DOSAGE & ADMINISTRATION SECTION.

2. DOSAGE AND ADMINISTRATION. The recommended dosage of RYTELO is 7.1 mg/kg administered as an intravenous infusion over hours every weeks. (2.1)Premedicate prior to dosing with RYTELO for potential infusion-related reactions. (2.2)See full prescribing information for preparation and administration instructions. (2.4). The recommended dosage of RYTELO is 7.1 mg/kg administered as an intravenous infusion over hours every weeks. (2.1). Premedicate prior to dosing with RYTELO for potential infusion-related reactions. (2.2). See full prescribing information for preparation and administration instructions. (2.4). 2.1. Recommended Dosage. The recommended dosage of RYTELO is 7.1 mg/kg administered as an intravenous infusion over hours every weeks. Discontinue RYTELO if patient does not experience decrease in red blood cell (RBC) transfusion burden after 24 weeks of treatment (administration of doses) or if unacceptable toxicity occurs at any time [see Dosage and Administration (2.3)].. 2.2. Recommended Premedications. Administer the following pre-treatment medications at least 30 minutes prior to dosing to prevent or reduce potential infusion-related reactions:diphenhydramine (or equivalent) 25 mg to 50 mg, intravenously or orallyhydrocortisone (or equivalent) 100 mg to 200 mg, intravenously or orallyMonitor patients for adverse reactions for at least one hour after the infusion has been completed [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].. diphenhydramine (or equivalent) 25 mg to 50 mg, intravenously or orally. hydrocortisone (or equivalent) 100 mg to 200 mg, intravenously or orally. 2.3. Dosage Modifications for Adverse Reactions. Recommended dose reductions for Grade and Grade adverse reactions are found in Table 1.The management of Grade and Grade adverse reactions may require temporary dose delay, dose reduction, or treatment discontinuation and are presented in Table and Table 3. RYTELO treatment should be permanently discontinued if the patient cannot tolerate the lowest dose level of 4.4 mg/kg.Table 1:Recommended Dose Reduction for RYTELO for Grade and Grade Adverse ReactionsDose Reduction Dose Every WeeksFirst dose reduction5.6 mg/kgSecond dose reduction4.4 mg/kg. Dosage Modifications for Hematologic (Grade and Grade 4) Adverse ReactionsMonitor complete blood cell counts prior to administration of RYTELO, weekly for the first two cycles, prior to each cycle thereafter, and as clinically indicated. Delay the next cycle if absolute neutrophil count is less than x 109/L or platelets are less than 50 109/L. Modify dose as described in Table 2.Table 2:Dosage Modifications for Patients with Hematologic Adverse Reactions (Grade and Grade 4)Adverse ReactionSeverity GradeSeverity based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03. OccurrenceTreatment ModificationAbbreviation: ANC absolute neutrophil count Thrombocytopenia [see Warnings and Precautions (5.1)]Grade 3FirstDelay RYTELO until recovery of platelets to 50 109/L; restart at same dose level. Second and ThirdDelay RYTELO until recovery of platelets to 50 109/L; restart at one dose level lower. FourthDiscontinue RYTELO.Grade 4First and SecondDelay RYTELO until recovery of platelets to 50 109/L; restart at one dose level lower.ThirdDiscontinue RYTELO.Neutropenia [see Warnings and Precautions (5.2)]Grade 3FirstDelay RYTELO until recovery of ANC to x 109/L; restart at same dose level. Second and ThirdDelay RYTELO until recovery of ANC to x 109/L; restart at one dose level lower. FourthDiscontinue RYTELO.Grade 4First and SecondDelay RYTELO until recovery of ANC to x 109/L; restart at one dose level lower. ThirdDiscontinue RYTELO.. Dosage Modifications for Non-hematologic Adverse ReactionsDosage modifications for infusion-related reactions and other adverse drug reactions, including elevated liver function tests (LFTs), are described in Table 3. Monitor liver function tests prior to administration of RYTELO, weekly for the first cycle, prior to each cycle thereafter, and as clinically indicated.Table 3:Dosage Modifications for Patients with Non-hematologic Adverse ReactionsAdverse ReactionSeverity GradeSeverity based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03. OccurrenceTreatment ModificationAbbreviation: LFT liver function testInfusion-Related Reactions [see Warnings and Precautions (5.3)]Grade or 3First and SecondInterrupt the RYTELO infusion until resolution of the adverse reaction or until the intensity of the reaction decreases to Grade 1; restart infusion at 50% of the infusion rate administered prior to the adverse reaction.ThirdFor Grade 2, stop infusion. May restart at next cycle.For Grade 3, permanently discontinue RYTELO.Grade 4FirstStop infusion, administer supportive care as appropriate and permanently discontinue RYTELO.Other adverse reactions including elevated LFTs [see Adverse Reactions (6.1)]Grade or 4First and SecondDelay RYTELO until recovery of adverse reactions to Grade or baseline; restart at one dose level lower.ThirdPermanently discontinue RYTELO.. 2.4. Preparation and Administration. RYTELO is provided as lyophilized powder in single-dose vial for intravenous infusion only and must be reconstituted and diluted prior to administration.Use aseptic technique to prepare RYTELO.RYTELO does not contain preservative.. Reconstitution:Calculate the dose of RYTELO needed based on the patients body weight (kg).Determine the number of RYTELO vials needed to achieve the required dose (total mg) per Table 4. More than one vial may be needed to achieve full dose.Remove the RYTELO vials from the refrigerator and allow the vials to sit for 10 minutes to 15 minutes (not to exceed 30 minutes) to adjust to room temperature 20C to 25C (68F to 77F) before use.Reconstitute each vial of RYTELO with the volume of 0.9% Sodium Chloride Injection provided in Table directly onto the lyophilized powder to obtain concentration of 31.4 mg/mL of imetelstat.Table 4:Reconstitution VolumesStrengthRecommended to use the appropriate combination of vial strengths to most closely match the intended dose based on the patients weight. Volume of 0.9% Sodium Chloride Injection for Reconstitution per VialFinal Concentration of Reconstituted Solution per VialDeliverable Volume per Vial47 mg1.8 mL31.4 mg/mLEach vial contains an overfill to account for loss of liquid during preparation and extraction of the reconstituted solution, resulting in the final concentration. 1.5 mL188 mg6.3 mL31.4 mg/mL mLSwirl each vial gently to avoid foaming until the powder is fully reconstituted (not to exceed 15 minutes). Do not shake.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution in each vial should appear as clear to slightly hazy solution, essentially free of visible contaminants, particles and/or particulates. Do not use if discoloration or particulate matter is present.Use the reconstituted solution immediately to prepare the RYTELO diluted solution in the infusion bag.. Calculate the dose of RYTELO needed based on the patients body weight (kg).. Determine the number of RYTELO vials needed to achieve the required dose (total mg) per Table 4. More than one vial may be needed to achieve full dose.. Remove the RYTELO vials from the refrigerator and allow the vials to sit for 10 minutes to 15 minutes (not to exceed 30 minutes) to adjust to room temperature 20C to 25C (68F to 77F) before use.. Reconstitute each vial of RYTELO with the volume of 0.9% Sodium Chloride Injection provided in Table directly onto the lyophilized powder to obtain concentration of 31.4 mg/mL of imetelstat.. Swirl each vial gently to avoid foaming until the powder is fully reconstituted (not to exceed 15 minutes). Do not shake.. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution in each vial should appear as clear to slightly hazy solution, essentially free of visible contaminants, particles and/or particulates. Do not use if discoloration or particulate matter is present.. Use the reconstituted solution immediately to prepare the RYTELO diluted solution in the infusion bag.. Dilution:Calculate the required volume of the reconstituted RYTELO solution needed to obtain the appropriate dose according to the patients body weight.Withdraw volume equal to the required reconstituted RYTELO solution from 500 mL infusion bag of 0.9% Sodium Chloride Injection and discard it.Add the required volume of reconstituted RYTELO solution into the infusion bag so that the total final volume of RYTELO solution in the bag is approximately 500 mL. Discard any unused portion of the reconstituted solution remaining in each vial.Gently invert the infusion bag at least times to ensure that the reconstituted RYTELO is well-mixed. Do not shake the infusion bag prior to administration.. Calculate the required volume of the reconstituted RYTELO solution needed to obtain the appropriate dose according to the patients body weight.. Withdraw volume equal to the required reconstituted RYTELO solution from 500 mL infusion bag of 0.9% Sodium Chloride Injection and discard it.. Add the required volume of reconstituted RYTELO solution into the infusion bag so that the total final volume of RYTELO solution in the bag is approximately 500 mL. Discard any unused portion of the reconstituted solution remaining in each vial.. Gently invert the infusion bag at least times to ensure that the reconstituted RYTELO is well-mixed. Do not shake the infusion bag prior to administration.. Diluted RYTELO Solution Storage:If not used immediately, ensure that diluted solution for infusion is used within the total timeframes specified below, according to storage temperature:When stored at room temperature 20C to 25C (68F to 77F):The total time from the reconstitution of RYTELO to completion of the intravenous infusion should not exceed 18 hours from the time of reconstitution.When stored refrigerated 2C to 8C (36F to 46F):The total time from the reconstitution of RYTELO to completion of the intravenous infusion should not exceed 48 hours from the time of reconstitution. If not used immediately, ensure that diluted solution for infusion is used within the total timeframes specified below, according to storage temperature:When stored at room temperature 20C to 25C (68F to 77F):The total time from the reconstitution of RYTELO to completion of the intravenous infusion should not exceed 18 hours from the time of reconstitution.When stored refrigerated 2C to 8C (36F to 46F):The total time from the reconstitution of RYTELO to completion of the intravenous infusion should not exceed 48 hours from the time of reconstitution. When stored at room temperature 20C to 25C (68F to 77F):The total time from the reconstitution of RYTELO to completion of the intravenous infusion should not exceed 18 hours from the time of reconstitution.. When stored refrigerated 2C to 8C (36F to 46F):The total time from the reconstitution of RYTELO to completion of the intravenous infusion should not exceed 48 hours from the time of reconstitution.. Administration: Administer the diluted RYTELO solution by intravenous infusion only over period of hours.. Administer the diluted RYTELO solution by intravenous infusion only over period of hours.

