Introduction

Donislecel-jujn, a cellular suspension of allogeneic pancreatic islet cells, is a cellular therapy.

Uses for Donislecel-jujn (Systemic)

Donislecel-jujn has the following uses:

Donislecel-jujn is an allogeneic pancreatic islet cellular therapy indicated for the treatment of adults with type 1 diabetes who are unable to approach target HbA1c because of current repeated episodes of severe hypoglycemia despite intensive diabetes management and education.

Donislecel-jujn is used in conjunction with immunosuppression. Immunosuppressive therapy should be initiated before the procedure and continued long-term to prevent islet graft rejection. When considering the risks associated with the infusion procedure and long-term immunosuppression, there is no evidence to show a benefit of administration of donislecel-jujn in patients whose diabetes is well-controlled with insulin therapy or patients with hypoglycemic unawareness who are able to prevent current repeated severe hypoglycemic events (neuroglycopenia requiring active intervention from a third party) using intensive diabetes management (including insulin, devices, and education).

Repeated intraportal islet infusions are not recommended in patients who have experienced prior portal thrombosis, unless the thrombosis was limited to second- or third-order portal vein branches.

There is no evidence to support the safe and effective use of donislecel-jujn in patients with liver disease, renal failure, or who have received a renal transplant.

Efficacy and safety of donislecel-jujn were evaluated in 2 prospective, open-label, single-arm studies in a total of 30 patients with type 1 diabetes mellitus and hypoglycemic unawareness. Patients received 1–3 infusions. Results showed that 25 subjects achieved insulin independence; among these patients, 4 (13.3%) were insulin independent for less than 1 year, 12 (36.7%) were insulin independent for 1 to 5 years, and 9 (33.3%) were insulin independent for greater than 5 years. The remaining 5 patients had no days of insulin independence.

Donislecel-jujn (Systemic) Dosage and Administration

General

Donislecel-jujn is available in the following dosage form(s) and strength(s):

The dosage form is a suspension of islet cells for infusion through the hepatic portal vein. Dosage strength depends on the total number of islets packaged for infusion, which is reported on the container label and associated documents. One lot of donislecel-jujn consists of islets manufactured from the pancreas of a single deceased donor. Each dose of donislecel-jujn is provided as two (2) infusion bags connected to each other via sterile connector. One bag contains donislecel-jujn up to a maximum of 1 × 10⁶ equivalent islet number (EIN) in 400 mL of transplant media and the second bag (Rinse Bag) contains transplant media used to rinse the bag and the infusion line.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

For infusion into the hepatic portal vein only.

• Do not irradiate.

• Do not use leukodepleting filters.

• Do not use if product time exceeds 6-hours post product release or if temperature is not maintained between 15 and 25° C.

• Provide pre-procedural induction immunosuppression 30–360 minutes prior to infusion.

• The recommended minimum dose is 5,000 equivalent islet number (EIN) per kg patient body weight for initial infusion (transplant) and 4,500 EIN/kg for subsequent infusions (same recipient). 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 3 infusions.

• Use donislecel-jujn as supplied and without further dilution. See Full Prescribing information for detailed instructions on administration and preparation. Failure to follow the manufacturer's directions may result in damage and decreased viability of the islets.

• Administer cells through the hepatic portal vein. The estimated tissue volume should not exceed 10 mL per transplant infusion.

• Do not administer donislecel-jujn (islet cell product and rinse bag) through IV lines that contain any other medications or infusates other than physiological saline.

• Monitor portal pressure and blood glucose levels during infusion; also monitor for signs and symptoms of portal vein branch thrombosis. Monitor patient in the hospital for a minimum of 24 hours after the infusion.

• Continue long-term medications for immunosuppression to prevent islet graft rejection.

Contraindications

Donislecel-jujn is contraindicated in patients for whom immunosuppression is contraindicated.

Warnings/Precautions

Risks from Concomitant Immunosuppression

Concomitant use of immunosuppression is required to maintain islet cell viability. The use of immunosuppression in patients receiving donislecel-jujn increases the risk of serious and potentially fatal adverse reactions.

Patients receiving immunosuppressants are at increased risk of bacterial, viral, fungal, and parasitic infections, including opportunistic infections; lymphomas and other malignancies, particularly of the skin; and severe anemia, sometimes requiring transfusion.

