Preparation & Administration of Ipilimumab CA184-169 Feb 2012 revision

Preparation of Ipilimumab for Infusion, 5 mg/mL Handling Precautions As with all injectable drugs, care should be taken when handling and preparing ipilimumab. Whenever possible, ipilimumab should be prepared in a laminar flow hood or safety cabinet using standard precautions for the safe handling of intravenous agents applying aseptic technique. Latex gloves are required.   If ipilimumab concentrate or solution comes in contact with skin or mucosa, immediately and thoroughly wash with soap and water. After final drug reconciliation, unused ipilimumab solution should be disposed at the site following procedures for the disposal of anticancer drugs. Supplies The supplies needed for ipilimumab preparation and administration include the following items: 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP Calibrated syringes Infusion containers (PVC (polyvinyl chloride), non-PVC/non-DEHP (di-(2-ethylhexyl) phthalate) or glass containers). Filtered extension set with standard injections site 16 inch low protein binding with 0.2 µm to 1.2 µm in-line polyethersulfone or 1.2 µm positively charged nylon filter. Recommended Storage and Use Conditions Ipilimumab injection may be stored undiluted, 50 mg/vial (5 mg/mL) or 200 mg/vial (5 mg/mL), or following dilution in 0.9% Sodium Chloride Injection, (USP) or 5% Dextrose Injection (USP) in PVC, non-PVC/ or glass containers for up to 24 hours in the refrigerator (2°C to 8°C) or at room temperature/room light. For longer storage, ipilimumab should be kept refrigerated (2C to 8C) with protection from light. Ipilimumab injection must not be frozen. Partially used vials or empty vials of Ipilimumab Injection should be discarded at the site according to appropriate drug disposal procedures. For further information, please refer to the Investigator Brochure.

Steps for Preparation of Ipilimumab for Infusion, 5 mg/mL Preparation of Ipilimumab Solution 1. As ipilimumab is stored long term at refrigerated temperatures (2-8ºC) and protected from light, allow the appropriate number of vials of ipilimumab to stand at room temperature for approximately five minutes. 2. Aseptically withdraw the required volume of ipilimumab solution into a syringe. Insert the needle at an angle into the ipilimumab vial by placing the needle – bevel side down – against the glass, with the tip touching the neck of the vial. The initial solution concentration is 5 mg/mL. [Note: A sufficient excess of ipilimumab is incorporated into each vial to account for withdrawal losses]. 3. Ensure that the ipilimumab solution is clear colorless, essentially free from particulate matter on visual inspection. If multiple vials are needed for a subject, it is important to use a separate sterile syringe and needle for each vial to prevent problems such as dulling of needle tip, stopper coring, repeated friction of plunger against syringe barrel wall, etc. Do not draw into each vial more than once. Discard partially used vials or empty vials. Preparation of Ipilimumab for Infusion 5. Ipilimumab solution should be added to an appropriate size infusion bag to accommodate the calculated final volume. When calculating the amount of IP needed for the individual drug preparation, always use the actual weight of the study participant including decimals. However, when entering the subject’s weight into IVRS, enter the weight in kilograms rounded to one decimal point in order to receive vial assignments for dosing. Use the * key as the decimal point when entering the subject’s weight in IVRS. For example, a weight of 45.3 Kg is entered into IVRS as 45*3. Total dose should be calculated using the most recent subject weight; if weight on dosing day differs by 10% from prior weight used to calculate dosing, the dose should be recalculated and study drug adjusted accordingly.

Steps for Preparation of Ipilimumab for Infusion, 5 mg/mL (Continued) All infusion bags should be further diluted to a final volume of 250 mL in order to maintain the study blind: Dilute with 0.9% Sodium Chloride Injection or 5% Dextrose Injection, to prepare a diluted solution with a final volume of 250mL. Mix diluted solution by gentle inversion. Store either the diluted final solutions in either PVC or non PVC or glass containers for no more than 24 hours under refrigeration (2 °C to 8 °C, 36-46 °F) or at room temperature (20-25 °C, 68-77 °F). Drug should be completely delivered to subject within 24 hours of preparation, including preparation time, transit time and infusion time. Calculation examples 3mg/kg ipilimumab arm: Pt weight = 64.42 Kg; Pt weight to be specified in IVRS = 64.4 Kg (enter weight to one decimal point) Pt weight for preparation of Ipilimumab infusion: 64.42kg x 3mg/kg = 193.26mg dose 193.26mg dose using 5mg/mL solution = 38.65mL of ipilimumab solution Dilute with 211.35mL of NS or D5W to a final volume of infusion 250mL  10mg/kg ipilimumab arm: 64.42kg x 10mg/kg = 644.2mg dose 644.2 mg dose using 5mg/mL solution = 128.84 mL of ipilimumab solution Dilute with 121.16mL of NS or D5W to a final volume of infusion 250mL 6. Mix by GENTLY inverting several times. DO NOT shake. 7. Visually inspect the final solution. If the initial diluted solution or final dilution for infusion is not clear or contents appear to contain precipitate, the solution should be discarded. Ipilimumab should be administered under the supervision of a physician experienced in the use of intravenous (IV) agents. Ipilimumab is administered as an IV infusion only.

Administration of Ipilimumab Injection 5 mg/mL   Administration Guidelines Ensure that informed consent has been documented as required by the institution/agency. Explain the procedure to the study participant. Prepare the study participant for the ipilimumab infusion. Administer the drug solution using a volumetric pump at the protocol-specific doses and rates through a PVC IV solution infusion set Ensure the IV line is patent. A small gauge needle (21 or 23 gauge) is adequate to infuse ipilimumab solutions. Administer ipilimumab as an IV drip over a period of 90 minutes with a 0.2 μm to 1.2 μm in-line polyethersulfone or 1.2 μm positively charged nylon filter. Maintain extravasations precaution throughout the infusion. Assess the IV line frequently for patency during the infusion. Immediately after the infusion is complete, flush with an adequate amount of 0.9% Sodium Chloride injection (USP) or 5% Dextrose injection (USP) to completely flush the residual fluid (dead space) in your administration set (approximately 30-50mL); this will ensure that all active drug is delivered to the study participant. Safely discard any unused portion of the infusion solution. Do not store for reuse.