DOSAGE FORMS & STRENGTHS SECTION.

3. DOSAGE FORMS AND STRENGTHS. For injection: 47 mg of imetelstat supplied as white to off-white or slightly yellow lyophilized powder in single-dose vial for reconstitution.For injection: 188 mg of imetelstat supplied as white to off-white or slightly yellow lyophilized powder in single-dose vial for reconstitution.. For injection: 47 mg of imetelstat supplied as white to off-white or slightly yellow lyophilized powder in single-dose vial for reconstitution.. For injection: 188 mg of imetelstat supplied as white to off-white or slightly yellow lyophilized powder in single-dose vial for reconstitution.. For injection: 47 mg powder in single-dose vial for reconstitution. (3)For injection: 188 mg powder in single-dose vial for reconstitution. (3). For injection: 47 mg powder in single-dose vial for reconstitution. (3). For injection: 188 mg powder in single-dose vial for reconstitution. (3).

ADVERSE REACTIONS SECTION.

6. ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Thrombocytopenia [see Warnings and Precautions (5.1)] Neutropenia [see Warnings and Precautions (5.2)]Infusion-Related Reactions [see Warnings and Precautions (5.3)] Thrombocytopenia [see Warnings and Precautions (5.1)] Neutropenia [see Warnings and Precautions (5.2)]. Infusion-Related Reactions [see Warnings and Precautions (5.3)] Most common adverse reactions (incidence >=10% with difference between arms of >5% compared to placebo), including laboratory abnormalities are decreased platelets, decreased white blood cells, decreased neutrophils, increased AST, increased alkaline phosphatase, increased ALT, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infections, and headache. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Geron Corporation at 1-855-437-6664 (1-855-GERONMI) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1. Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Low- to Intermediate-Risk Myelodysplastic SyndromesThe safety of RYTELO was evaluated in randomized, double-blind, placebo-controlled, multicenter trial (IMerge) in 177 adult patients with International Prognostic Scoring System (IPSS) low- to intermediate-1 risk MDS who were transfusion-dependent and relapsed or refractory to or ineligible for ESA treatment [see Clinical Studies (14)]. The safety population included patients who received at least one dose of either RYTELO (n=118) or placebo (n=59) at 7.1 mg/kg as an intravenous infusion administered over two hours every weeks. The median time on treatment with RYTELO was months (range, to 38 months); 69% of patients were exposed to RYTELO for 24 weeks or longer and 45% were exposed for 48 weeks or longer.The median age of patients who received at least one dose of RYTELO was 72 years (range: 44 to 87 years) with 77% of patients 65 years of age and older and 30% of patients 75 years of age and older. Participants were 60% male, 81% White, 7% Asian, and 0.8% Black.Serious adverse reactions occurred in 32% of patients who received RYTELO. Serious adverse reactions in 2% of patients included sepsis (4.2%), fracture (3.4%), cardiac failure (2.5%), and hemorrhage (2.5%). Fatal adverse reactions occurred in 0.8% of patients who received RYTELO, including sepsis (0.8%).Permanent discontinuation of RYTELO due to an adverse reaction occurred in 15% of patients. Adverse reactions which resulted in permanent discontinuation of RYTELO in 2% of patients included neutropenia and thrombocytopenia.Dosage interruptions of RYTELO due to an adverse reaction occurred in 80% of patients. Adverse reactions which required dosage interruption in 5% of patients included neutropenia, thrombocytopenia and infections.Dose reductions of RYTELO due to an adverse reaction occurred in 49% of patients. Adverse reactions which required dose reductions in 2% of patients included neutropenia and thrombocytopenia.The most common (>=10% with difference between arms of >5% compared to placebo) adverse reactions, including laboratory abnormalities, were decreased platelets, decreased white blood cells, decreased neutrophils, increased AST, increased alkaline phosphatase, increased ALT, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infections, and headache.Table summarizes the adverse reactions in IMerge.Table 5: Adverse Reactions (>=5%) in Patients with MDS Who Received RYTELO with Difference Between Arms of >2% Compared to Placebo in IMergeAdverse ReactionRYTELO(N=118)Placebo(N=59)All Grades%Grades or 4%All Grades%Grades or 4%Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.General disorders and administrative site conditions FatigueFatigue: asthenia, fatigue, and malaise. 290203.4Musculoskeletal and connective tissue disorders Arthralgia/myalgiaArthralgia/myalgia: arthralgia, back pain, bone pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain, pain in extremity, pain in jaw, and pelvic pain. 252.5195Infections and infestations COVID-19COVID-19: asymptomatic COVID-19, COVID-19, COVID-19 pneumonia, and SARS-CoV-2 antibody test positive. 191.7145 Urinary tract infectionUrinary tract infection: cystitis, Escherichia urinary tract infection, renal abscess, and urinary tract infection. 92.570Nervous system disorders Headache130.850 SyncopeSyncope: fall, pre-syncope, and syncope. 71.71.70Immune system disorders Infusion-related reactionsInfusion-related reactions: abdominal pain, arthralgia, asthenia, back pain, bone pain, diarrhea, erythema, headache, hypertensive crisis, malaise, non-cardiac chest pain, pruritus, and urticaria. Only events considered related to infusion-related reactions are included. 81.73.40Respiratory, thoracic and mediastinal disorders Epistaxis7000Vascular disorders Hematoma6000Skin and subcutaneous tissue disorders Pruritus601.70Cardiac disorders Atrial arrhythmiaAtrial arrhythmia: atrial fibrillation and atrial flutter. 61.73.41.7Injury, poisoning and procedural complications FracturesFractures: femur fracture, hand fracture, hip fracture, humerus fracture, lumbar vertebral fracture, and thoracic vertebral fracture. 53.41.71.7Clinically relevant adverse reactions in 5% of patients who received RYTELO included febrile neutropenia, sepsis, gastrointestinal hemorrhage, and hypertension.Table summarizes the laboratory abnormalities in IMerge.Table 6: Select Laboratory Abnormalities (>=10%) That Worsened from Baseline in Patients with MDS Who Received RYTELO with Difference Between Arms of >2% Compared to Placebo in IMergeLaboratory AbnormalityRYTELOThe denominator used to calculate the rate varied from 97 to 118 based on the number of patients with baseline value and at least one post-treatment value. PlaceboThe denominator used to calculate the rate varied from 50 to 59 based on the number of patients with baseline value and at least one post-treatment value. All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.ALP alkaline phosphatase; ALT alanine aminotransferase; AST aspartate aminotransferase; PTT partial thromboplastin timeHematologyPlatelet count decreased9765348White blood cell count decreased9453591.7Neutrophil count decreased9272477PTT prolonged261184ChemistryAST increased530.8221.7ALP increased480120ALT increased433.4375.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with imetelstat.In vitro, imetelstat was not mutagenic in the bacterial mutagenicity assay (Ames test) or clastogenic in the chromosomal aberrations assay using cultured human peripheral blood lymphocytes. Imetelstat was not genotoxic in an in vivo mouse micronucleus assay at intravenous dose levels up to approximately 104 mg/kg.Fertility studies have not been conducted with imetelstat. Female monkeys given 14.1 mg/kg once weekly for months exhibited uterine endometrial atrophy in general toxicology study. This effect was observed at mean exposure (based on AUC) that is approximately 14.4-times the human exposure at the recommended clinical dose. This finding was not present in animals following 14-week recovery period.

CLINICAL PHARMACOLOGY SECTION.

12. CLINICAL PHARMACOLOGY. 12.1. Mechanism of Action. Imetelstat is an oligonucleotide human telomerase inhibitor that binds to the template region of the RNA component of human telomerase (hTR), inhibits telomerase enzymatic activity and prevents telomere binding.Increased telomerase activity and human telomerase reverse transcriptase (hTERT) RNA expression have been reported in MDS and malignant stem and progenitor cells. Nonclinical studies showed imetelstat treatment led to reduction of telomere length, reduction of malignant stem and progenitor cell proliferation, and induction of apoptotic cell death.. 12.2. Pharmacodynamics. Grade and ThrombocytopeniaHigher imetelstat exposure is associated with higher incidence of Grade and thrombocytopenia in patients with MDS.. Cardiac ElectrophysiologyAt the maximum recommended dose, clinically significant QTc interval prolongation was not observed.. 12.3. Pharmacokinetics. Imetelstat plasma geometric mean (coefficient of variation [CV] %) maximum concentration (Cmax) is 18.3 uM (27.3%) and the area under the concentration-time curve from time to 28 days (AUC0-28) was 114.2 huM (43.2%). Imetelstat does not accumulate between treatment cycles.. DistributionFollowing single intravenous dose of 7.1 mg/kg of RYTELO administered over hours in patients with MDS, the geometric mean (CV%) volume of distribution is approximately 14.1 (27.2%). In vitro human plasma protein binding is greater than 94%.. EliminationThe imetelstat geometric mean (CV%) apparent plasma half-life is approximately 4.9 hours (43.2%) at the approved recommended dosage.. MetabolismImetelstat is expected to be metabolized by nucleases to nucleotides of various lengths.. Specific populationsNo clinically significant differences in the pharmacokinetics of imetelstat were observed based on age (21 to 87 years), sex, race (81% White, 4% Asian, 7% Black, 8% other/unknown), mild to moderate renal impairment (CLcr 30 to 90 mL/min), mild hepatic impairment (total bilirubin <= ULN and AST ULN, or total bilirubin 1x to 1.5x ULN and any AST), or moderate hepatic impairment (total bilirubin 1.5x to 3x ULN and any AST). The effect of severe renal impairment (CLcr 15 to 30 mL/min), end-stage renal disease, or severe hepatic impairment (total bilirubin 3x ULN and any AST) has not been established.. Drug Interaction Studies. In Vitro Studies. CYP Enzymes: Imetelstat is not an inhibitor or inducer of CYP450 enzymes. Transporter systems: Imetelstat is an inhibitor of OATP1B1 and OATP1B3. 12.6. Immunogenicity. The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of RYTELO.Seventeen percent (28/166) of evaluable patients with low- or intermediate-1 risk MDS tested positive for imetelstat anti-drug antibodies, with median onset of 38 weeks following the study drug dosage of RYTELO for median duration of treatment of 35 weeks in Phase and Phase of the IMerge study. There was no clinically significant effect of ADA on the PK, safety, or efficacy of RYTELO among the study participants who developed anti-drug antibodies.

CLINICAL STUDIES SECTION.

