Signifor Lar (Pasireotide)

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. (
  1.1     Acromegaly

  SIGNIFOR LAR is 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.
  )
• Patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative. (
  1.2     Cushing's Disease

  SIGNIFOR LAR is indicated for the treatment of patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.
  )

• Evaluate fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), liver enzyme tests, electrocardiogram (ECG), serum magnesium, and serum potassium prior to starting. (
  2.1     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 (FPG) and hemoglobin A1c (HbA1c)
    [see Warnings and Precautions (5.1)]
  • Liver tests
    [see Warnings and Precautions (5.3)]
  • Electrocardiogram (ECG), serum potassium and serum magnesium levels
    [see Warnings and Precautions (5.2)]

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

  [see Warnings and Precautions (5.1)]

  .
  )
• Optimize glucose control in patients with poorly controlled diabetes mellitus prior to starting. (
  2.1     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 (FPG) and hemoglobin A1c (HbA1c)
    [see Warnings and Precautions (5.1)]
  • Liver tests
    [see Warnings and Precautions (5.3)]
  • Electrocardiogram (ECG), serum potassium and serum magnesium levels
    [see Warnings and Precautions (5.2)]

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

  [see Warnings and Precautions (5.1)]

  .
  )
• Must be administered by a health care professional only by intramuscular injection in the right or left gluteus immediately after reconstitution. (
  2.2     Important Administration Instructions

  SIGNIFOR LAR must be reconstituted by a trained healthcare professional immediately before use. Illustrations on reconstitution are found in Instructions for Use

  [see Dosage and Administration (2.6)]

  .

  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 healthcare professional only by intramuscular injection in the right or left gluteus immediately after reconstitution. SIGNIFOR LAR must never be administered intravenously.
  )
• Initial Dose:
  • Acromegaly: The initial dose is 40 mg by intramuscular injection once every 4 weeks (every 28 days). (
    2.3     Recommended Initial Dose

    Acromegaly

    The recommended initial dose of SIGNIFOR LAR for the treatment of acromegaly is 40 mg administered by intramuscular injection once every 4 weeks (every 28 days)

    [see Dosage and Administration (2.6)].

    Cushing's Disease

    The recommended initial dose of SIGNIFOR LAR for the treatment of Cushing's disease is 10 mg administered by intramuscular injection once every 4 weeks (every 28 days)

    [see Dosage and Administration (2.6)].
    )
  • Cushing's Disease: The initial dose is 10 mg by intramuscular injection once every 4 weeks (every 28 days). (
    2.3     Recommended Initial Dose

    Acromegaly

    The recommended initial dose of SIGNIFOR LAR for the treatment of acromegaly is 40 mg administered by intramuscular injection once every 4 weeks (every 28 days)

    [see Dosage and Administration (2.6)].

    Cushing's Disease

    The recommended initial dose of SIGNIFOR LAR for the treatment of Cushing's disease is 10 mg administered by intramuscular injection once every 4 weeks (every 28 days)

    [see Dosage and Administration (2.6)].
    )
• Adjust dose based on response and tolerability. (
  2.4 Dose Adjustment and Monitoring

  Acromegaly

  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

  [see Warnings and Precautions (5)]

  .

  Cushing's Disease

  Following 4 months of treatment with the initial dose of 10 mg once every 28 days, the dose may be increased for patients who have not normalized 24-hour urinary free cortisol (UFC) and who tolerate this dose, up to a maximum dose of 40 mg once every 28 days.

  Management of suspected adverse reactions or over-response to treatment (e.g., cortisol levels less than the lower limit of the normal range or in the low part of the normal range in patients with symptoms suggestive of adrenal insufficiency) may require dose reduction to the previous tolerated dose, dose interruption, or drug discontinuation of SIGNIFOR LAR. For patients treated with 10 mg once every 28 days, the dose may be either interrupted or discontinued

  [see Warnings and Precautions (5)]

  .
  )
• Patients with Hepatic Impairment:
  • Child-Pugh B
    :
    • Acromegaly:
      Recommended initial dose is 20 mg once every 4 weeks and maximum dose is 40 mg once every 4 weeks (
      2.5 Dose in Patients With Hepatic Impairment

      For patients with moderately impaired hepatic function (Child-Pugh B)

      [see Use in Specific Populations (8.6)]

      :

      • Acromegaly: The recommended initial dose for acromegaly patients with moderately impaired hepatic function is 20 mg once every 4 weeks and the maximum recommended dose is 40 mg once every 4 weeks.
      • Cushing's Disease: The recommended initial dose for Cushing's disease patients with moderately impaired hepatic function is 10 mg once every 4 weeks and the maximum recommended dose is 20 mg once every 4 weeks.

