donislecel (Rx)

>10%

Infection (87%)

Malignancy (37%)

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

Any severity

• Nausea (83%)
• Fatigue (83%)
• Anemia (80%)
• Diarrhea (80%)
• Abdominal pain (67%)
• Asthenia (67%)
• Headache (67%)
• Hyponatremia (63%)
• Transaminases increased (63%)
• Upper respiratory tract infection (63%)
• Vomiting (60%)
• Urinary tract infection (53%)
• Hypoalbuminemia (47%)
• Low-density lipoprotein increased (43%)
• Myalgia (43%)
• Sinusitis (40%)
• Chills (40%)
• Hemoglobin decreased (37%)
• Tinnitus (30%)
• Decreased appetite (27%)
• Hypertension (23%)
• Pneumonia (20%)
• Hypercholesterolemia (20%)
• Depression (20%)
• Menstruation irregular (20%)

≥Grade 3

• Low density lipoprotein increased (37%)
• Anemia (27%)
• Pneumonia (17%)
• Diarrhea (13%)
• Hyponatremia (13%)

1-10%

Elevated portal pressure (7%)

≥Grade 3

• Urinary tract infection (10%)
• Nausea (7%)
• Vomiting (7%)
• Abdominal pain (7%)
• Asthenia (7%)
• Transaminases increased (7%)
• Sinusitis (7%)
• Hypertension (7%)
• Fatigue (3%)
• Headache (3%)
• Upper respiratory tract infection (3%)
• Hypoalbuminemia (3%)
• Myalgia (3%)
• Chills (3%)
• Hemoglobin decreased (3%)
• Tinnitus (3%)
• Decreased appetite (3%)
• Hypercholesterolemia (3%)
• Depression (3%)
• Menstruation irregular (3%)

Adverse Effects After Initial Infusion to 1 Year Following Final Infusion

Common adverse reactions (occurring in ≥20% but ≤90% of patients)

• Blood and lymphatic system disorders: Anemia, leukopenia
• Cardiac disorders: Palpitations
• Ear and labyrinth disorders: Ear pain, tinnitus
• Eye disorders: Eye pain, blurred vision
• Gastrointestinal disorders: Abdominal pain, diarrhea, dry mouth, mouth ulceration, nausea, stomatitis, vomiting
• General disorders and administration site conditions: Asthenia, chills, edema peripheral, fatigue, feeling cold, thirst
• Hepatobiliary disorders: Hepatic steatosis, hyperbilirubinemia
• Infections and infestations: Herpes zoster, pneumonia, sinusitis, upper respiratory tract infection, urinary tract infection
• Injury, poisoning, and procedural complications: Contusion
• Investigations: Aspartate aminotransferase increased, blood bicarbonate decreased, blood cholesterol increased, hemoglobin decreased, low-density lipoprotein increased, transaminases increased
• Metabolism and nutrition disorders: Abnormal loss of weight, anorexia and bulimia syndrome, appetite disorder, decreased appetite, hypercholesterolemia, hyperkalemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia
• Musculoskeletal and connective tissue disorders: Arthralgia, muscle spasms, musculoskeletal stiffness, myalgia, pain in extremity
• Neoplasms benign, malignant, and unspecified (including cysts and polyps): Thyroid neoplasm
• Nervous system disorders: Disturbance in attention, dizziness, headache, hypoesthesia, tremor
• Psychiatric disorders: Anhedonia, anxiety, depressed mood, depression, insomnia, nervousness
• Renal and urinary disorders: Hematuria, hypertonic bladder, nocturia, pollakiuria, urinary incontinence
• Reproductive system and breast disorders: Menstruation irregular
• Respiratory, thoracic, and mediastinal disorders: Cough, dysphonia, dyspnea, nasal congestion, oropharyngeal pain, sinus disorder
• Skin and subcutaneous tissue disorders: Acne, dry skin, onychoclasis, pruritus, rash
• Vascular disorders: Hypertension

Less common adverse reactions (occurring in ≥5% but <20% of patients)

