Ryoncil

Q: Who makes Ryoncil?

Ryoncil is listed by 1 labeler in the FDA NDC directory, including Mesoblast.

remestemcel-l-rknd · Kit

Prescription (Rx)

Uses

1 INDICATIONS AND USAGE RYONCIL is indicated for the treatment of steroid refractory acute graft versus host disease (SR-aGvHD) in pediatric patients 2 months of age and older. RYONCIL is an allogeneic bone marrow-derived mesenchymal stromal cell (MSC) therapy indicated for the treatment of steroid-refractory acute graft versus host disease (SR-aGvHD) in pediatric patients 2 months of age and older.

Dosage and administration

For intravenous use only. For intravenous use only. The recommended dosage of RYONCIL is 2 × 10 6 MSC/kg body weight per intravenous infusion given twice per week for 4 consecutive weeks. 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. Recommended Treatment Based on Day 28 Response Response Recommendation Complete Response (CR) No further treatment with RYONCIL Partial or Mixed Response Repeat administration of RYONCIL once a week for additional 4 weeks (4 infusions total) No Response Consider alternative treatments Recurrence of GvHD after CR Repeat administration of RYONCIL twice a week for an additional 4 consecutive weeks (8 infusions total) 2.1 Recommended Dosage The recommended dosage of RYONCIL is 2 × 10 6 mesenchymal stromal cells (MSC)/kg body weight per intravenous infusion given twice a week for 4 consecutive weeks for a total of 8 infusions. Administer infusions at least 3 days apart. Assess response 28 ± 2 days after the first dose and administer further treatment as appropriate as described in Table 1 based on Day 28 response. Table 1: Recommended Treatment based on Day 28 Response Response Recommendation Complete Response No further treatment with RYONCIL Partial or Mixed Response Partial response defined as organ improvement of at least one stage without worsening in any other organ, whereas mixed response was defined as improvement of at least one evaluable organ with worsening in another organ as per International Blood and Marrow Transplantation Registry Severity Index Criteria grading system. Repeat administration of RYONCIL once a week for additional 4 weeks (4 infusions total) No Response Consider alternative treatments Recurrence of GvHD after complete response Repeat administration of RYONCIL twice a week for an additional 4 consecutive weeks (8 infusions total) 2.2 Preparation and Administration Instructions Receipt and Storage of RYONCIL RYONCIL is shipped directly to the clinical facility in a liquid nitrogen dry shipper maintained at a temperature of ≤ -135°C. RYONCIL must remain frozen at ≤ -135°C in liquid nitrogen vapor phase until thawed immediately prior to administration [see How Supplied/Storage and Handling (16) ] . Preparation RYONCIL and Plasma-Lyte ® A should be prepared following aseptic technique in a Biological Safety Cabinet (BSC). Spray and wipe down the following materials with 70% alcohol prior to transferring them into the BSC preparation area. All materials should remain in the BSC preparation area unless discarded. Prepare a sterile water bath to a minimum depth of 4 inches and warm to 37°C (± 2°C) at least 30 minutes prior for thawing. Supplies needed for preparation of RYONCIL and Plasma-Lyte ® A RYONCIL vials Plasma-Lyte ® A Infusion bag Interlink blood bag spikes (2) Interlink threaded lock cannula (1 per syringe) 60 mL luer-lock syringe (1) 5 mL luer-lock syringe (1 per each thawed vial) 18-gauge needle (1 per each thawed vial) Note: Use a 1mL syringe if volume to be removed from vial is less than 1mL Airtight zip seal plastic bag(s) (1 per each vial for thaw) Water bath Alcohol wipes Note: Plasma-Lyte ® A may be substituted by Plasma-Lyte ® 148 (pH 7.4 with no glucose). Preparation of Plasma-Lyte ® A 1- Insert the Interlink blood bag spike into the Plasma-Lyte ® A bag. 2- Aseptically attach the threaded lock cannula to a 60 mL syringe. 3- Use an alcohol wipe to scrub the membrane of the Plasma-Lyte ® A bag interlink spike injection site. 4- Attach the threaded lock cannula/syringe assembly to the Plasma-Lyte ® A bag to the injection site. 5- Measure and withdraw 40 mL of Plasma-Lyte ® A from the bag Note: DO NOT remove the syringe containing Plasma-Lyte ® A from the Plasma-Lyte ® A bag. Set aside for later use. Preparation of RYONCIL 1. Prior to RYONCIL thaw, verify that the pre-arranged time for the RYONCIL administration is still feasible. Patient infusion must occur within 5 hours from the start time of first vials of RYONCIL thaw. 2. Remove RYONCIL vial(s) from cryo-storage. 3. Place vial(s) into an airtight zip seal plastic bag(s) and immerse closed bag(s) into the water bath (37ºC), maintaining the top closure above the water line. Use a separate zip seal plastic bag for each vial of RYONCIL. Note: A maximum of 4 vials can be thawed in the water bath at the same time. 4. To thaw, gently agitate the sealed zip seal bag(s) with the vial(s) for approximately 5 to 8 minutes to thaw. 5. Remove vials from the water bath prior to the last visible crystal of ice melting. Note: Do not exceed 15 minutes for each set of four vials. 6. Inspect vial(s) while still in the bag(s) to identify there is no leakage of vial contents. 7. Remove the RYONCIL vial(s) from the sealed plastic bag(s). 8. Inspect for foreign particulate matter (FPM). If FPM is found via visual inspection – DO NOT USE! Retain the offending vial(s). Call the Mesoblast contact number 844-889-MESO (6376). 9. Remove the tab from the RYONCIL vial cap to expose the vial stopper and wipe the exposed surface of the stopper with one provided sterile alcohol wipe. 10. Promptly withdraw the required amount of RYONCIL (based on actual patient body weight) from the vial(s). One syringe and an 18-gauge needle per thawed vial is required. 11. Carefully remove the needle from the syringe containing RYONCIL. 12. Attach the threaded lock cannula to the syringe. 13. Retrieve the infusion bag. 14. Wipe the membrane of the infusion bag interlink spike injection site with sterile alcohol wipe. 15. Insert 1 interlink blood bag spike into the outermost port on the infusion bag (leave the middle port for the infusion line.) 16. Attach the syringe to the spike and transfer the RYONCIL into the infusion bag. 17. Remove the syringe with the threaded lock cannula and discard the syringe and the threaded lock cannula. 18.

