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.

Dosing & Administration

Dosing

The recommended initial dose of SIGNIFOR® LAR (pasireotide) for injectable suspension is 40 mg administered by intramuscular injection once every 4 weeks (every 28 days).

Download Patient Guide to SIGNIFOR® LAR

Dose Adjustment and Monitoring

The dose may be increased to a maximum of 60 mg for patients who have not normalized growth hormone (GH) and/or age- and sex-adjusted insulin-like growth factor-1 (IGF-1) levels after 3 months of treatment with SIGNIFOR® LAR at 40 mg and who tolerate this dose.

Management of SIGNIFOR® LAR-related adverse reactions or over-response to treatment (age- and sex-adjusted IGF-1 less than the lower limit of normal) may require dose reduction. The dose may be decreased, either temporarily or permanently, by 20 mg decrements.

Related Safety Information

Drug Interactions: Caution is required when co-administering SIGNIFOR® LAR (pasireotide) for injectable suspension with drugs that prolong QT interval, cyclosporine, and bromocriptine.

Dose Adjustment

Missed Dose

If a dose of SIGNIFOR® LAR (pasireotide) for injectable suspension is missed and the patient returns prior to the next scheduled dose, a dose may be given up to but no later than 14 days prior to the next dose.

Recommended Baseline Evaluations Prior to Initiation of SIGNIFOR® LAR

Prior to the initiation of SIGNIFOR® LAR, it is recommended that patients have the following baseline evaluations:


  • Fasting plasma glucose and hemoglobin A1c

  • Liver tests

  • Electrocardiogram, serum potassium and serum magnesium levels


Patients with poorly controlled diabetes mellitus who have inadequate glucose control should have anti-diabetic therapy optimized prior to starting SIGNIFOR® LAR.

Hepatic Impairment

Liver enzyme test elevations are associated with SIGNIFOR® LAR use. Liver function tests are recommended prior to and during treatment 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 pretreatment levels. Treatment with SIGNIFOR® LAR should be discontinued if signs or symptoms suggestive of clinically significant liver impairment develop.

Degree Of ImpairmentDose Adjustment
Mild (Child-Pugh class A) No dose adjustment required
Moderate (Child-Pugh class B) Initial dose is 20 mg every 4 weeks and maximum dose is 40 mg every 4 weeks
Severe (Child-Pugh class C) Avoid use of SIGNIFOR® LAR
 
Related Safety Information
 

Warnings and Precautions

Liver enzyme test elevations are associated with SIGNIFOR® (pasireotide) for injectable suspension use. Liver function tests are recommended prior to and during treatment 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 pretreatment levels. Treatment with SIGNIFOR® LAR should be discontinued if signs or symptoms suggestive of clinically significant liver impairment develop.

Cholelithiasis is associated with SIGNIFOR® LAR use. Patients should be monitored periodically.

Inhibition of pituitary hormones other than GH/IGF-1, may occur with SIGNIFOR® LAR treatment. Monitoring of pituitary function should occur prior to initiation of therapy and periodically during treatment with SIGNIFOR® LAR. Adrenal insufficiency may occur with SIGNIFOR® LAR treatment, which may require glucocorticoid therapy per standard of care.

References:

  1. SIGNIFOR LAR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2014

Administration

This video demonstrates the correct technique for reconstituting, or mixing, SIGNIFOR® LAR (pasireotide) for injectable suspension.

 

  • SIGNIFOR® LAR must be reconstituted by a trained health care professional immediately before use
  • SIGNIFOR® LAR must be inspected visually before use. The suspension should appear free of foreign particulates and should be homogeneous after mixing
  • SIGNIFOR® LAR must be administered by a trained health care professional only by intramuscular injection in the right or left gluteus immediately after reconstitution. SIGNIFOR® LAR must never be administered intravenously

PAY PARTICULAR ATTENTION:

There are two critical steps in the reconstitution of SIGNIFOR® LAR. Not following these two steps could result in failure to deliver the drug appropriately.