14. CLINICAL STUDIES. 14.1.Myelodysplastic Syndromes (MDS). The efficacy of RYTELO was evaluated in randomized, double-blind, placebo-controlled, multicenter trial (IMerge; NCT02598661) in 178 patients enrolled with International Prognostic Scoring System (IPSS) low- or intermediate-1 risk MDS who were transfusion-dependent (requiring >= red blood cell (RBC) units over an 8-week period during the 16 weeks prior to randomization). Eligible patients were required to have failed to respond or have lost response or be ineligible for erythropoiesis-stimulating agents (ESAs); and had an absolute neutrophil count of 1.5 109/L or greater and platelets 75 109/L or greater. Patients were ineligible if they had del(5q) cytogenetic abnormality or had received prior treatment with lenalidomide or hypomethylating agents.Participants were randomized in 2:1 ratio to receive an intravenous infusion of RYTELO (n=118) 7.1 mg/kg or placebo (n=60) in 28-day treatment cycles until disease progression, unacceptable toxicity, or withdrawal from the study. Randomization was stratified by prior RBC transfusion burden and by IPSS risk group. All patients received supportive care, which included RBC transfusions.Of the 178 patients enrolled, the median age was 72 years (range: 39 to 87 years), with 62% male, and 80% White, 6% Asian, 1.7% Black, 12% other or not reported. The key baseline disease characteristics of the efficacy population are shown in Table 7.Table 7: Baseline Disease Characteristics of Patients with MDS in IMergeDisease CharacteristicRYTELO(N=118)Placebo(N=60)Abbreviations: ECOG Eastern Cooperative Oncology Group; ESA erythropoietin stimulating agents; IPSS International Prognostic Scoring System; RBC Red Blood Cell; MDS myelodysplastic syndromes; sEPO serum erythropoietin; WHO World Health OrganizationTime since original diagnosis Median years (range)3.5 (0.1, 26.7)2.8 (0.2, 25.7)ECOG Score (0, 1, 2), (%) 0: Asymptomatic42 (35.6)21 (35) 1: Symptomatic fully ambulatory70 (59.3)39 (65) 2: Symptomatic in bed less than 50% of the day6 (5.1)0IPSS Risk Classification, (%) Low80 (67.8)39 (65) Intermediate-138 (32.2)21 (35)Prior RBC transfusion burdenPrior RBC transfusion burden is defined as the maximum number of RBC units transfused over an 8-week period during the 16 weeks prior to randomization., (%) to units62 (52.5)33 (55) 6 units56 (47.5)27 (45)WHO Classification (2008), (%) RS+RS+ includes refractory anemia with ring sideroblasts (RARS)/refractory cytopenia with multilineage dysplasia and >= 15% ringed sideroblasts (RCMD-RS). 73 (61.9)37 (61.7) RSRS includes others. 44 (37.3)23 (38.3) Missing1 (0.8)0Baseline sEPO, (%) <= 500 mU/mL87 (73.7)36 (60) 500 mU/mL26 (22)22 (36.7) Missing5 (4.2)2 (3.3)Prior ESA Use, (%) Yes108 (91.5)52 (86.7) No10 (8.5)8 (13.3)Baseline blood counts, median Neutrophils (cells/L)2.6 109 2.7 109 Hemoglobin (g/dL)7.97.8 Platelets (cells/L)230 109 230 109 Efficacy was established after median follow up time of 19.5 months (range: 1.4 to 36.2) in the imetelstat group and 17.5 months (range: 0.7 to 34.3) in the placebo group based upon the proportion of patients who achieved >= 8-week and >= 24-week RBC-TI, defined as the absence of RBC transfusion(s) during any consecutive 8-week (56-day) period, and during any consecutive 24-week (168-day) period, respectively, from randomization until the start of subsequent anti-cancer therapy (if any). The efficacy results are summarized in Table 8.Table 8: Efficacy Results of RYTELO in IMergeRYTELO(N=118)Placebo(N=60)% Difference(95% CI)95% CI based on Wilson Score method. p-valuep-value is based on Cochran-Mantel-Haenszel (CMH) controlling for prior RBC transfusion burden (<= versus >6 units RBC) and IPSS risk group (low versus intermediate-1) applied to randomization.Abbreviations: CI Confidence Interval; RBC Red Blood Cell; TI Transfusion IndependenceRate of >= 8-week RBC TI >= 8-week RBC TI, (%)47 (39.8)9 (15.0)24.8(9.9, 36.9)< 0.001 95% CI for response rate (%)Exact Clopper-Pearson confidence interval. (30.9, 49.3)(7.1, 26.6)Rate of >= 24-week RBC TI >= 24-week RBC TI, (%)33 (28.0)2 (3.3)24.6 95% CI for response rate (%) (20.1, 37.0)(0.4, 11.5)(12.6, 34.2)< 0.001.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1. Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Low- to Intermediate-Risk Myelodysplastic SyndromesThe safety of RYTELO was evaluated in randomized, double-blind, placebo-controlled, multicenter trial (IMerge) in 177 adult patients with International Prognostic Scoring System (IPSS) low- to intermediate-1 risk MDS who were transfusion-dependent and relapsed or refractory to or ineligible for ESA treatment [see Clinical Studies (14)]. The safety population included patients who received at least one dose of either RYTELO (n=118) or placebo (n=59) at 7.1 mg/kg as an intravenous infusion administered over two hours every weeks. The median time on treatment with RYTELO was months (range, to 38 months); 69% of patients were exposed to RYTELO for 24 weeks or longer and 45% were exposed for 48 weeks or longer.The median age of patients who received at least one dose of RYTELO was 72 years (range: 44 to 87 years) with 77% of patients 65 years of age and older and 30% of patients 75 years of age and older. Participants were 60% male, 81% White, 7% Asian, and 0.8% Black.Serious adverse reactions occurred in 32% of patients who received RYTELO. Serious adverse reactions in 2% of patients included sepsis (4.2%), fracture (3.4%), cardiac failure (2.5%), and hemorrhage (2.5%). Fatal adverse reactions occurred in 0.8% of patients who received RYTELO, including sepsis (0.8%).Permanent discontinuation of RYTELO due to an adverse reaction occurred in 15% of patients. Adverse reactions which resulted in permanent discontinuation of RYTELO in 2% of patients included neutropenia and thrombocytopenia.Dosage interruptions of RYTELO due to an adverse reaction occurred in 80% of patients. Adverse reactions which required dosage interruption in 5% of patients included neutropenia, thrombocytopenia and infections.Dose reductions of RYTELO due to an adverse reaction occurred in 49% of patients. Adverse reactions which required dose reductions in 2% of patients included neutropenia and thrombocytopenia.The most common (>=10% with difference between arms of >5% compared to placebo) adverse reactions, including laboratory abnormalities, were decreased platelets, decreased white blood cells, decreased neutrophils, increased AST, increased alkaline phosphatase, increased ALT, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infections, and headache.Table summarizes the adverse reactions in IMerge.Table 5: Adverse Reactions (>=5%) in Patients with MDS Who Received RYTELO with Difference Between Arms of >2% Compared to Placebo in IMergeAdverse ReactionRYTELO(N=118)Placebo(N=59)All Grades%Grades or 4%All Grades%Grades or 4%Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.General disorders and administrative site conditions FatigueFatigue: asthenia, fatigue, and malaise. 290203.4Musculoskeletal and connective tissue disorders Arthralgia/myalgiaArthralgia/myalgia: arthralgia, back pain, bone pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain, pain in extremity, pain in jaw, and pelvic pain. 252.5195Infections and infestations COVID-19COVID-19: asymptomatic COVID-19, COVID-19, COVID-19 pneumonia, and SARS-CoV-2 antibody test positive. 191.7145 Urinary tract infectionUrinary tract infection: cystitis, Escherichia urinary tract infection, renal abscess, and urinary tract infection. 92.570Nervous system disorders Headache130.850 SyncopeSyncope: fall, pre-syncope, and syncope. 71.71.70Immune system disorders Infusion-related reactionsInfusion-related reactions: abdominal pain, arthralgia, asthenia, back pain, bone pain, diarrhea, erythema, headache, hypertensive crisis, malaise, non-cardiac chest pain, pruritus, and urticaria. Only events considered related to infusion-related reactions are included. 81.73.40Respiratory, thoracic and mediastinal disorders Epistaxis7000Vascular disorders Hematoma6000Skin and subcutaneous tissue disorders Pruritus601.70Cardiac disorders Atrial arrhythmiaAtrial arrhythmia: atrial fibrillation and atrial flutter. 61.73.41.7Injury, poisoning and procedural complications FracturesFractures: femur fracture, hand fracture, hip fracture, humerus fracture, lumbar vertebral fracture, and thoracic vertebral fracture. 53.41.71.7Clinically relevant adverse reactions in 5% of patients who received RYTELO included febrile neutropenia, sepsis, gastrointestinal hemorrhage, and hypertension.Table summarizes the laboratory abnormalities in IMerge.Table 6: Select Laboratory Abnormalities (>=10%) That Worsened from Baseline in Patients with MDS Who Received RYTELO with Difference Between Arms of >2% Compared to Placebo in IMergeLaboratory AbnormalityRYTELOThe denominator used to calculate the rate varied from 97 to 118 based on the number of patients with baseline value and at least one post-treatment value. PlaceboThe denominator used to calculate the rate varied from 50 to 59 based on the number of patients with baseline value and at least one post-treatment value. All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.ALP alkaline phosphatase; ALT alanine aminotransferase; AST aspartate aminotransferase; PTT partial thromboplastin timeHematologyPlatelet count decreased9765348White blood cell count decreased9453591.7Neutrophil count decreased9272477PTT prolonged261184ChemistryAST increased530.8221.7ALP increased480120ALT increased433.4375.

