RYTELOTM (imetelstat) for injection
Drug UPDATES: [Drug information (pdf)]
PACKAGE INSERT -Dosing: Click (+) next to Dosage and Administration section (drug info link)
Dosing information below.
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.
| Strength* | Volume of 0.9% Sodium Chloride Injection for Reconstitution per Vial | Final Concentration of Reconstituted Solution per Vial | Deliverable Volume per Vial |
|---|---|---|---|
| 47 mg | 1.8 mL | 31.4 mg/mL† | 1.5 mL |
| 188 mg | 6.3 mL | 31.4 mg/mL† | 6 mL |
- *Recommended to use the appropriate combination of vial strengths to most closely match the intended dose based on the patient's weight.
- †Each vial contains an overfill to account for loss of liquid during preparation and extraction of the reconstituted solution, resulting in the final concentration.
- 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.
- When stored at room temperature 20°C to 25°C (68°F to 77°F):
Administration:
- Administer the diluted RYTELO solution by intravenous infusion only over a period of 2 hours.
RYTELO for injection contains imetelstat, an oligonucleotide telomerase inhibitor for intravenous use. Imetelstat sodium is a 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 a formula weight of 4896 g/mol. The molecular formula for the free acid form is C148H211N68O53P13S13 which equates to a formula weight of 4610 g/mol.
RYTELO (imetelstat) for injection is a 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).
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.
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).
None.
- Thrombocytopenia: Grade 3 and Grade 4 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 3 and Grade 4 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 a fetus and to use effective contraception. (5.4, 8.1, 8.3)
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. (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.
See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide. Drug information (pdf)
The recommended dosage of RYTELO is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 4 weeks. 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 [see Dosage and Administration (2.3)].
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 [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].
Recommended dose reductions for Grade 3 and Grade 4 adverse reactions are found in Table 1.
The management of Grade 3 and Grade 4 adverse reactions may require temporary dose delay, dose reduction, or treatment discontinuation and are presented in Table 2 and Table 3. RYTELO treatment should be permanently discontinued if the patient cannot tolerate the lowest dose level of 4.4 mg/kg.
| Dose Reduction | Dose Every 4 Weeks |
|---|---|
| First dose reduction | 5.6 mg/kg |
| Second dose reduction | 4.4 mg/kg |
Dosage Modifications for Hematologic (Grade 3 and Grade 4) Adverse Reactions
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. Delay the next cycle if absolute neutrophil count is less than 1 × 109/L or platelets are less than 50 × 109/L. Modify dose as described in Table 2 - Refer to insert: Table 2: Dosage Modifications for Patients with Hematologic Adverse Reactions (Grade 3 and Grade 4) Drug information (pdf).
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.
Table 3: Dosage Modifications for Patients with Non-hematologic Adverse Reactions- see Drug information (pdf).
2.4. 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.
| Strength* | Volume of 0.9% Sodium Chloride Injection for Reconstitution per Vial | Final Concentration of Reconstituted Solution per Vial | Deliverable Volume per Vial |
|---|---|---|---|
| 47 mg | 1.8 mL | 31.4 mg/mL† | 1.5 mL |
| 188 mg | 6.3 mL | 31.4 mg/mL† | 6 mL |
- *Recommended to use the appropriate combination of vial strengths to most closely match the intended dose based on the patient's weight.
- †Each vial contains an overfill to account for loss of liquid during preparation and extraction of the reconstituted solution, resulting in the final concentration.
- 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.
- When stored at room temperature 20°C to 25°C (68°F to 77°F):
Administration:
- Administer the diluted RYTELO solution by intravenous infusion only over a period of 2 hours.
- For injection: 47 mg powder in a single-dose vial for reconstitution.
- For injection: 188 mg powder in a single-dose vial for reconstitution.
Do not freeze.
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.
- When stored at room temperature 20°C to 25°C (68°F to 77°F):