  • 1) The injection kit must reach room temperature (see Step 1 below). Remove the injection kit from the fridge and let the kit stand at room temperature for a minimum of 30 minutes before reconstitution, but do not exceed 24 hours.
  • 2) After adding the diluent solution, shake the vial moderately in a horizontal direction for a minimum of 30 seconds until uniform suspension is formed (see Step 4 below).
1
Remove the SIGNIFOR® LAR for injectable suspension kit from refrigerated storage.
 
PAY PARTICULAR ATTENTION: It is essential to start the reconstitution process only after the injection kit has reached room temperature. Let the kit stand at room temperature for at least 30 minutes before starting reconstitution, but not more than 24 hours.
 
Note: The kit can be re-refrigerated if needed.
Step 1
2
Remove the plastic cap from the vial and clean the rubber stopper with an alcohol wipe.
 
Remove the lid film of the vial adapter packaging, but do NOT remove the vial adapter from its packaging.
 
Holding the vial adapter packaging, position the vial adapter on top of the vial and push it fully down so that it snaps in place. You will hear an audible "click" when the vial adapter snaps in place.
 
Lift the packaging off the vial adapter with a vertical movement.
Step 2
3
Remove the cap from the syringe prefilled with diluent solution and screw the syringe onto the vial adapter.
 
Slowly push the plunger all the way down to transfer all the diluent solution in the vial.
Step 3
4
ATTENTION: Keep the plunger pressed and shake the vial moderately in a horizontal direction for a minimum of 30 seconds so that the powder is completely suspended. Repeat moderate shaking for another 30 seconds if the powder is not completely suspended.
Step 4
5
Turn the syringe and vial upside down, slowly pull the plunger back and draw the entire content from the vial into the syringe.
 
Unscrew the syringe from the vial adapter.
Step 5
6
Screw the safety injection needle onto the syringe.
 
Pull the protective cover straight off the needle.
 
To avoid sedimentation and maintain a uniform suspension, you may gently shake the syringe.
 
Gently tap the syringe to remove any visible bubbles and expel them from the syringe.
 
The reconstituted SIGNIFOR® LAR is now ready for immediate administration.
Step 6
7
SIGNIFOR® LAR must only be given by intramuscular injection and NEVER intravenously.
 
Prepare the injection site by wiping with an alcohol wipe.
 
Insert the needle fully into the left or right gluteus at a 90° angle to the skin.
 
Slowly pull back the plunger to check that no blood vessel has been penetrated (reposition if a blood vessel has been penetrated).
 
Slowly depress the plunger until the syringe is empty. Withdraw the needle from the injection site and activate the safety guard (as shown in Step 8).
Step 7
8
Activate the safety guard over the needle using one of the 2 methods shown:
  • either press the hinged section of the safety guard down onto a hard surface (figure A),
  • or push the hinge forward with your finger (figure B).
 
An audible "click" will confirm proper activation of the safety guard.
 
Dispose of syringe immediately in a sharps container.
 
Any unused product or waste material should be disposed of in accordance with local requirements.
Step 8

INTRAMUSCULAR INJECTION TECHNIQUES FOR THE ADMINISTRATION OF SIGNIFOR LAR

Refresh your knowledge of intramuscular (IM) techniques to enhance patient comfort and ensure successful IM injection of Signifor LAR

Download Intramuscular Injection Techniques for the Administration of Signifor LAR

Please see Dosing Section of Full Prescribing Information for detailed administration instructions

 
Related Safety Information
 

Warnings and Precautions

Hyperglycemia (sometimes severe) and diabetes may occur with SIGNIFOR® LAR therapy.

Glucose monitoring is recommended, especially in the months that follow initiation, dose adjustment or discontinuation of SIGNIFOR® LAR therapy and may require initiation or adjustment of anti-diabetic treatment per standard of care.

Treatment with SIGNIFOR® LAR may lead to bradycardia and QT prolongation. Use with caution in at-risk patients. ECG testing and electrolyte monitoring is recommended prior to dosing and during treatment. Hypokalemia or hypomagnesemia must be corrected prior to initiating SIGNIFOR® LAR and should be monitored periodically during therapy.

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