• Blood and lymphatic system disorders: Increased tendency to bruise, lymphadenopathy, neutropenia, thrombocytopenia
• Cardiac disorders: Myocardial ischemia
• Ear and labyrinth disorders: Deafness, vertigo
• Endocrine disorders: Hypoglycemia, thyroid cyst
• Eye disorders: Cataract, conjunctival hemorrhage, eye edema, eye pruritus
• Gastrointestinal disorders: Barrett esophagus, bowel movement irregularity, colitis, constipation, dyspepsia, gastroesophageal reflux disease, oral pain, toothache
• General disorders and administration site conditions: Catheter site pain, chest pain, feeling of body temperature change, gait disturbance, influenza-like illness, injection site extravasation, mucosal inflammation, pain, pyrexia
• Hepatobiliary disorders: Cholelithiasis
• Immune system disorders: Sensitization
• Infections and infestations: Bacterial vaginosis, cellulitis, cytomegalovirus infection, ear infection, Epstein-Barr infection, eye infection, fungal infection, gastroenteritis, gastroenteritis viral, localized infection, nail infection, nasopharyngitis, onychomycosis, oral candidiasis, oral herpes, osteomyelitis, rhinitis, tooth infection, vaginal infection, viral upper respiratory tract infection, vulvovaginal mycotic infection
• Injury, poisoning, and procedural complications: Hepatic hematoma, limb injury, meniscus injury
• Investigations: Alanine aminotransferase increased, blood alkaline phosphatase increased, blood creatinine increased, glomerular filtration rate decreased, neutrophil count decreased, urine albumin/creatinine ratio, urine protein/creatinine ratio increased, weight decreased, weight increased
• Metabolism and nutrition disorders: dehydration, hyperchloremia, hyperlipidemia, hypertriglyceridemia, hypokalemia, hypophosphatemia
• Musculoskeletal and connective tissue disorders: Arthritis, back pain, intervertebral disc protrusion, joint stiffness, joint swelling, muscular weakness, musculoskeletal pain, neck pain, osteoarthritis, osteopenia, osteoporosis
• Neoplasms benign, malignant, and unspecified (including cysts and polyps): Basal cell carcinoma, squamous cell carcinoma
• Nervous system disorders: Carpal tunnel syndrome, cognitive disorder, dysgeusia, dyskinesia, head titubation, migraine, neuropathy peripheral, paresthesia, poor quality sleep, sinus headache, syncope
• Psychiatric disorders: Agitation, decreased interest, libido decreased
• Renal and urinary disorders: Hemoglobinuria, hydronephrosis, proteinuria, urine flow decreased
• Reproductive system and breast disorders: Erectile dysfunction, menorrhagia, vaginal hemorrhage
• Respiratory, thoracic, and mediastinal disorders: Dyspnea exertional, epistaxis, pleural effusion, rhinorrhea, wheezing
• Skin and subcutaneous tissue disorders: Alopecia, dermatitis, erythema, hidradenitis, nail disorder, night sweats, rash pruritic, rosacea, skin exfoliation, skin lesion
• Vascular disorders: Peripheral artery stenosis

Contraindications

Patients who have concomitant diseases or conditions, including pregnancy, that contraindicate the procedure for infusion or immunosuppression

Cautions

Risks from concomitant immunosuppression

• Concomitant use of immunosuppression is required to maintain islet cell viability
• Immunosuppression increases risk of serious and potentially fatal adverse reactions

• Immunosuppressants increase risk of

  • Bacterial, viral, fungal, and parasitic infections, including opportunistic infections
  • Lymphomas and other malignancies, particularly of the skin
  • Severe anemia, sometimes requiring transfusion

• Before treatment

  • Vaccination: To mitigate risk of infection, patients should receive recommended immunizations before treatment