Dosage forms and strengths

3 DOSAGE FORMS AND STRENGTHS RYONCIL is available as a cell suspension for intravenous infusion in a target concentration of 6.68 X 10 6 MSCs per mL in 3.8 mL at cryopreservation contained in a 6 mL cryovial. Each 6 mL cryovial contains approximately 25 x 10 6 MSCs. Cryopreserved MSCs are combined with Plasma-Lyte ® A for administration. RYONCIL is available as a cell suspension for intravenous infusion in a target concentration of 6.68 X 10 6 MSCs per mL in 3.8 mL contained in a 6 mL cryovial.

Contraindications

Do not use RYONCIL in patients with known hypersensitivity to dimethyl sulfoxide (DMSO) or porcine and bovine proteins. Known hypersensitivity to dimethyl sulfoxide (DMSO) or Porcine and Bovine proteins. ( 4 )

Warnings and precautions

Hypersensitivity/Acute Infusion reactions : Monitor for hypersensitivity reactions during infusion and premedicate with corticosteroids and antihistamines. ( 5.1 ) Transmission of Infectious Agents: RYONCIL may transmit infectious agents. ( 5.2 ) Ectopic Tissue Formation: Ectopic tissue formation may occur following treatment with RYONCIL. ( 5.3 ) 5.1 Hypersensitivity and Acute Infusion Reactions Hypersensitivity reactions including acute infusion reactions have occurred with RYONCIL administration [see Adverse Reactions (6.1) ] . 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 RYONCIL 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 RYONCIL infusion. Do not administer RYONCIL in patients who experience serious or life-threatening reactions. 5.2 Transmission of Infectious Agents Transmission of infectious disease or agents may occur with RYONCIL 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 Syphilis ( Treponema pallidum ). Only screening was performed for Creutzfeldt-Jakob disease (CJD) and communicable disease risks associated with xenotransplantation. RYONCIL 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. 5.3 Ectopic Tissue Formation Ectopic tissue formation may occur following treatment with RYONCIL due to the ability of human mesenchymal stromal cells to differentiate into mesenchymal lineage cells such as bone, cartilage and fat cells.

