Donislecel

Transmission of Donor-Derived Infections : Monitor for signs of infection following infusion and treat accordingly. Panel Reactive Antibodies (PRA) : Product administration may elevate PRA and negatively impact candidacy for renal transplant. 5.1 Risks from Concomitant Immunosuppression Concomitant use of immunosuppression is required to maintain islet cell viability.

The T- and B-cell crossmatch assay is binary. T- and B-cell both need to be negative. 5.4 Transmission of Donor-Derived Infections There is a risk of communicable disease transmission from donor to recipient that exists for LANTIDRA. Monitor patients for signs of active infection following LANTIDRA infusion and treat appropriately if infection is suspected. 5.5 Panel Reactive Antibodies (PRA) Product administration may elevate PRA and negatively impact candidacy for renal transplant.

Consider benefit-risk of administering LANTIDRA to a patient who may require a renal transplant in the future.

Recommended Dose The recommended minimum dose is 5,000 EIN/kg for initial infusion and 4,500 EIN/kg for subsequent infusion in the same recipient. The maximum dose per infusion is dictated by the estimated tissue volume, which should not exceed 10 cc per infusion, and the total EIN present in the infusion bag (up to a maximum of 1 × 10 6 EIN per bag).

A second infusion may be performed if the patient does not achieve independence from exogenous insulin within one year of infusion or within one year after losing independence from exogenous insulin after a previous infusion. A third infusion may be performed using the same criteria as for the second infusion. There are no data regarding the effectiveness or safety for patients receiving more than three infusions.

Pre-procedural medications Provide pre-procedural induction immunosuppression 30 – 360 minutes prior to LANTIDRA infusion. Include the following, at the discretion of the treating physician who is experienced with management of immunosuppression regimens for islet cell transplantation: Non-depleting monoclonal anti-interleukin-2 (anti-IL-2) receptor antibody 120 minutes prior to islet infusion Note: In patients who are sensitized (hypersensitivity with a past history of anaphylactic reaction) to non-depleting monoclonal anti-interleukin-2 (anti-IL-2) receptor antibody therapies, a polyclonal, T-cell-depleting antibody should be used instead.

Calcineurin inhibitor Mammalian target of rapamycin (mTOR) inhibitor Tumor necrosis factor (TNF) blocker. Periprocedural antibiotic prophylaxis is recommended.

Preparation Keep LANTIDRA in the insulated container at 15°C to 25°C no longer than 48 hours from time of product release (See carton label and certificate of analysis). Dispose of any product not used within 48 hours. Do not irradiate. Select and prepare units under the direction of a medical professional who is experienced in islet infusion (transplantation).

Use LANTIDRA as supplied and without further dilution.

Administration Failure to follow these directions may result in damage and decreased viability of the islets. Do not administer with leukodepleting filters. To optimize viability, administer LANTIDRA as soon as possible after product release. LANTIDRA should be administered only by interventional radiologists and surgeons with experience in islet cell transplantation under aseptic conditions in an interventional radiology or operating suite.

Perform all steps aseptically. Use a 5 or 6 French angiographic catheter indicated for the delivery of drugs or other therapeutic fluids for infusion of LANTIDRA. Catheter length: 65 cm or less. Internal diameter: 0.97mm (0.038 inches) or greater. Use only sheaths and introducers in combination with a catheter with the specified dimensions listed above to deliver LANTIDRA.

Pre-Infusion Patient Preparation 1. Confirm the identity of the patient for the specified unit of LANTIDRA. 2. Confirm that the patient has received appropriate premedication [See Pre-procedural medication ] . 3. Confirm that appropriate medications and blood products are available to manage any potential emergencies, such as hemorrhage, portal vein thrombosis, allergic reactions, glycemic lability, bleeding, and pain. 4.

Confirm that the patient is hydrated adequately prior to infusion. 5. If indicated, administer a saline/glucose infusion and administer insulin using an intravenous insulin pump during the periprocedural period. Pre-Infusion LANTIDRA Preparation 6. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. a.

LANTIDRA is a cellular suspension (light yellow liquid with the presence of visible cellular aggregates). b. The Rinse Bag contains transplant media (light yellow liquid only with no cellular aggregates present). 7. Inspect the LANTIDRA infusion bag and the Rinse Bag for leaks and breaches of container integrity. 8. Ensure the connector between the LANTIDRA infusion bag and the Rinse Bag is secure and closed.

