphokinase increased 13 12
Alanine aminotransferase increased 8 4
Aspartate aminotransferase increased 6 4
Weight decreased 5 4
General and Injection Site Related Adverse Reactions
Fatigue 10 10
Injection site reactionc 7 7
Musculoskeletal and Connective Tissue Related Adverse Reactions
Arthralgia 10 12
Back pain 8 11
Pain in extremity 7 4
Blood Related Adverse Reactions
Anemia 6 6

a Diabetes mellitus includes the following preferred terms (PTs): Diabetes mellitus and type 2 diabetes mellitus
b Sinus bradycardia includes the following PTs: Bradycardia and sinus bradycardia
c Injection site reaction related AEs includes the following PTs: Injection site pain, Injection site reaction, Injection site haematoma, Injection site pruritus, Injection site swelling, Injection site erythema

Adverse reactions occurring in ≥5% of patients exposed to SIGNIFOR LAR for injectable suspension in patients with acromegaly inadequately controlled at baseline on other somatostatin analogs1:

Adverse Drug ReactionsSIGNIFOR® LAR (40 mg)
(%)
N=63
SIGNIFOR® LAR (60 mg)
(%)
N=62
Active Comparators
(%)
N=66
Hyperglycemia Related Adverse Reactions
Hyperglycemia 33 30 14
Diabetes mellitusa 21 31 9
Blood glucose increased 5 7 0
Hypoglycemia 3 7 0
Gastrointestinal Related Adverse Reactions
Diarrhea 16 19 5
Abdominal pain 8 8 3
Nausea 3 7 3
Hepatobiliary Related Adverse Reactions
Cholelithiasis 10 13 14
Cardiac Related Adverse Reactions
Atrioventricular block first degree 6 0 0
Nervous System Related Adverse Reactions
Headache 14 3 5
Dizziness 8 2 3
Skin and Subcutaneous Tissue Related Adverse Reactions
Alopecia 2 7 0
Infections Related Adverse Reactions
Nasopharyngitis 6 11 3
Blood Related Adverse Reactions
Anemia 6 3 3

aDiabetes mellitus includes the following PTs: diabetes mellitus and type 2 diabetes mellitus

Adverse Reaction Management

Hyperglycemia1,2

SIGNIFOR® LAR (pasireotide) for injectable suspension can cause increases in blood glucose levels which are sometimes severe. In the study of patients with acromegaly, five patients naive to drug therapy exposed to SIGNIFOR LAR (two of whom were normoglycemic at baseline) were hospitalized for blood glucose in the range of 359-506 mg/dL and none in the active comparator group. Two additional patients who had received active comparator in the main trial and were switched to SIGNIFOR LAR in the extension trial were hospitalized for elevated glucose levels while on SIGNIFOR LAR treatment during the extension; one of those patients developed diabetic ketoacidosis. Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia.

In the clinical development program, treatment with SIGNIFOR LAR caused an increase in the incidence of diabetes and pre-diabetes. A majority of patients, including those with normal glucose tolerance, pre-diabetes and diabetes experienced increased glucose levels within the first 2 to 3 months of treatment with SIGNIFOR LAR. In the drug-naive patient trial, the prevalence of diabetes increased from 30% at baseline to 60% at month 12. In the trial evaluating patients previously treated with somatostatin analogs, the prevalence of diabetes increased from 71% at baseline to 87% at month 6 in patients treated with SIGNIFOR LAR 40 mg and from 60% to 84% in patients treated with SIGNIFOR LAR 60 mg.

Fasting plasma glucose and hemoglobin A1c should be assessed prior to starting treatment with SIGNIFOR LAR. In patients with poorly controlled diabetes mellitus, anti-diabetic treatment should be optimized before SIGNIFOR LAR treatment is started. Blood glucose monitoring should be done weekly for the first three months after initiating SIGNIFOR LAR and the first four to six weeks after dose increases. Periodic monitoring should continue thereafter, as clinically appropriate.

Patients who develop significant hyperglycemia on SIGNIFOR LAR may require initiation of anti-diabetic therapy(ies) or adjustment in the dose or type of anti-diabetic therapy(ies) per standard of care. The optimal treatment for the management of SIGNIFOR LAR-induced hyperglycemia is not known. If hyperglycemia cannot be controlled despite medical management, the dose of SIGNIFOR LAR should be reduced or SIGNIFOR LAR should be discontinued.

After treatment discontinuation, fasting plasma glucose and hemoglobin A1c should be assessed if indicated. Patients on anti-diabetic therapy discontinuing SIGNIFOR LAR may require more frequent blood glucose monitoring and anti-diabetic drug therapy dose adjustment to mitigate the risk of hypoglycemia.