Side 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 ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Mesoblast at toll-free phone #1-844-889-MESO (6376) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety data described in this section reflect exposure to RYONCIL in 54 patients in Study MSB-GVHD001 for the treatment of SR-aGvHD. Patients received intravenous infusion of RYONCIL at a dosage of 2 x 10 6 MSCs/kg twice a week for four consecutive weeks, for a total of eight infusions. Patients with partial or mixed response at Day 28 received additional infusions of RYONCIL 2 x 10 6 MSCs/kg once a week for an additional four weeks [see Clinical Studies (14) ] . The median number of doses administered were 10 (range 1 to 16), and the treatment was administered over a median of 43 days (range 1 to 104 days). Serious adverse reactions occurred in 35 patients (65%) including pyrexia (n=5;9%), respiratory failure (n=5;9%), pneumatosis intestinalis (n=4;7%) and staphylococcal bacteremia (n=2;<5%). Eight patients had discontinuation of RYONCIL treatment due to the following: acute infusion reactions (n=3), hypotension (n=1), gastroenteritis (n=1), and death (n=3). Table 2 summarizes most common adverse reactions that occurred in ≥10% patients in Study MSB-GVHD001. Table 2: Adverse Reactions** Occurring in ≥10% of Patients in Study MSB-GVHD001 (N=54) a Based on National Cancer Institute Adverse Event Common Toxicity Criteria version 4.03 b No grade 4 or 5 adverse reactions occurred in the study *Is a composite that includes multiple related terms **Includes adverse reactions up to 100 days following RYONCIL treatment Adverse Reactions All Grades a n (%) Grade 3 b n (%) Viral infectious disorders* 30 (56) 8 (15) Bacterial infectious disorders* 24 (44) 10 (19) Infections - pathogen unspecified* 22 (41) 8 (15) Pyrexia 19 (35) 2 (4) Hemorrhage* 15 (28) 4 (7) Edema* 12 (22) 1 (2) Abdominal pain 11 (20) 4 (7) Hypertension 11 (20) 3 (6) Vomiting 10 (19) 3 (6) Arrhythmia* 9 (17) 2 (4) Diarrhea 9 (17) 1 (2) Rash* 9 (17) 0 (0) Arthralgia 8 (15) 0 (0) Fungal infectious disorders* 8 (15) 2 (4) Hypotension 8 (15) 2 (4) Cough 7 (13) 0 (0) Respiratory Failure 6 (11) 6 (11) Table 3 presents the most common grade 3 or 4 laboratory abnormalities that worsened from baseline in ≥10% of patients Table 3: Grade 3 or 4 Laboratory Abnormalities that Worsened from Baseline in ≥ 10% of Patients in Study MSB-GVHD001 (N=54) Laboratory Parameter Grade 3 or higher a % a Based on National Cancer Institute Adverse Event Common Toxicity Criteria version 4.03 Gamma-glutamyl transferase increased 32 Thrombocytopenia 28 Blood bilirubin increased 11

Use in specific populations

8.1 Pregnancy Risk Summary There are no available data for RYONCIL use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with RYONCIL to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known if RYONCIL has the potential to be transferred to the fetus. Therefore, RYONCIL 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. 8.2 Lactation Risk Summary There is no information regarding the presence of RYONCIL 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 RYONCIL and any potential adverse effects on the breastfed infant from RYONCIL or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of RYONCIL for treatment of SR-GvHD have been established in pediatric patients 2 months of age and older. The use of RYONCIL in these age groups is supported by evidence from an adequate and well-controlled trial [see Adverse Reactions (6) and Clinical Studies (14) ] .

Pregnancy

Pediatric use

8.4 Pediatric Use The safety and effectiveness of RYONCIL for treatment of SR-GvHD have been established in pediatric patients 2 months of age and older. The use of RYONCIL in these age groups is supported by evidence from an adequate and well-controlled trial [see Adverse Reactions (6) and Clinical Studies (14) ] .

Description

11 DESCRIPTION RYONCIL is provided as a frozen cell suspension in a cryogenic vial. The active ingredient in RYONCIL is comprised of culture-expanded mesenchymal stromal cells (MSCs) isolated from the bone marrow of healthy human adult donors. Each cryovial contains nominally 25 x 10 6 MSCs in 3.8 mL (a target concentration 6.68 x 10 6 cells/mL) formulated in Plasma Lyte ® -A (70% v/v), Human Serum Albumin (HSA) Solution (25%) (20% v/v) and Dimethyl sulfoxide (DMSO) (10% v/v). The product is thawed and combined with Plasma-Lyte ® A prior to intravenous administration.