CONTRAINDICATIONS SECTION.

4. CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11. DESCRIPTION. RYTELO for injection contains imetelstat, an oligonucleotide telomerase inhibitor for intravenous use. Imetelstat sodium is white to off-white or slightly yellow, amorphous, solid powder. It is highly soluble in aqueous solutions, including in 0.9% Sodium Chloride Injection, at both refrigerated and room temperatures. Imetelstat sodium is hygroscopic.The chemical name for the imetelstat sodium drug substance is DNA, d(3-amino-3-deoxy-P-thio) (T-A-G-G-G-T-T-A-G-A-C-A-A), 5-[O-[2-hydroxy-3-(hexadecanoylamino)propyl] phosphorothioate], sodium salt (1:13). The molecular formula is C148H198N68O53P13S13Na13 (as sodium salt), which equates to formula weight of 4896 g/mol. The molecular formula for the free acid form is C148H211N68O53P13S13 which equates to formula weight of 4610 g/mol. The structural formula for imetelstat sodium is:RYTELO (imetelstat) for injection is sterile, preservative-free, white to off-white or slightly yellow lyophilized powder for intravenous infusion after reconstitution and dilution. Each single-dose vial provides either 47 mg of imetelstat (equivalent to 50 mg imetelstat sodium) or 188 mg of imetelstat (equivalent to 200 mg imetelstat sodium). The following inactive ingredients may be added during manufacturing: sodium carbonate anhydrous (for the 47 mg preparation) sodium carbonate monohydrate (for the 188 mg preparation) or hydrochloric acid (to adjust to pH of 7.0 to 8.5).. Chemical Structure.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3. Females and Males of Reproductive Potential. Based on findings from animal studies, RYTELO can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating treatment with RYTELO.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with RYTELO and for week after the last dose [see Use in Specific Populations (8.1)].. Infertility FemalesBased on findings in animals, RYTELO may impair fertility in females of reproductive potential. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5. Geriatric Use. Of the 118 patients with low- to intermediate-1 risk myelodysplastic syndromes (MDS) in the clinical trial who received RYTELO, 91 (77.1%) patients were 65 years of age and older and 35 (29.7%) patients 75 years of age and older. No differences in safety or efficacy were observed between older (>= 65 years) and younger patients.

HOW SUPPLIED SECTION.

16. HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedRYTELO (imetelstat) for injection is preservative free, white to off-white or slightly yellow, lyophilized powder available as:Carton ContentsNDCOne RYTELO 47 mg single-dose vial82959-112-01One RYTELO 188 mg single-dose vial82959-111-01. StorageStore vials refrigerated at 2C to 8C (36F to 46F) in original carton.Do not freeze.

IMMUNOGENICITY.

12.6. Immunogenicity. The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of RYTELO.Seventeen percent (28/166) of evaluable patients with low- or intermediate-1 risk MDS tested positive for imetelstat anti-drug antibodies, with median onset of 38 weeks following the study drug dosage of RYTELO for median duration of treatment of 35 weeks in Phase and Phase of the IMerge study. There was no clinically significant effect of ADA on the PK, safety, or efficacy of RYTELO among the study participants who developed anti-drug antibodies.

INDICATIONS & USAGE SECTION.

1. INDICATIONS AND USAGE. RYTELO is indicated for the treatment of adult patients with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia requiring or more red blood cell units over weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESA).. RYTELO is an oligonucleotide telomerase inhibitor indicated for the treatment of adult patients with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia requiring or more red blood cell units over weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESA). (1).

INFORMATION FOR PATIENTS SECTION.

17. PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).Discuss the following with patients prior to and during treatment with RYTELO.. ThrombocytopeniaAdvise patients of the risk of thrombocytopenia with RYTELO, and that their blood counts will be monitored routinely while on treatment and dose of RYTELO delayed or reduced as needed. Instruct patients to notify healthcare provider immediately if they show signs or symptoms of thrombocytopenia such as unusual bleeding or bruising [see Warnings and Precautions (5.1)].. NeutropeniaAdvise patients of the risk of neutropenia with RYTELO and that their blood counts will be monitored routinely while on treatment and the dose of RYTELO may be delayed or reduced as needed. Instruct patients to notify healthcare provider immediately if they show signs or symptoms of neutropenia, such as fever or infection [see Warnings and Precautions (5.2)].. Infusion-Related ReactionsInform patients that infusion-related reactions can occur during treatment with RYTELO and premedications will be given prior to each infusion. Patients will be monitored by their healthcare provider for at least an hour after the infusion [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)].Advise patients that their healthcare provider may decide to give RYTELO more slowly or stop the infusion if an infusion-related reaction occurs [see Adverse Reactions (6.1)] Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with RYTELO and for week after the last dose [see Use in Specific Populations (8.3)].. LactationAdvise women not to breastfeed during treatment with RYTELO and for week after the last dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2. Lactation. Risk Summary There is no data on the presence of imetelstat in human milk, or the effects RYTELO on the breastfed child, or milk production. Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with RYTELO and for week after the last dose.

MECHANISM OF ACTION SECTION.

12.1. Mechanism of Action. Imetelstat is an oligonucleotide human telomerase inhibitor that binds to the template region of the RNA component of human telomerase (hTR), inhibits telomerase enzymatic activity and prevents telomere binding.Increased telomerase activity and human telomerase reverse transcriptase (hTERT) RNA expression have been reported in MDS and malignant stem and progenitor cells. Nonclinical studies showed imetelstat treatment led to reduction of telomere length, reduction of malignant stem and progenitor cell proliferation, and induction of apoptotic cell death.