      Avoid use in patients with severe hepatic impairment (Child-Pugh C)

      [see Use in Specific Populations (8.6)]

      .
      ,
      8.6     Hepatic Impairment

      Dose adjustment is not required in patients with mild impaired hepatic function (Child-Pugh A), but is required for patients with moderately impaired hepatic function (Child-Pugh B). The safety and efficacy of SIGNIFOR LAR have not been established in patients with severe hepatic impairment (Child-Pugh C). No dosage recommendation can be given for patients with severe hepatic impairment (Child-Pugh C)

      [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)]

      .
      )
    • Cushing's Disease:
      Recommended initial dose is 10 mg once every 4 weeks and maximum dose is 20 mg once every 4 weeks (
      2.5 Dose in Patients With Hepatic Impairment

      For patients with moderately impaired hepatic function (Child-Pugh B)

      [see Use in Specific Populations (8.6)]

      :

      • Acromegaly: The recommended initial dose for acromegaly patients with moderately impaired hepatic function is 20 mg once every 4 weeks and the maximum recommended dose is 40 mg once every 4 weeks.
      • Cushing's Disease: The recommended initial dose for Cushing's disease patients with moderately impaired hepatic function is 10 mg once every 4 weeks and the maximum recommended dose is 20 mg once every 4 weeks.

      Avoid use in patients with severe hepatic impairment (Child-Pugh C)

      [see Use in Specific Populations (8.6)]

      .
      ,
      8.6     Hepatic Impairment

      Dose adjustment is not required in patients with mild impaired hepatic function (Child-Pugh A), but is required for patients with moderately impaired hepatic function (Child-Pugh B). The safety and efficacy of SIGNIFOR LAR have not been established in patients with severe hepatic impairment (Child-Pugh C). No dosage recommendation can be given for patients with severe hepatic impairment (Child-Pugh C)

      [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)]

      .
      )
  • Child-Pugh C
    : Avoid use in these patients (
    2.5 Dose in Patients With Hepatic Impairment

    For patients with moderately impaired hepatic function (Child-Pugh B)

    [see Use in Specific Populations (8.6)]

    :

    • Acromegaly: The recommended initial dose for acromegaly patients with moderately impaired hepatic function is 20 mg once every 4 weeks and the maximum recommended dose is 40 mg once every 4 weeks.
    • Cushing's Disease: The recommended initial dose for Cushing's disease patients with moderately impaired hepatic function is 10 mg once every 4 weeks and the maximum recommended dose is 20 mg once every 4 weeks.

    Avoid use in patients with severe hepatic impairment (Child-Pugh C)

    [see Use in Specific Populations (8.6)]

    .
    ,
    8.6     Hepatic Impairment

    Dose adjustment is not required in patients with mild impaired hepatic function (Child-Pugh A), but is required for patients with moderately impaired hepatic function (Child-Pugh B). The safety and efficacy of SIGNIFOR LAR have not been established in patients with severe hepatic impairment (Child-Pugh C). No dosage recommendation can be given for patients with severe hepatic impairment (Child-Pugh C)

    [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)]

    .
    )
• Follow reconstitution and administration instructions. (
  2.6 Reconstitution and Intramuscular Injection Instructions

  After reconstitution of the SIGNIFOR LAR vial with the provided 2 mL diluent, the intramuscular injectable suspension will have a final concentration of:

  Strength per Vial	Final Concentration When Reconstituted (total product strength per total volume)	Final Concentration When Reconstituted (per mL)
  10 mg	10 mg/2 mL	5 mg/mL
  20 mg	20 mg/2 mL	10 mg/mL
  30 mg	30 mg/2 mL	15 mg/mL
  40 mg	40 mg/2 mL	20 mg/mL
  60 mg	60 mg/2 mL	30 mg/mL

  The entire contents of the reconstituted solution should be administered immediately.

  PAY PARTICULAR ATTENTION:

  There are 2 critical steps in the reconstitution of SIGNIFOR LAR. Not following these 2 steps could result in failure to deliver the drug appropriately .

  1) The injection kit must reach room temperature (see Step 1in Instructions for Use) . Remove the SIGNIFOR LAR injection kit from refrigerated storage 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 in Instructions for Use) .

  The following items are included in the injection kit

  :

  a) One vial containing SIGNIFOR LAR powder

  b) One prefilled syringe containing the diluent solution for reconstitution

  c) One vial adapter for drug product reconstitution

  d) One safety injection needle (20G x 1.5")

  Figure 1. Items Included in Injection Kit

  

  SIGNIFOR LAR suspension must only be reconstituted

  immediately

  before administration.

  Follow the directions in the Instructions for Use to ensure proper reconstitution of SIGNIFOR LAR before intramuscular injection.

  SIGNIFOR LAR should only be administered by a trained healthcare professional.

  Instructions for Use
  Step 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 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 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 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 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 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 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 8 Activate the safety guard over the needle using 1 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.

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  )

SIGNIFOR LAR for injectable suspension: 10 mg, 20 mg, 30 mg, 40 mg, or 60 mg of slightly yellow to yellow powder in a vial and 2 mL diluent.

• Females and Males of Reproductive Potential
  : Advise premenopausal females of the potential for an unintended pregnancy (
  8.3     Females and Males of Reproductive Potential

  Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in GH levels and normalization of IGF-1 in acromegalic females treated with pasireotide may lead to improved fertility.

  Similarly, the therapeutic benefits of a reduction or normalization of serum cortisol levels in female patients with Cushing's disease treated with pasireotide may also lead to improved fertility.
  )