Mechanism of action

12.1 Mechanism of Action The mechanism of action for RYONCIL is not clear but may be related to immunomodulatory effects. Data from in vitro studies demonstrate that MSCs inhibit T cell activation as measured by proliferation and secretion of pro-inflammatory cytokines. Acute 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 aGvHD.

How supplied

16 HOW SUPPLIED/STORAGE AND HANDLING RYONCIL is supplied as a sterile, cryopreserved cell suspension of ex-vivo culture-expanded allogeneic bone marrow-derived mesenchymal stromal cells (MSC) in vials. RYONCIL is provided as a customized kit to meet dosing requirements for a single dose for each patient [see Dosage and Administration (2.1) ] , with each kit containing: Cartons containing sufficient RYONCIL for one infusion based on the patient weight (see Table 5 ) Sufficient alcohol wipes for preparation of the RYONCIL infusions. Kit sizes and National Drug Codes (NDC) are provided in Table 5. Table 5: RYONCIL Kit Sizes Patient weight (kg) Kit contents (single infusion) Number of kits needed for: 4-vial cartons 1-vial cartons Total cartons Number of alcohol wipes NDC Number Initial course 2 nd course Relapse after CR <12.5 0 1 1 1 73648-111-01 8 4 8 12.5-<25 0 2 2 2 73648-112-02 25-<37.5 0 3 3 3 73648-113-03 37.5-<50 1 0 1 4 73648-114-01 50-<62.5 1 1 2 5 73648-115-02 62.5-<75 1 2 3 6 73648-116-03 75-<87.5 1 3 4 7 73648-117-04 87.5-<100 2 0 2 8 73648-118-02 100-<112.5 2 1 3 9 73648-119-03 112.5-<125 2 2 4 10 73648-120-04 125-<137.5 2 3 5 11 73648-121-05 137.5-<150 3 0 3 12 73648-122-03 RYONCIL is shipped to the clinical facility in a liquid nitrogen dry shipper maintained at a temperature of ≤ -135°C. Storage conditions : RYONCIL must remain frozen at ≤ -135°C in liquid nitrogen vapor phase until thawed immediately prior to administration. Handling : Restrict preparation and administration of RYONCIL to a medical facility in which the medical personnel are trained in aseptic technique. Disposal: Dispose empty or partially used RYONCIL vials according to the institutional guidelines for disposal of biohazard materials. Do not save thawed RYONCIL vials for future use.

Patient information

Discuss the following with patients and/or caregivers. Hypersensitivity and Acute infusion reactions: 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 RYONCIL 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, breathing problems [see Warnings and Precautions (5.1 ] . Transmission of Infectious Agents: Inform patients and/or caregivers about the possible risk of transmission of infectious agents with RYONCIL administration [see Warnings and Precautions (5.2) ] . Ectopic Tissue Formation: Inform patients and/or caregivers about the possible risk of ectopic tissue formation with RYONCIL administration [see Warnings and Precautions (5.3) ] . Manufactured for: Mesoblast, Inc. 1114 Sixth Avenue, Fourth Floor New York, NY 10036 US License number: 2140 RYONCIL is a registered trademark of Mesoblast. All rights reserved. ©2024 Mesoblast, Inc. All rights Reserved V 3

Label text from the FDA structured product label by Mesoblast (revised Sep 11, 2025). Long sections are shortened; the complete label is on DailyMed.

Ryoncil NDC products (12)

NDC	Strength & form	Labeler	Type
73648-111	Kit	Mesoblast	BLA
73648-112	Kit	Mesoblast	BLA
73648-113	Kit	Mesoblast	BLA
73648-114	Kit	Mesoblast	BLA
73648-115	Kit	Mesoblast	BLA
73648-116	Kit	Mesoblast	BLA
73648-117	Kit	Mesoblast	BLA
73648-118	Kit	Mesoblast	BLA
73648-119	Kit	Mesoblast	BLA
73648-120	Kit	Mesoblast	BLA
73648-121	Kit	Mesoblast	BLA
73648-122	Kit	Mesoblast	BLA