NONCLINICAL TOXICOLOGY SECTION.

13. NONCLINICAL TOXICOLOGY. 13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with imetelstat.In vitro, imetelstat was not mutagenic in the bacterial mutagenicity assay (Ames test) or clastogenic in the chromosomal aberrations assay using cultured human peripheral blood lymphocytes. Imetelstat was not genotoxic in an in vivo mouse micronucleus assay at intravenous dose levels up to approximately 104 mg/kg.Fertility studies have not been conducted with imetelstat. Female monkeys given 14.1 mg/kg once weekly for months exhibited uterine endometrial atrophy in general toxicology study. This effect was observed at mean exposure (based on AUC) that is approximately 14.4-times the human exposure at the recommended clinical dose. This finding was not present in animals following 14-week recovery period.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 47 mg Vial Label. NDC 82959-112-01RYTELO(TM) (imetelstat) for Injection47 mg/vialFor intravenous infusion after reconstitution and dilution.Single-Dose Vial. Discard Unused Portion.. PRINCIPAL DISPLAY PANEL 47 mg Vial Label.

PEDIATRIC USE SECTION.

8.4. Pediatric Use. Safety and effectiveness of RYTELO in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2. Pharmacodynamics. Grade and ThrombocytopeniaHigher imetelstat exposure is associated with higher incidence of Grade and thrombocytopenia in patients with MDS.. Cardiac ElectrophysiologyAt the maximum recommended dose, clinically significant QTc interval prolongation was not observed.

PHARMACOKINETICS SECTION.

12.3. Pharmacokinetics. Imetelstat plasma geometric mean (coefficient of variation [CV] %) maximum concentration (Cmax) is 18.3 uM (27.3%) and the area under the concentration-time curve from time to 28 days (AUC0-28) was 114.2 huM (43.2%). Imetelstat does not accumulate between treatment cycles.. DistributionFollowing single intravenous dose of 7.1 mg/kg of RYTELO administered over hours in patients with MDS, the geometric mean (CV%) volume of distribution is approximately 14.1 (27.2%). In vitro human plasma protein binding is greater than 94%.. EliminationThe imetelstat geometric mean (CV%) apparent plasma half-life is approximately 4.9 hours (43.2%) at the approved recommended dosage.. MetabolismImetelstat is expected to be metabolized by nucleases to nucleotides of various lengths.. Specific populationsNo clinically significant differences in the pharmacokinetics of imetelstat were observed based on age (21 to 87 years), sex, race (81% White, 4% Asian, 7% Black, 8% other/unknown), mild to moderate renal impairment (CLcr 30 to 90 mL/min), mild hepatic impairment (total bilirubin <= ULN and AST ULN, or total bilirubin 1x to 1.5x ULN and any AST), or moderate hepatic impairment (total bilirubin 1.5x to 3x ULN and any AST). The effect of severe renal impairment (CLcr 15 to 30 mL/min), end-stage renal disease, or severe hepatic impairment (total bilirubin 3x ULN and any AST) has not been established.. Drug Interaction Studies. In Vitro Studies. CYP Enzymes: Imetelstat is not an inhibitor or inducer of CYP450 enzymes. Transporter systems: Imetelstat is an inhibitor of OATP1B1 and OATP1B3.

PREGNANCY SECTION.