• After treatment

  • Administer Pneumocystis jirovecii pneumonia (PCP) and cytomegalovirus (CMV) prophylaxis following administration
  • 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 life-threatening infection or cancer develops and treatment requires discontinuation of immunosuppression
  • If a patient has been dependent on exogenous insulin for 2 years after their last infusion, then immunosuppression should be discontinued
  • However, may consider continuation of immunosuppression if 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 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
• Manage hemostasis in catheter track using standard practices following infusion, to reduce the risk of bleeding
• Monitor for bleeding clinically and with laboratory assessments
• Blood transfusions have been required
• Elevated portal blood pressure has occurred during and following intraportal islet infusion
• Monitor portal pressure; pause infusion if portal pressure rises to >22 mmHg and do not resume until it falls below 18 mmHg
• Terminate infusion if portal pressure remains >22 mmHg for >10 minutes
• Portal vein branch thrombosis may occur following infusion
• Repeated intraportal islet infusions are not recommended in patients who have experienced prior portal thrombosis unless 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 cross match between recipient serum and donor lymphocytes may immediately reject the islet cells
• T- and B-cell cross match assay is binary
• T- and B-cell both need to be negative

Transmission of donor-derived infections

• Risk of communicable disease transmission from donor to recipient
• Monitor for signs of active infection following 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 to a patient who may require a future renal transplant

Pregnancy

Contraindicated

Owing to risk of fetal malformations associated with required concomitant medications, including immunosuppressants, females of reproductive potential should have a confirmed negative pregnancy test before administration

Counsel female patients of reproductive potential to contact their transplant team immediately if they become pregnant

Contraception

• Inform females of childbearing potential of potential risks that immunosuppressants pose during pregnancy
• Instruct females to use effective contraception before 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
• Males: Review concomitant medications and determine if there is potential for production of abnormal sperm

Lactation

Risk of donislecel components exposure to children during breastfeeding has not been assessed

However, some required concomitant medications, including immunosuppressants, may be excreted in milk in at least trace amounts; because of this, a decision should be made about whether to discontinue breastfeeding in patients who will receive a donislecel infusion

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Allogeneic pancreatic islet cellular therapy that provides transplanted islets from donated pancreases from single-source deceased organ donors

Pancreatic islets regulate blood glucose levels through highly regulated, pulsatile secretion of multiple hormones in response to fluctuations in blood glucose; endocrine cells within pancreatic islets release insulin, glucagon, somatostatin, pancreatic peptide, and ghrelin

Primary mechanism of action of donislecel is thought to be secretion of insulin by infused (transplanted) beta cells

Preparation

Keep donislecel in insulated container at 15-25ºC no longer than 6 hr from time of product release (see carton label and certificate of analysis)

Dispose of any product not used within 6 hr

Do not irradiate

Select and prepare units under direction of a medical professional who is experienced in islet infusion (transplantation)

Use as supplied and without further dilution

Preprocedural medication

• Provide preprocedural induction immunosuppression 30-360 minutes before infusion

• Include the following, at discretion of 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 before islet infusion; note that in patients who are sensitized (hypersensitivity with a history of anaphylactic reaction) to anti-IL-2 receptor antibody therapies, use a polyclonal, T-cell-depleting antibody instead
  • Calcineurin inhibitor
  • Mammalian target of rapamycin (mTOR) inhibitor
  • Tumor necrosis factor (TNF) blocker
  • Periprocedural antibiotic prophylaxis recommended

Preinfusion patient preparation

• Confirm identity of patient for specified unit of donislecel
• Confirm that patient has received appropriate premedication and hydration before infusion
• Confirm appropriate medications and blood products are available to manage any potential emergencies (eg, hemorrhage, portal vein thrombosis, allergic reactions, glycemic lability, bleeding, and pain)
• If indicated, administer saline/glucose infusion and administer insulin using IV insulin pump during periprocedural period

Do not administer with leukodepleting filters

• To optimize viability, administer as soon as possible after product release
• Interventional radiologists and surgeons with expertise in islet cell infusion may administer donislecel in an interventional radiology suite or operating suite, under controlled aseptic conditions
• Perform all steps aseptically
• Use a 5 or 6 French angiographic catheter indicated for drug delivery or other therapeutic fluids for donislecel infusion
• Catheter length: ≤65 cm
• Internal diameter: ≥0.97mm (0.038 inches)
• Use only sheaths and introducers in combination with a catheter with the specified dimensions listed above to administer

