Rytelo Drug Information

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 4 or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESA).

2. DOSAGE AND ADMINISTRATION The recommended dosage of RYTELO is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 4 weeks. Premedicate prior to dosing with RYTELO for potential infusion-related reactions.

See full prescribing information for preparation and administration instructions. 2.1. Discontinue RYTELO if a patient does not experience a decrease in red blood cell (RBC) transfusion burden after 24 weeks of treatment (administration of 6 doses) or if unacceptable toxicity occurs at any time. 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 orally hydrocortisone (or equivalent) 100 mg to 200 mg, intravenously or orally Monitor patients for adverse reactions for at least one hour after the infusion has been completed. 2.3.

Dosage Modifications for Adverse Reactions Recommended dose reductions for Grade 3 and Grade 4 adverse reactions are found in Table 1. RYTELO treatment should be permanently discontinued if the patient cannot tolerate the lowest dose level of s Monitor complete blood cell counts prior to administration of RYTELO, weekly for the first two cycles, prior to each cycle thereafter, and as clinically indicated. Modify dose as described in Table 2.

Table 2: Dosage Modifications for Patients with Hematologic Dosage Modifications for Non-hematologic Adverse Reactions Dosage 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. Preparation and Administration RYTELO is provided as a lyophilized powder in a 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 a preservative. Reconstitution: Calculate the dose of RYTELO needed based on the patient's 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 a 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 20°C to 25°C (68°F to 77°F) before use.

Reconstitute each vial of RYTELO with the volume of 0.9% Sodium Chloride Injection provided in Table 4 directly onto the lyophilized powder to obtain a concentration of 31.4 mg/mL of imetelstat. Table 4: Reconstitution Volumes 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 a 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 patient's body weight. Withdraw a volume equal to the required reconstituted RYTELO solution from a 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 5 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 20°C to 25°C (68°F to 77°F): 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 2°C to 8°C (36°F to 46°F): 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 a period of 2 hours.

6. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Thrombocytopenia Neutropenia Infusion-Related Reactions Most common adverse reactions (incidence ≥10% with a 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. 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 a 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 Syndromes The safety of RYTELO was evaluated in a 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. 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 4 weeks.

Serious adverse reactions occurred in 32% of patients who received RYTELO. 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. Table 5 summarizes the adverse reactions in IMerge.

Table 5: Adverse Reactions (≥5%) in Patients with MDS Who Received RYTELO with a Difference Between Arms of >2% Compared to Placebo in IMerge Clinically relevant adverse reactions in < 5% of patients who received RYTELO included febrile neutropenia, sepsis, gastrointestinal hemorrhage, and hypertension. Table 6 summarizes the laboratory abnormalities in IMerge.

8.1. Pregnancy Risk Summary Based on findings in animal studies, RYTELO can cause embryo-fetal harm when administered to a 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 a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

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 a 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.

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

4. CONTRAINDICATIONS None. None.