Get your patient on Lantidra (Donislecel)

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.

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 (2.1) ] .
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

1. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
   1. LANTIDRA is a cellular suspension (light yellow liquid with the presence of visible cellular aggregates).
   2. The Rinse Bag contains transplant media (light yellow liquid only with no cellular aggregates present).
2. Inspect the LANTIDRA infusion bag and the Rinse Bag for leaks and breaches of container integrity.
3. 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

1. 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.
2. Remove the first drape bag and transfer the product to an infusion operator to remove the second drape bag.
3. 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

1. Insert the catheter into the portal vein.
2. 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.
3. Infuse all infusion bags by gravity flow over approximately 30 minutes at rates ≤ 25 mL/kg/h.
4. Flush the infusion lines periodically to clear them.
5. Do not administer LANTIDRA (islet cell product and rinse bag) through intravenous lines that contain any other medications or infusates other than physiological saline.
6. Reduce infusion rate if the fluid load is not tolerated.
7. Discontinue the infusion in the event of an allergic reaction or if the patient develops a moderate to severe infusion reaction.
8. 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.
9. 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 (2) 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

Risk Summary

Pregnancy risk has not been assessed for LANTIDRA. No animal reproductive and development toxicity studies have been conducted with LANTIDRA. However, there is a risk of fetal malformations associated with certain immunosuppression medications that may be used following LANTIDRA administration. Additionally, the risks to the patient and fetus from the procedure for LANTIDRA infusion in pregnant women has not been assessed.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Risk Summary

The risk of exposing a child to LANTIDRA components during breastfeeding has not been assessed. However, some required concomitant medications, including immunosuppressants, may be excreted in milk at least in trace amounts. Because of this, a decision should be made about whether to discontinue breastfeeding in patients who will receive a LANTIDRA infusion.

Pregnancy Testing

Due to the risk of fetal malformations associated with required concomitant medications, including immunosuppressants, females of reproductive potential should have a confirmed negative pregnancy test prior to LANTIDRA infusion.

Female patients of reproductive potential should be counselled to contact their transplant team immediately if they become pregnant.

Contraception

Because long-term immunosuppression is required following LANTIDRA administration, women of childbearing potential should be informed of the potential risks that these medications pose during pregnancy and should be told to use effective contraception prior to initiation of immunosuppression and thereafter for as long as they retain reproductive potential.

Infertility

Male and female fertility may be compromised by certain medications used for maintenance immunosuppression following LANTIDRA administration.

For male patients, review the concomitant medications and determine if there is a potential for production of abnormal sperm.

Before Treatment

• Vaccination: To mitigate the risk of infection, patients should receive recommended immunizations prior to treatment.

After Treatment

• Administer PCP and CMV prophylaxis following administration of LANTIDRA.
• Avoid live vaccination while receiving immunosuppression.
• Monitor for fever and other signs of infection; initiate appropriate treatment early.
• Clinically monitor for malignancy, including skin cancer.
• Monitor hemoglobin/hematocrit and give blood products as indicated.

Considerations for discontinuation of immunosuppression

• If a patient develops a life-threatening infection or cancer and treatment requires discontinuation of immunosuppression.
• If a patient has been dependent on exogenous insulin for two years after their last infusion, then immunosuppression should be discontinued. However, the treatment team may consider continuation of immunosuppression if they determine that the patient has achieved target HbA1c without recurrent severe hypoglycemia in the presence of clinically relevant C-peptide, that provides a potential ongoing benefit that outweighs the risks of severe and potentially life-threatening effects of immunosuppression.
• If a patient becomes pregnant.

Immunosuppression-Related Adverse Reactions

Risks of common community-acquired infections and opportunistic infections increases with immunosuppression. In total, 211 infections were reported for 26 subjects; one was life-threatening, 22 reactions severe, and 115 events moderate in severity. Additionally, one subject died of multi-organ failure from sepsis in the second year after infusion.

Discontinuation of immunosuppression resulted in loss of islet cell function and if achieved insulin independence. This was described for 8 (27%) subjects.

Malignancy risk is known to increase with immunosuppression. In total, 16 adverse reactions of malignancy were reported in 11 subjects; three malignancies were life-threatening. The malignancies included 12 skin cancers, and one post-transplant lymphoproliferative disease, one breast cancer, and one thyroid cancer. Anemia was reported in 24 (80%) of subjects. Of the 90 adverse reactions reported, one reaction was life-threatening (Hgb <6.5gm/dL), 9 reactions were severe (<8-6.5 gm/dL), and 27 reactions were moderate in severity (<10-8 gm/dL).

Anemia was attributed to bleeding because of procedural complications as well as immunosuppression. Transfusion was required for severe and life-threatening reactions. Overall, five transfusions were administered to five subjects. Three transfusions were for procedural related complications and two were non-procedure related. Alterations in red blood cell turnover and transfusion can alter the accuracy of HbA1c measurements. Therefore, in addition to monitoring for the development of anemia as a result of immunosuppression or a result of a procedural complications, healthcare providers should consider the occurrence of anemia in the interpretation and use of HbA1c in the management of patients with type 1 diabetes who have received LANTIDRA.