Pre-infusion donislecel preparation

• Inspect visually for particulate matter and discoloration before administration
• Donislecel infusion is a cellular suspension (light yellow liquid with presence of visible cellular aggregates)
• Rinse bag contains transplant media (light yellow liquid with no cellular aggregates present)
• Inspect infusion bag and rinse bag for leaks and breaches of container integrity
• Ensure connector between the 2 bags is secure and closed
• Do not infuse if product irregularities present or if container appears damaged or otherwise compromised; immediately notify transplant physician/team and CellTrans at 1-800-500-1617
• Gently agitate donislecel infusion bag to ensure that islets are suspended and to prevent clumping
• Do NOT shake bag, as this may damage islets cells; repeat gentle agitation periodically throughout infusion process
• Remove first drape bag and transfer product to an infusion operator to remove second drape bag
• Ensure IV tubing is closed, then connect donislecel infusion bag, fill drip chamber, and open roller clamp to fill tubing and remove air

Hepatic Portal Vein Administration

Infusion procedure

• Insert catheter into portal vein
• Once catheter placement in portal vein confirmed, connect IV tubing from donislecel infusion bag to catheter using a Luer lock connector
• Infuse all infusion bags by gravity flow over ~30 minutes ≤25 mL/kg/hr
• Flush infusion lines periodically to clear them
• Do not administer through IV lines that contain any other medications or infusates other than physiologic saline
• Reduce infusion rate if fluid load is not tolerated
• Discontinue infusion if an allergic reaction occurs or if a moderate-to-severe infusion reaction develops
• Once islet infusion completed, open roller clamp on rinse bag tubing to allow refilling and rinsing of donislecel infusion bag; gently agitate donislecel infusion bag with small amounts of rinse solution to ensure that all cells have been administered; repeat until rinse bag is empty
• Withdraw catheter tip from main portal vein into the liver parenchyma until it lies within a few centimeters (cm) of the liver capsule
• Before withdrawing catheter completely, manage hemostasis in the catheter track using standard practices, to reduce risk of bleeding

Monitoring during infusion

• Measure portal pressure during infusion

  • Pause infusion if portal pressure rises to >22 mmHg; do not resume until it falls to <18 mmHg
  • Terminate infusion if portal pressure remains >22 mmHg for >10 minutes

• Blood glucose

  • Monitor blood glucose levels q15min during infusion, then q30min first 4-8 hr after infusion
  • Provide appropriate treatment if blood glucose levels fall to <70 mg/dL
  • Monitor blood glucose levels as needed once blood glucose levels have stabilized
  • After acute period (first 4-8 hr following infusion), continue to monitor blood glucose (laboratory, capillary blood glucose, or continuous glucose monitor)
  • Use only blood glucose meters and continuous glucose monitoring systems labeled for use in hospital

• 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 monitoring

• Monitor patient in hospital for minimum of 24 hr
• Perform abdominal ultrasonography and Doppler examination of 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 for adverse reactions
• Continue to monitor blood glucose levels and manage according to inpatient standard of care

Post-infusion medications

• Anti-infective medications: Administer PCP and CMV prophylaxis immediately following donislecel infusion and continue treatment as described in the prescribing information for the specific anti-infective medications
• Non-depleting monoclonal anti-IL-2 receptor antibody: Administer at Week 2 after infusion for a total of 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

• Immunosuppression: Continue immunosuppression permanently to prevent islet graft rejection
• Avoid systemic steroids; use combination of a calcineurin inhibitor and an mTOR inhibitor or appropriate alternatives, at discretion of physician
• Monitor trough levels of maintenance immunosuppressant drugs, and adjust dose to maintain appropriate blood levels

Storage

Store in insulated container at 15-25ºC for up to 6 hr from time of product release

Dispose used bags and infusion lines as biohazard material