To mitigate the risk of infection, patients should receive recommended immunizations prior to treatment. After treatment, administer Pneumocystis jirovecii pneumonia (PCP) and cytomegalovirus (CMV) prophylaxis following administration of donislecel-jujn. 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.

Consider discontinuation of immunosuppression in the following situations:

• 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.

Procedural Complications

Liver laceration, hemorrhage and intra-abdominal bleeding have occurred with portal administration of donislecel-jujn. Manage hemostasis in the catheter track using standard practices following infusion of donislecel-jujn to reduce the risk of bleeding. Monitor for bleeding clinically and with laboratory assessments. Blood transfusions have been required.

Elevation in portal blood pressure has occurred during and following intraportal islet infusion. Monitor portal pressure; 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.

Portal vein branch thrombosis may occur following infusion of donislecel-jujn. Repeated intraportal islet infusions are not recommended in patients who have experienced prior portal thrombosis unless the thrombosis was limited to second- or third-order portal vein branches.

Increased Risk of Islet Graft Rejection

Patients with a positive T- and B-cell crossmatch between recipient serum and donor lymphocytes may immediately reject the islet cells. The T- and B-cell crossmatch assay is binary. T- and B-cell both need to be negative.

Transmission of Donor-derived Infections

There is a risk of communicable disease transmission from donor to recipient that exists for donislecel-jujn. Monitor patients for signs of active infection following donislecel-jujn infusion and treat appropriately if infection is suspected.

Panel Reactive Antibodies (PRA)

Product administration may elevate PRA and negatively impact candidacy for renal transplant. Consider benefit-risk of administering donislecel-jujn to a patient who may require a renal transplant in the future.

Specific Populations

Pregnancy

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

Lactation

The risk of exposing a child to donislecel-jujn 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 donislecel-jujn infusion.

Females and Males of Reproductive Potential

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 donislecel-jujn infusion.

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

Because long-term immunosuppression is required following donislecel-jujn 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.

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

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

Pediatric Use

The safety and effectiveness of donislecel-jujn have not been established in pediatric patients with type 1 diabetes.

Geriatric Use

The safety and effectiveness of donislecel-jujn have not been established in geriatric patients with type 1 diabetes and hypoglycemic unawareness. Clinical studies of donislecel-jujn did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently than younger patients.

Common Adverse Effects

Ninety percent (90%) of subjects had at least one serious adverse reaction. The major causes are attributed to the infusion procedure or immunosuppression:

• Liver laceration/hematoma, hemorrhage, and intra-abdominal bleeding (13%)

• Elevation of portal pressure (7%)

• Infection (87%)

• Malignancy (37%)

General

Donislecel-jujn is available in the following dosage form(s) and strength(s):

The dosage form is a suspension of islet cells for infusion through the hepatic portal vein. Dosage strength depends on the total number of islets packaged for infusion, which is reported on the container label and associated documents. One lot of donislecel-jujn consists of islets manufactured from the pancreas of a single deceased donor. Each dose of donislecel-jujn is provided as two (2) infusion bags connected to each other via sterile connector. One bag contains donislecel-jujn up to a maximum of 1 × 10⁶ equivalent islet number (EIN) in 400 mL of transplant media and the second bag (Rinse Bag) contains transplant media used to rinse the bag and the infusion line.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

For infusion into the hepatic portal vein only.

• Do not irradiate.

• Do not use leukodepleting filters.

• Do not use if product time exceeds 6-hours post product release or if temperature is not maintained between 15 and 25° C.

• Provide pre-procedural induction immunosuppression 30–360 minutes prior to infusion.

• The recommended minimum dose is 5,000 equivalent islet number (EIN) per kg patient body weight for initial infusion (transplant) and 4,500 EIN/kg for subsequent infusions (same recipient). 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 3 infusions.

• Use donislecel-jujn as supplied and without further dilution. See Full Prescribing information for detailed instructions on administration and preparation. Failure to follow the manufacturer's directions may result in damage and decreased viability of the islets.

• Administer cells through the hepatic portal vein. The estimated tissue volume should not exceed 10 mL per transplant infusion.

• Do not administer donislecel-jujn (islet cell product and rinse bag) through IV lines that contain any other medications or infusates other than physiological saline.

• Monitor portal pressure and blood glucose levels during infusion; also monitor for signs and symptoms of portal vein branch thrombosis. Monitor patient in the hospital for a minimum of 24 hours after the infusion.

• Continue long-term medications for immunosuppression to prevent islet graft rejection.