SIGNIFOR LAR and Blood Glucose

SIGNIFOR LAR (pasireotide) FOR INJECTABLE SUSPENSION: BLOOD GLUCOSE

Tony Heaney MD – Associate Professor, David Geffen School of Medicine, University of California, Los Angeles (UCLA)
Dr. Heaney discusses the potential mechanism by which SIGNIFOR LAR (pasireotide) for injectable suspension may affect blood glucose levels in patients with acromegaly as well as the approaches for the management of elevated blood glucose associated with SIGNIFOR LAR treatment.

References:

  1. SIGNIFOR LAR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2014
  2. American Diabetes Association. Standards of medical care in diabetes-2016. Diabetes Care. 2016;39 (suppl 1): S1-S112.

SIGNIFOR® LAR (pasireotide) for injectable suspension, for intramuscular use

INDICATION

SIGNIFOR LAR is a somatostatin analog indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions:

  • Hyperglycemia and Diabetes: SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia.

    A majority of patients, including those with normal glucose tolerance, pre-diabetes and diabetes, experienced increased glucose levels within the first 2 to 3 months of treatment with SIGNIFOR LAR.

    Fasting plasma glucose and hemoglobin A1c should be assessed prior to starting treatment with SIGNIFOR LAR. In patients with poorly controlled diabetes mellitus, anti-diabetic treatment should be optimized before SIGNIFOR LAR treatment is started. Blood glucose monitoring should be done weekly for the first 3 months after initiating SIGNIFOR LAR and the first 4 to 6 weeks after dose increases. Periodic monitoring should continue thereafter, as clinically appropriate.

    Patients who develop significant hyperglycemia on SIGNIFOR LAR may require initiation of anti-diabetic therapy(ies) or adjustment in the dose or type of anti-diabetic therapy(ies) per standard of care. The optimal treatment for the management of SIGNIFOR LAR-induced hyperglycemia is not known. If hyperglycemia cannot be controlled, despite medical management, the dose of SIGNIFOR LAR should be reduced or discontinued.

    After treatment discontinuation, fasting plasma glucose and hemoglobin A1c should be assessed if indicated. Patients on anti-diabetic therapy discontinuing SIGNIFOR LAR may require more frequent blood glucose monitoring and anti-diabetic dose adjustment to mitigate the risk of hypoglycemia.

  • Bradycardia and QT Prolongation

    Bradycardia

    Bradycardia has been reported with the use of SIGNIFOR LAR. Patients with cardiac disease and/or risk factor for bradycardia, such as history of clinically significant bradycardia, high-grade heart block, or concomitant use of drugs associated with bradycardia, should be monitored. Adjustments in the dose of drugs known to slow the heart rate (e.g., beta-blockers, calcium channel blockers) and correction of electrolyte disturbances, may be necessary when initiating or during the course of SIGNIFOR LAR treatment.

    QT Prolongation

    SIGNIFOR LAR is associated with QT prolongation and should be used with caution in patients who are at significant risk of developing prolongation of the QT interval. A baseline ECG is recommended prior to initiating therapy with SIGNIFOR LAR and periodically while on treatment. Hypokalemia or hypomagnesemia must be corrected prior to initiating SIGNIFOR LAR and should be monitored periodically during therapy.

  • Liver Test Elevations

    Increases in liver enzymes have been observed with SIGNIFOR LAR. ALT or AST elevation greater than 3 times the upper limit of normal (ULN) were observed in 3% of patients and ALT or AST elevation greater than 5 times the upper limit of normal (ULN) were observed in 1% of patients treated with SIGNIFOR LAR.

    Assessment of liver function is recommended prior to treatment with SIGNIFOR LAR, and after the first 2 to 3 weeks, then monthly for 3 months. Thereafter, liver function should be monitored as clinically indicated. Patients who develop increased transaminase levels should be monitored until values return to pre-treatment levels. Treatment with SIGNIFOR LAR should be discontinued if signs or symptoms suggestive of clinically significant liver impairment develop.

  • Cholelithiasis: Cholelithiasis was reported in up to 33% of patients treated with SIGNIFOR LAR in clinical trials. Patients should be monitored periodically.
  • Pituitary Hormone Deficiency(ies): Suppression of pituitary hormones other than GH/IGF-1, may occur on SIGNIFOR LAR. Monitoring pituitary function (e.g., thyroid, adrenal, gonadal) prior to initiation of therapy with SIGNIFOR LAR, as well as periodically during treatment, as clinically appropriate, is recommended. Patients should be monitored for and instructed on the signs and symptoms of adrenal insufficiency during therapy. If adrenal insufficiency is suspected it should be confirmed and treated per standard of care with exogenous glucocorticoids at replacement doses.

Adverse Reactions

Adverse reactions associated with SIGNIFOR LAR and occurring in ≥20% of patients were diarrhea, cholelithiasis, hyperglycemia and diabetes mellitus.

Drug Interactions

Caution is advised when co-administering drugs that prolong the QT interval with SIGNIFOR LAR

The following drugs may require monitoring and possible dose adjustment when used with SIGNIFOR LAR: cyclosporine and bromocriptine

Contraindications

None

Please see full Prescribing Information