Remestemcel-L-rknd (Monograph)

Brand name: Ryoncil
Drug class: Cellular Therapy

Introduction

Remestemcel-L-rknd, an allogeneic bone marrow-derived mesenchymal stromal cell (MSC) therapy, is a cellular suspension of MSCs isolated from the bone marrow of healthy human donors.

Uses for Remestemcel-L-rknd

Remestemcel-L-rknd has the following uses:

Remestemcel-L-rknd is indicated for the treatment of steroid-refractory acute graft versus host disease (SR-aGvHD) in pediatric patients 2 months of age and older. The cellular therapy has been designated an orphan drug by FDA for the treatment of acute GvHD.

Efficacy of remestemcel-L-rknd was evaluated in a multicenter, prospective, single-arm study (MSB-GVHD001; NCT02336230) in pediatric patients with SR-aGVHD Grade B to D after receiving allogeneic hematopoietic stem cell transplantation (HSCT). Patients who received a second-line therapy for aGVHD prior to screening were excluded. Remestemcel-L-rknd was administered by IV infusion at a dosage of 2 x 10⁶ MSCs/kg twice a week for 4 consecutive weeks, for a total of 8 infusions. Among the 54 patients treated, overall response rate (ORR) at Day 28 was 70%; complete response occurred in 30% of patients and partial response occurred in 41% of patients.

Remestemcel-L-rknd Dosage and Administration

General

Remestemcel-L-rknd is available in the following dosage form(s) and strength(s):

Cell suspension for IV infusion in a target concentration of 6.68 x 10⁶ mesenchymal stromal cells (MSCs) per mL in 3.8 mL contained in a 6 mL cryovial.

Dosage

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

Pediatric Patients

Dosage and Administration

For IV use only.

• Remestemcel-L-rknd is shipped directly to the clinical facility in a liquid nitrogen dry shipper maintained at a temperature of -135°C. The product must remain frozen as directed until thawed immediately prior to administration. Prior to thawing, verify that the pre-arranged time for the remestemcel-L-rknd administration is still feasible. Patient infusion must occur within 5 hours from the start time of first vials of remestemcel-L-rknd thaw.

• Cryopreserved MSCs are combined with Plasma-Lyte A for administration. Remestemcel-L-rknd and Plasma-Lyte A should be prepared following aseptic technique in a Biological Safety Cabinet (BSC). See Full Prescribing Information for additional instructions for preparation and administration.

• The recommended dosage of remestemcel-L-rknd in pediatric patients 2 months of age or older is 2 × 10⁶ MSC/kg body weight per IV infusion given twice a week for 4 consecutive weeks for a total of 8 infusions. Infusions should be administered at least 3 days apart.

• Assess response 28 ± 2 days after the first dose and administer further treatment as appropriate as described in the table below.

Cautions for Remestemcel-L-rknd

Contraindications

Known hypersensitivity to dimethyl sulfoxide (DMSO) or Porcine and Bovine proteins.

Warnings/Precautions

Hypersensitivity and Acute Infusion Reactions

Hypersensitivity reactions including acute infusion reactions have occurred with remestemcel-L-rknd administration. Serious hypersensitivity reactions, including anaphylaxis, may occur due to DMSO and trace amounts of porcine or bovine proteins. Signs and symptoms may include fever, dyspnea, and hypotension during or after remestemcel-L-rknd infusion.

Premedicate patients with antihistamine and corticosteroids and monitor closely for signs and symptoms of hypersensitivity or acute infusion reactions.

If a hypersensitivity or infusion reaction occurs, interrupt remestemcel-L-rknd infusion. Do not administer remestemcel-L-rknd in patients who experience serious or life-threatening reactions.

Transmission of Infectious Agents

Transmission of infectious disease or agents may occur with remestemcel-L-rknd administration because it contains cells from human donors and is manufactured using human, porcine and bovine-derived reagents. Donors are screened and tested for Human Immune-deficiency Virus 1 (HIV-1); Human Immune-deficiency Virus 2 (HIV-2); Hepatitis B Virus (HBV); Hepatitis C Virus (HCV); Human T-cell Leukemia-lymphoma Virus 1 (HTLV-1); Human T-cell Leukemia-lymphoma Virus 2 (HTLV-2); West Nile Virus (WNV); Cytomegalovirus (CMV); Epstein-Barr Virus (EBV); and SyphilisTreponema pallidum Only screening was performed for Creutzfeldt-Jakob disease (CJD) and communicable disease risks associated with xenotransplantation. Remestemcel-L-rknd cell banks are tested for human and animal viruses, retroviruses, bacteria, fungi, yeast, and mycoplasma. Human and animal-derived reagents are tested for human and animal viruses, bacteria, fungi, and mycoplasma before use. These measures do not eliminate the risk of transmitting these or other infectious diseases or agents.

Ectopic Tissue Formation

Ectopic tissue formation may occur following treatment with remestemcel-L-rknd due to the ability of human mesenchymal stromal cells to differentiate into mesenchymal lineage cells such as bone, cartilage and fat cells.

Specific Populations

Pregnancy

There are no available data for remestemcel-L-rknd use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with remestemcel-L-rknd to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known if remestemcel-L-rknd has the potential to be transferred to the fetus. Therefore, remestemcel-L-rknd is not recommended for women who are pregnant. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 10-20%, respectively.

Lactation

There is no information regarding the presence of remestemcel-L-rknd in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for remestemcel-L-rknd and any potential adverse effects on the breastfed infant from remestemcel-L-rknd or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of remestemcel-L-rknd for treatment of steroid refractory acute graft versus host disease (SR-GvHD) have been established in pediatric patients 2 months of age and older. The use of remestemcel-L-rknd in these age groups is supported by evidence from an adequate and well-controlled trial.

Common Adverse Effects

The most common non-laboratory adverse reactions (incidence ≥20%) are viral infectious disorders, bacterial infectious disorders, infection – pathogen unspecified, pyrexia, hemorrhage, edema, abdominal pain and hypertension.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

The mechanism of action for remestemcel-L-rknd is not clear but may be related to immunomodulatory effects. Data from in vitro studies demonstrate that mesenchymal stromal cells (MSCs) inhibit T cell activation as measured by proliferation and secretion of pro-inflammatory cytokines. Acute graft versus host disease (GvHD) occurs when alloreactive donor-derived T cells within the donated tissue (graft) trigger an immunological response, and alloreactive donor-derived T cells play a role in mediating the systemic inflammation, cytotoxicity and potential end organ damage associated with acute graft versus host disease.

Advice to Patients

• Inform patients and/or caregivers that hypersensitivity and acute infusion reactions due to the presence of porcine and bovine protein, and DMSO may occur with remestemcel-L-rknd infusion. Advise patients and/or caregivers to seek immediate medical evaluation if any signs and symptoms of hypersensitivity or acute infusion reactions occur, such as fever, rash or hives, low blood pressure, or breathing problems.

• Inform patients and/or caregivers about the possible risk of transmission of infectious agents with remestemcel-L-rknd administration.

• Inform patients and/or caregivers about the possible risk of ectopic tissue formation with remestemcel-L-rknd administration.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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