Note: If there are any product irregularities present or if the container appears damaged or otherwise compromised, do not infuse product and immediately notify the transplant physician/team and CellTrans at 1-800-500-1617 9. Gently agitate the LANTIDRA infusion bag to ensure that the islets are suspended and to prevent clumping.

Do not shake the bag, as this may damage the islets. Repeat gentle agitation periodically throughout the infusion process. 10. Remove the first drape bag and transfer the product to an infusion operator to remove the second drape bag. 11. Ensure that the intravenous tubing is closed, then connect the LANTIDRA infusion bag, fill the drip chamber, and open the roller clamp to fill the tubing and remove air.

LANTIDRA Infusion Procedure 12. Insert the catheter into the portal vein. 13. Once the catheter placement in the portal vein is confirmed, connect the intravenous tubing from the LANTIDRA infusion bag to the catheter using a Luer lock connector. 14. Infuse all infusion bags by gravity flow over approximately 30 minutes at rates ≤ 25 mL/kg/h. 15.

Flush the infusion lines periodically to clear them. 16. Do not administer LANTIDRA (islet cell product and rinse bag) through intravenous lines that contain any other medications or infusates other than physiological saline. 17. Reduce infusion rate if the fluid load is not tolerated. 18. Discontinue the infusion in the event of an allergic reaction or if the patient develops a moderate to severe infusion reaction. 19.

Once the islet infusion is complete, open the roller clamp on the Rinse Bag tubing to allow refilling and rinsing of the LANTIDRA infusion bag. Gently agitate the LANTIDRA infusion bag with small amounts of rinse solution to ensure that all cells have been administered. Repeat until the Rinse Bag is empty. 20. Withdraw the catheter tip from the main portal vein into the liver parenchyma until it lies within a few centimeters (cm) of the liver capsule.

Before withdrawing the catheter completely, manage hemostasis in the catheter track using standard practices to reduce the risk of bleeding. Monitoring during LANTIDRA Infusion Measure portal pressure during the infusion. Pause infusion if portal pressure rises above 22 mmHg and do not resume until it falls below 18 mmHg.

Terminate infusion if portal pressure remains above 22 mmHg for longer than 10 minutes. Monitor blood glucose levels every 15 minutes during the infusion and then every 30 minutes for the first 4 to 8 hours after infusion. Provide appropriate treatment if blood glucose levels fall below 70 mg/dL. Monitor blood glucose levels as needed once blood glucose levels have stabilized.

After the acute period (first 4 to 8 hours following infusion), continue to monitor blood glucose (laboratory, capillary blood glucose, or continuous glucose monitor). Only use blood glucose meters and continuous glucose monitoring systems labelled for use in the hospital. Monitor the patient for portal vein branch thrombosis.

Early diagnosis and prompt management with systemic heparinization may prevent clot propagation. However, anticoagulation therapy may lead to intra-abdominal hemorrhage requiring blood transfusion and surgical intervention. Post-Infusion Monitor the patient in hospital for a minimum of 24 hours. Perform an abdominal ultrasound and Doppler examination of the liver after catheter removal to detect portal vein thrombosis and intra-abdominal bleeding.

Repeat these examinations at least on days 1 and 7 post infusion procedure. Continue to monitor the patient for adverse reactions. Continue to monitor blood glucose levels following infusion and manage according to inpatient standard of care. Post-Infusion Medications Anti-infective medications: Administer Pneumocystis jirovecii pneumonia (PCP) and cytomegalovirus (CMV) prophylaxis immediately following infusion of LANTIDRA and continue treatment as described in the prescribing information for the specific anti-infective medications.

A non-depleting monoclonal anti-IL-2 receptor antibody: Administer at Week 2 after infusion for a total of two doses, except in sensitized patients, who should instead be administered a polyclonal, T-cell-depleting antibody. Tumor necrosis factor (TNF) blocker: Administer on post-infusion Days 3, 7, and 10. Long-term Medications Immunosuppression : Continue immunosuppression permanently to prevent islet graft rejection. [See Warnings and Precautions ] . (See Section 5.1 for reasons to discontinue immunosuppression.) Avoid systemic steroids.

Use a combination of a calcineurin inhibitor and an mTOR inhibitor or appropriate alternatives, at the discretion of the physician. Monitor trough levels of maintenance immunosuppressant drugs, and adjust the dose to maintain appropriate blood levels.