8.1. Pregnancy. Risk SummaryBased on findings in animal studies, RYTELO can cause embryo-fetal harm when administered to pregnant woman. There are no available data on RYTELO use in pregnant women to evaluate for drug-associated risk. In embryo-fetal developmental toxicity studies, administration of imetelstat to pregnant mice and rabbits during the period of organogenesis resulted in embryo-fetal mortality, which in mice occurred at maternal exposures approximately 2.5 times the human exposure at the recommended clinical dose. Advise pregnant women of the potential risk to fetus [see Data].In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataIn embryo-fetal developmental toxicity studies, imetelstat was administered by IV bolus injection at doses of 4.7, 9.4, 14.1 or 28.2 mg/kg/day on gestation days 6, 9, and 12 in mice, or by 2-hour intravenous infusion at doses of 4.7, 14.1, or 28.2 mg/kg on gestation days and 13 in rabbits. In rabbits, the dose of 28.2 mg/kg was maternally toxic. Increased post-implantation loss due to an increase in early resorptions, resulting in decrease in viable fetuses and litter was noted in mice at 28.2 mg/kg and in rabbits starting at 14.1 mg/kg; corresponding to exposures (based on AUC) that are approximately 2.5-times (mice) or 9.3-times (rabbits) the human exposure at the recommended clinical dose.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Issued: 6/2024 MEDICATION GUIDERYTELO(TM) (ri-TEL-o)(imetelstat)for injection, for intravenous useWhat is the most important information should know about RYTELORYTELO may cause serious side effects, including:Low platelet counts (thrombocytopenia). Low platelet counts are common during treatment with RYTELO and can also be severe. Low platelet counts can increase your risk for bleeding. Your healthcare provider may give you platelet transfusions to reduce the risk of bleeding if you develop low platelet count during treatment with RYTELO. Tell your healthcare provider right away if you develop any signs or symptoms of bleeding, including:unusual bleeding or bruisingbleeding that lasts long timenosebleedsvomiting bloodblood in your stool or black tarry stoolLow neutrophil counts (neutropenia). Low counts of type of white blood cell called neutrophils are common during treatment with RYTELO and can also be severe. Low neutrophil counts can increase your risk for infections, including serious infections and sepsis. Your healthcare provider may give you medicines before you start treatment to help prevent neutropenia and infections and may treat you with medicines if you develop these problems during treatment with RYTELO. Tell your healthcare provider right away if you develop any signs or symptoms of infection during treatment with RYTELO, including:fevershortness of breath or trouble breathingcoughchillspain or burning when you urinateYour healthcare provider will do blood tests to check your platelet and neutrophil counts before starting treatment with RYTELO, weekly for the first cycles of treatment, before you receive each additional cycle, and as needed during your treatment.Your healthcare provider may delay your next treatment, decrease your dose, or stop treatment with RYTELO if you develop thrombocytopenia or neutropenia during treatment.See What are the possible side effects of RYTELO for more information about side effects.What is RYTELORYTELO is prescription medicine used to treat condition called low- to intermediate-1 risk myelodysplastic syndromes (MDS) in adults: with anemia (low red blood cell counts) who need blood transfusions of or more red blood cell units over weeks and who have not responded to, have stopped responding to, or cannot be treated with other medicines called erythropoiesis-stimulating agents (ESAs).It is not known if RYTELO is safe and effective in children.Before receiving RYTELO, tell your healthcare provider about all of your medical conditions, including if you:are pregnant or plan to become pregnant. RYTELO may harm your unborn baby and may cause loss of pregnancy (miscarriage). Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with RYTELO. Females who are able to become pregnant: Your healthcare provider will perform pregnancy test before you are given RYTELO.You should use effective birth control (contraception) during treatment with RYTELO and for week after your last dose. are breastfeeding or plan to breastfeed. It is not known if RYTELO passes into your breastmilk. Do not breastfeed during treatment with RYTELO and for week after your last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine. How will receive RYTELORYTELO will be given as an intravenous infusion into your vein over period of hours by your healthcare provider.RYTELO is usually given every weeks.Your healthcare provider will prescribe RYTELO in dose that is right for you and may change your dose, change your dosing schedule, or stop treatment depending on how you respond to RYTELO.Your healthcare provider will do certain blood tests during treatment with RYTELO to check for side effects and to see how well you respond to treatment. Your healthcare provider will decide how long you will continue treatment with RYTELO.What are the possible side effects of RYTELORYTELO may cause serious side effects, including:See What is the most important information should know about RYTELOInfusion-related reactions. RYTELO can cause infusion-related reactions during or after your infusion that can be severe, including severe sudden increase in blood pressure called hypertensive crisis. Your healthcare provider will give you medicines before each RYTELO infusion to help prevent or lessen infusion-related reactions and will watch you for at least hour after your infusion. If you develop infusion-related reactions, your healthcare provider may infuse RYTELO more slowly, temporarily stop, or permanently stop your treatment. Tell your healthcare provider if you develop any signs or symptoms of infusion-related reactions, including:stomach painjoint painweakness and tirednessback and bone paindiarrhearednessheadachehigh blood pressure not feeling wellchest pain that is not related to your heartitchinghivesThe most common side effects of RYTELO include:decreased platelet countsdecreased white blood cell countsdecreased neutrophil countsincreased liver enzymes (AST, alkaline phosphatase, and ALT)tirednesslonger than usual blood clotting timesjoint, bone and muscle painCovid-19 infectionsheadacheRYTELO may cause fertility problems in females. This could affect your ability to get pregnant. Talk to your healthcare provider if this is concern for you.These are not all of the possible side effects of RYTELO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of RYTELO.