1.1     Acromegaly

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.

 2.1     Important Administration Instructions

SIGNIFOR LAR must be reconstituted by a trained health care professional immediately before use. Illustrations on reconstitution are found below [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 health care professional only by intramuscular injection in the right or left gluteus immediately after reconstitution. SIGNIFOR LAR must never be administered intravenously.

 2.2     Recommended Initial Dose

The recommended initial dose of SIGNIFOR LAR is 40 mg administered by intramuscular injection once every 4 weeks (every 28 days) [see Dosage and Administration (2.6)].

 2.3     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 [see Adverse Reactions (6) and Clinical Studies ( 14)].

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)].

 2.4     Dose in Patients with Hepatic Impairment

The recommended initial dose for patients with moderately impaired hepatic function (Child-Pugh B) is 20 mg every 4 weeks and the maximum recommended dose is 40 mg every 4 weeks. Avoid use in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.6)].

 2.5     Recommended Baseline eva luations Prior to Initiation of SIGNIFOR LAR

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

• Fasting plasma glucose and hemoglobin A1c [see Warnings and Precautions (5.1)]
• Liver tests [see Warnings and Precautions (5.3)]
• Electrocardiogram, 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)].

 2.6     Reconstitution and Intramuscular Injection Instructions

After reconstitution of the 20 mg, 40 mg, or 60 mg SIGNIFOR LAR vials with the provided 2 mL diluent, the injectable suspension will have a final concentration of 10 mg/mL, 20 mg/mL and 30 mg/mL and should be delivered in its entirety.

The following items are included in the injection kit:

1. One vial containing SIGNIFOR LAR powder
2. One prefilled syringe containing the diluent solution for reconstitution
3. One vial adapter for drug product reconstitution
4. 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 instructions in the figures below to ensure proper reconstitution of SIGNIFOR LAR before intramuscular injection.

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

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 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 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.

2.7     Missed Dose

If a dose 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.