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warnings and cautions
5 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.
6 ADVERSE REACTIONS 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
<table width="75%"><caption>Table 3: Grade 3 or 4 Laboratory Abnormalities that Worsened from Baseline in ≥ 10% of Patients in Study MSB-GVHD001 (N=54)</caption><col width="50%" align="left"/><col width="50%" align="left"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule">Laboratory Parameter</th><th styleCode="Lrule Rrule" align="center">Grade 3 or higher<sup>a</sup> %</th></tr></thead><tfoot><tr><td align="left" colspan="2"><sup>a</sup> Based on National Cancer Institute Adverse Event Common Toxicity Criteria version 4.03</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Gamma-glutamyl transferase increased</td><td styleCode="Rrule Lrule" align="center">32</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Thrombocytopenia</td><td styleCode="Rrule Lrule" align="center">28</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Blood bilirubin increased</td><td styleCode="Rrule Lrule" align="center">11</td></tr></tbody></table>