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or healthcare provider for information about RYTELO that is written for health professionals.What are the ingredients in RYTELOActive ingredient: imetelstat Inactive ingredients: 47 mg: sodium carbonate anhydrous or hydrochloric acid may be added during manufacturing to adjust the pH188 mg: sodium carbonate monohydrate or hydrochloric acid may be added during manufacturing to adjust the pH Manufactured for: Geron Corporation, 919 E. Hillsdale Blvd., Suite 250, Foster City, CA 94404Manufactured by (47 mg vials):Patheon Italia, S.p.A, Trav. SX Via Morolense, 5, 03013 Ferentino (FR), ItalyManufactured by (188 mg vials):Catalent Indiana, LLC, 1300 Patterson Drive, Bloomington, IN 47403GER006-01For more information about RYTELO, go to www.RYTELO.com or call 1-866-471-0921.. Low platelet counts (thrombocytopenia). Low platelet counts are common during treatment with RYTELO and can also be severe. Low platelet counts can increase your risk for bleeding. Your healthcare provider may give you platelet transfusions to reduce the risk of bleeding if you develop low platelet count during treatment with RYTELO. Tell your healthcare provider right away if you develop any signs or symptoms of bleeding, including:. unusual bleeding or bruising. bleeding that lasts long time. nosebleeds. vomiting blood. blood in your stool or black tarry stool. Low neutrophil counts (neutropenia). Low counts of type of white blood cell called neutrophils are common during treatment with RYTELO and can also be severe. Low neutrophil counts can increase your risk for infections, including serious infections and sepsis. Your healthcare provider may give you medicines before you start treatment to help prevent neutropenia and infections and may treat you with medicines if you develop these problems during treatment with RYTELO. Tell your healthcare provider right away if you develop any signs or symptoms of infection during treatment with RYTELO, including:. fever. shortness of breath or trouble breathing. cough. chills. pain or burning when you urinate. with anemia (low red blood cell counts) who need blood transfusions of or more red blood cell units over weeks and who have not responded to, have stopped responding to, or cannot be treated with other medicines called erythropoiesis-stimulating agents (ESAs).. are pregnant or plan to become pregnant. RYTELO may harm your unborn baby and may cause loss of pregnancy (miscarriage). Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with RYTELO. Females who are able to become pregnant: Your healthcare provider will perform pregnancy test before you are given RYTELO.You should use effective birth control (contraception) during treatment with RYTELO and for week after your last dose. Your healthcare provider will perform pregnancy test before you are given RYTELO.. You should use effective birth control (contraception) during treatment with RYTELO and for week after your last dose.. are breastfeeding or plan to breastfeed. It is not known if RYTELO passes into your breastmilk. Do not breastfeed during treatment with RYTELO and for week after your last dose. RYTELO will be given as an intravenous infusion into your vein over period of hours by your healthcare provider.. RYTELO is usually given every weeks.. Your healthcare provider will prescribe RYTELO in dose that is right for you and may change your dose, change your dosing schedule, or stop treatment depending on how you respond to RYTELO.. Your healthcare provider will do certain blood tests during treatment with RYTELO to check for side effects and to see how well you respond to treatment. Your healthcare provider will decide how long you will continue treatment with RYTELO.. See What is the most important information should know about RYTELO. Infusion-related reactions. RYTELO can cause infusion-related reactions during or after your infusion that can be severe, including severe sudden increase in blood pressure called hypertensive crisis. Your healthcare provider will give you medicines before each RYTELO infusion to help prevent or lessen infusion-related reactions and will watch you for at least hour after your infusion. If you develop infusion-related reactions, your healthcare provider may infuse RYTELO more slowly, temporarily stop, or permanently stop your treatment. Tell your healthcare provider if you develop any signs or symptoms of infusion-related reactions, including:. stomach pain. joint pain. weakness and tiredness. back and bone pain. diarrhea. redness. headache. high blood pressure not feeling well. chest pain that is not related to your heart. itching. hives. decreased platelet counts. decreased white blood cell counts. decreased neutrophil counts. increased liver enzymes (AST, alkaline phosphatase, and ALT). tiredness. longer than usual blood clotting times. joint, bone and muscle pain. Covid-19 infections. headache. 47 mg: sodium carbonate anhydrous or hydrochloric acid may be added during manufacturing to adjust the pH. 188 mg: sodium carbonate monohydrate or hydrochloric acid may be added during manufacturing to adjust the pH.

SPL UNCLASSIFIED SECTION.

2.1. Recommended Dosage. The recommended dosage of RYTELO is 7.1 mg/kg administered as an intravenous infusion over hours every weeks. Discontinue RYTELO if patient does not experience decrease in red blood cell (RBC) transfusion burden after 24 weeks of treatment (administration of doses) or if unacceptable toxicity occurs at any time [see Dosage and Administration (2.3)].

STORAGE AND HANDLING SECTION.

StorageStore vials refrigerated at 2C to 8C (36F to 46F) in original carton.Do not freeze.

USE IN SPECIFIC POPULATIONS SECTION.

8. USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1. Pregnancy. Risk SummaryBased on findings in animal studies, RYTELO can cause embryo-fetal harm when administered to pregnant woman. There are no available data on RYTELO use in pregnant women to evaluate for drug-associated risk. In embryo-fetal developmental toxicity studies, administration of imetelstat to pregnant mice and rabbits during the period of organogenesis resulted in embryo-fetal mortality, which in mice occurred at maternal exposures approximately 2.5 times the human exposure at the recommended clinical dose. Advise pregnant women of the potential risk to fetus [see Data].In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataIn embryo-fetal developmental toxicity studies, imetelstat was administered by IV bolus injection at doses of 4.7, 9.4, 14.1 or 28.2 mg/kg/day on gestation days 6, 9, and 12 in mice, or by 2-hour intravenous infusion at doses of 4.7, 14.1, or 28.2 mg/kg on gestation days and 13 in rabbits. In rabbits, the dose of 28.2 mg/kg was maternally toxic. Increased post-implantation loss due to an increase in early resorptions, resulting in decrease in viable fetuses and litter was noted in mice at 28.2 mg/kg and in rabbits starting at 14.1 mg/kg; corresponding to exposures (based on AUC) that are approximately 2.5-times (mice) or 9.3-times (rabbits) the human exposure at the recommended clinical dose.. 8.2. Lactation. Risk Summary There is no data on the presence of imetelstat in human milk, or the effects RYTELO on the breastfed child, or milk production. Because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with RYTELO and for week after the last dose.. 8.3. Females and Males of Reproductive Potential. Based on findings from animal studies, RYTELO can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating treatment with RYTELO.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with RYTELO and for week after the last dose [see Use in Specific Populations (8.1)].. Infertility FemalesBased on findings in animals, RYTELO may impair fertility in females of reproductive potential. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].. 8.4. Pediatric Use. Safety and effectiveness of RYTELO in pediatric patients have not been established.. 8.5. Geriatric Use. Of the 118 patients with low- to intermediate-1 risk myelodysplastic syndromes (MDS) in the clinical trial who received RYTELO, 91 (77.1%) patients were 65 years of age and older and 35 (29.7%) patients 75 years of age and older. No differences in safety or efficacy were observed between older (>= 65 years) and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5. WARNINGS AND PRECAUTIONS. Thrombocytopenia: Grade and Grade thrombocytopenia occurred; obtain complete blood cell counts prior to initiation of RYTELO, weekly for the first two cycles, and prior to each cycle thereafter to monitor. Delay or dose reduce as recommended. (2.3, 5.1)Neutropenia: Grade and Grade neutropenia occurred; obtain complete blood cell counts prior to initiation of RYTELO, weekly for the first two cycles, and prior to each cycle thereafter to monitor. Delay or dose reduce as recommended. (2.3, 5.2)Infusion-Related Reactions: Premedicate before infusion. Interrupt, decrease the rate of infusion, or permanently discontinue RYTELO based on severity. (2.2, 2.3, 5.3)Embryo-Fetal Toxicity: Can cause embryo-fetal harm. Advise females of reproductive potential of potential risk to fetus and to use effective contraception. (5.4, 8.1, 8.3). Thrombocytopenia: Grade and Grade thrombocytopenia occurred; obtain complete blood cell counts prior to initiation of RYTELO, weekly for the first two cycles, and prior to each cycle thereafter to monitor. Delay or dose reduce as recommended. (2.3, 5.1). Neutropenia: Grade and Grade neutropenia occurred; obtain complete blood cell counts prior to initiation of RYTELO, weekly for the first two cycles, and prior to each cycle thereafter to monitor. Delay or dose reduce as recommended. (2.3, 5.2). Infusion-Related Reactions: Premedicate before infusion. Interrupt, decrease the rate of infusion, or permanently discontinue RYTELO based on severity. (2.2, 2.3, 5.3). Embryo-Fetal Toxicity: Can cause embryo-fetal harm. Advise females of reproductive potential of potential risk to fetus and to use effective contraception. (5.4, 8.1, 8.3). 5.1. Thrombocytopenia. RYTELO can cause thrombocytopenia based on laboratory values. In the clinical trial, new or worsening Grade or decreased platelets occurred in 65% of patients with MDS treated with RYTELO [see Adverse Reactions (6.1)].Median time to onset of first occurrence of Grade or decreased platelets was weeks (range: to 88 weeks) and median time to recovery from each occurrence of Grade or decreased platelets to Grade or lower, or last value available, was 1.3 weeks (range: 0.1 to 13 weeks). Grade or decreased platelets occurred throughout treatment with RYTELO, with 48% of patients experiencing Grade or Grade thrombocytopenia during cycles 1-3, 31% during cycles 4-6, 33% during cycles 7-12, and 24% during cycles 13 and beyond. Grade or bleeding was seen in 2.5% of patients, including gastrointestinal bleeding (1.7%) and hematuria (0.8%).Monitor patients with thrombocytopenia for bleeding.Monitor complete blood cell counts prior to initiation of RYTELO, weekly for the first two cycles, prior to each cycle thereafter, and as clinically indicated. Administer platelet transfusions as appropriate. Delay the next cycle and resume at the same or reduced dose, or discontinue as recommended [see Dosage and Administration (2.3)].. 5.2. Neutropenia. RYTELO can cause neutropenia based on laboratory values. In the clinical trial, new or worsening Grade or decreased neutrophils occurred in 72% of patients with MDS treated with RYTELO [see Adverse Reactions (6.1)].Median time to onset of first occurrence of Grade or decreased neutrophils was 4.6 weeks (range: to 81 weeks) and median time to recovery from each occurrence of Grade or decreased neutrophils to Grade or lower, or last value available, was 1.9 weeks (range: to 16 weeks). Grade or decreased neutrophils occurred throughout treatment with RYTELO, with 65% of patients experiencing Grade or Grade neutropenia during cycles 1-3, 35% during cycles 4-6, 32% during cycles 7-12, and 39% during cycles 13 and beyond. Febrile neutropenia occurred in 0.8% and sepsis in 4.2%.Monitor patients with Grade or neutropenia for infections, including sepsis.Monitor complete blood cell counts prior to initiation of RYTELO, weekly for the first two cycles, prior to each cycle thereafter, and as clinically indicated. Administer growth factors and anti-infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose, or discontinue as recommended [see Dosage and Administration (2.3)].. 5.3. Infusion-Related Reactions. RYTELO can cause infusion-related reactions. In the clinical trial, infusion-related reactions occurred in 8% of patients with MDS treated with RYTELO; Grade or infusion-related reactions occurred in 1.7%, including hypertensive crisis (0.8%). The most common infusion-related reaction was headache (4.2%). Infusion-related reactions usually occur during or shortly after the end of the infusion.Premedicate patients at least 30 minutes prior to infusion with diphenhydramine and hydrocortisone as recommended and monitor patients for at least one hour following the infusion as recommended [see Dosage and Administration (2.2)]. Manage symptoms of infusion-related reactions with supportive care and infusion interruptions, decrease infusion rate, or permanently discontinue as recommended [see Dosage and Administration (2.3)].. 5.4. Embryo-Fetal Toxicity. Based on findings in animals, RYTELO can cause embryo-fetal harm when administered to pregnant woman. In animal reproduction studies, administration of imetelstat to pregnant mice during the period of organogenesis resulted in embryo-fetal mortality at maternal exposures (AUC) 2.5-times the human exposure at the recommended clinical dose. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with RYTELO and for week after the last dose [see Use in Specific Populations (8.1, 8.3)].