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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 106 MSCs in 3.8 mL (a target concentration 6.68 x 106 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.
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.
For intravenous use only.
Table 1: Recommended Treatment based on Day 28 Response
| Response | Recommendation |
| Complete Response | 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 complete response | Repeat administration of RYONCIL twice a week for an additional 4 consecutive weeks (8 infusions total) |
| *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. | |
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].
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
Note: Plasma-Lyte® A may be substituted by Plasma-Lyte® 148 (pH 7.4 with no glucose).
Note: DO NOT remove the syringe containing Plasma-Lyte® A from the Plasma-Lyte® A bag. Set aside for later use.
Note: Patient infusion must occur within 5 hours from the start time of first vial(s) of RYONCIL thaw.
RYONCIL is available as a cell suspension for intravenous infusion in a target concentration of 6.68 X 106 MSCs per mL in 3.8 mL at cryopreservation contained in a 6 mL cryovial.
Each 6 mL cryovial contains approximately 25 x 106 MSCs.
Cryopreserved MSCs are combined with Plasma-Lyte® A for administration.
RYONCIL is supplied as a sterile, cryopreserved cell suspension of ex-vivo culture-expanded allogeneic bone marrow-derived mesenchymal stromal cells (MSC) in vials in the following package sizes:
| NDC Number | Presentation | Package Size |
| 73648-154-01 | Single-Use Vial (target 25 x 106 MSCs in 3.8 mL) | Carton containing 1 vial |
| 73648-154-04 | Single-Use Vial (target 25 x 106 MSCs in 3.8 mL) | Carton containing 4 vials |
RYONCIL is shipped 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.
Restrict preparation and administration of RYONCIL to a medical facility in which the medical personnel are trained in aseptic technique.
Dispose empty or partially used RYONCIL vials according to the institutional guidelines for disposal of biohazard materials.
Do not save reconstituted RYONCIL vials for future use.
Manufactured for: Mesoblast, Inc., 1114 Sixth Avenue, Fourth Floor, New York, NY 10036. Revised: N/A
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 106 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 106 MSCs/kg once a week for an additional four weeks [see Clinical Studies]. 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)
| Adverse Reactions | All Gradesa n (%) | Grade 3b 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) |
| 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 |
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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 highera % |
| Gamma-glutamyl transferase increased | 32 |
| Thrombocytopenia | 28 |
| Blood bilirubin increased | 11 |
| a Based on National Cancer Institute Adverse Event Common Toxicity Criteria version 4.03 | |
No Information provided
Included as part of the PRECAUTIONS section.
Hypersensitivity reactions including acute infusion reactions have occurred with RYONCIL administration [see ADVERSE REACTIONS]. 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.
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.
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.
No animal studies have been performed to evaluate the effects of RYONCIL on carcinogenesis, mutagenesis or impairment of fertility.
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.
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.
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 and Clinical Studies].
No Information provided
Do not use RYONCIL in patients with known hypersensitivity to dimethyl sulfoxide (DMSO) or porcine and bovine proteins.
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.
Human pharmacodynamic data were obtained from analysis of blood samples in pediatric subjects with SR-aGvHD (n=40; age range 0.6-17 years) following treatment with RYONCIL at a dose of 2x106 cells/kg. At Baseline, elevated levels of tumor necrosis factor receptor type I (TNFR1) and suppressor of tumorigenicity 2 (ST2) were observed consistent with the inflammatory state of aGvHD. Treatment with RYONCIL reduced the levels of TNFR1 and ST2 by 79% and 75%, respectively, at Day 180 as compared to baseline values. Further, the circulating levels of CD3+CD4+CD25+HLA-DR+ T cells, which represent activated T cells, were reduced by 64% at Day 180 following treatment with RYONCIL as compared to the baseline values.
No studies have been performed to evaluate the pharmacokinetics of RYONCIL.
The efficacy of RYONCIL was evaluated in a multicenter, prospective, single-arm study (MSB-GVHD 001; NCT02336230). The study enrolled pediatric patients with SR-GvHD Grade B to D (excluding Grade B skin alone) as per International Blood and Marrow Transplantation Registry Severity Index Criteria (IBMTR) after receiving allogeneic hematopoietic stem cell transplantation (HSCT). SR-aGvHD was defined as aGvHD that progressed within 3 days or did not improve within 7 consecutive days of treatment with methylprednisolone 2 mg/kg/day or equivalent. Patients who received a second line therapy for aGvHD prior to screening were excluded.
RYONCIL was administered by intravenous infusion at a dosage of 2 x 106 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 106 MSCs/kg once a week for an additional four consecutive weeks. Patients with complete response at Day 28 who experienced recurrence of aGvHD received infusions of RYONCIL 2 x 106 MSCs/kg twice a week for an additional four consecutive weeks.
A total of 55 patients were enrolled, and 54 were treated with RYONCIL. Among the treated patients (n=54), the demographic characteristics were as follows: median age was 7 years (range: 7 months to 17 years); 36% were females; 56% were White, 19% reported “other” race, 15% were Black, 6% were Asian, 6% American Indian or Alaska Native 33% were Hispanic and 65% were non-Hispanic. Among enrolled patients, hematologic malignancies (67%) and non-malignant diseases (33%) were the underlying reasons for allogenic HSCT. SR-GvHD severity was as follows at baseline: Grade B (11%), Grade C (43%), Grade D (46%). Organ involvement at baseline were as follows: skin alone (26%), lower gastrointestinal tract only (39%), multi-organ involvement (35%). The median duration of prior corticosteroid treatment at baseline was 8 days (range: 2 to 46 days).
The main efficacy outcome measures were Day-28 overall response rate (complete response rate and partial response rate) and the duration of response.
The efficacy results are summarized in Table 4.
Table 4: Efficacy Results for Study MSB-GVHD001
| Response at Day 28 | N=54 |
| Overall Response Rate | |
| n (%) | 38 (70%) |
| 95% CIa | 56.4, 82.0 |
| Durationb (days) | 54 (7, 159+) |
| Median (range) | |
| Complete Response Ratec | |
| n (%) | 16 (30%) |
| 95% CIa | 18.0, 43.6 |
| Partial Response Rated | |
| n (%) | 22 (41%) |
| 95% CIa | 27.6, 55.0 |
| CI=confidence interval a Two-sided exact binomial confidence interval at the 95% level b Duration of response was calculated from Day-28 response to either progression (worsening by one stage in any organ without improvement in other organs in comparison to prior response assessment), new systemic therapy for aGvHD or death from any cause. c Complete response was defined as resolution of aGvHD in all involved organs as per IBMTR grading system. d Partial response was defined as organ improvement of at least one stage without worsening of any other organ as per IBMTR grading system. |
|
Overall response rate at Day 28 by baseline disease severity is as follows: Grade B (3/6; 50%), Grade C (16/23; 70%), and Grade D (19/25; 76%).
Among the 38 responders, the median time from Day-28 response to either death or need for systemic therapy for aGvHD (non-RYONCIL systemic therapy for aGvHD or increase in the dose of corticosteroids to methylprednisolone 2 mg/kg or equivalent) was 111.5 days (range 9, 182+).
Discuss the following with patients and/or caregivers.
