Rytelo
(imetelstat)Dosage & Administration
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Rytelo Prescribing Information
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).
. Recommended Dosage
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)].
. 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 [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].
. Dosage Modifications for Adverse Reactions
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.
| Adverse Reaction | Severity Grade * | Occurrence | Treatment Modification |
|---|---|---|---|
| Abbreviation: ANC = absolute neutrophil count | |||
| |||
| Thrombocytopenia [see Warnings and Precautions (5.1)] | Grade 3 | First | Delay RYTELO until recovery of platelets to 50 × 109/L; restart at same dose level. |
| Second and Third | Delay RYTELO until recovery of platelets to 50 × 109/L; restart at one dose level lower. | ||
| Fourth | Discontinue RYTELO. | ||
| Grade 4 | First and Second | Delay RYTELO until recovery of platelets to 50 × 109/L; restart at one dose level lower. | |
| Third | Discontinue RYTELO. | ||
| Neutropenia [see Warnings and Precautions (5.2)] | Grade 3 | First | Delay RYTELO until recovery of ANC to 1 × 109/L; restart at same dose level. |
| Second and Third | Delay RYTELO until recovery of ANC to 1 × 109/L; restart at one dose level lower. | ||
| Fourth | Discontinue RYTELO. | ||
| Grade 4 | First and Second | Delay RYTELO until recovery of ANC to 1 × 109/L; restart at one dose level lower. | |
| Third | Discontinue RYTELO. | ||
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.
| Adverse Reaction | Severity Grade * | Occurrence | Treatment Modification |
|---|---|---|---|
| Abbreviation: LFT = liver function test | |||
| |||
| Infusion-Related Reactions [see Warnings and Precautions (5.3)] | Grade 2 or 3 | First and Second | Interrupt 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. |
| Third | For Grade 2, stop infusion. May restart at next cycle. For Grade 3, permanently discontinue RYTELO. | ||
| Grade 4 | First | Stop infusion, administer supportive care as appropriate and permanently discontinue RYTELO. | |
| Other adverse reactions including elevated LFTs [see Adverse Reactions (6.1)] | Grade 3 or 4 | First and Second | Delay RYTELO until recovery of adverse reactions to Grade 1 or baseline; restart at one dose level lower. |
| Third | Permanently discontinue RYTELO. | ||
. 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 |
- 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 of imetelstat supplied as a white to off-white or slightly yellow lyophilized powder in a single-dose vial for reconstitution.
- For injection: 188 mg of imetelstat supplied as a white to off-white or slightly yellow lyophilized powder in a single-dose vial for reconstitution.
. 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 [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 Data
In 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 6 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 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.
. 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 1 week after the last dose.
. Females and Males of Reproductive Potential
Based on findings from animal studies, RYTELO can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating treatment with RYTELO.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with RYTELO and for 1 week after the last dose [see Use in Specific Populations (8.1)].
Infertility
Females
Based on findings in animals, RYTELO may impair fertility in females of reproductive potential. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].
. Pediatric Use
Safety and effectiveness of RYTELO in pediatric patients have not been established.
. 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.
None.
. Thrombocytopenia
RYTELO can cause thrombocytopenia based on laboratory values. In the clinical trial, new or worsening Grade 3 or 4 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 3 or 4 decreased platelets was 6 weeks (range: 2 to 88 weeks) and median time to recovery from each occurrence of Grade 3 or 4 decreased platelets to Grade 2 or lower, or last value available, was 1.3 weeks (range: 0.1 to 13 weeks). Grade 3 or 4 decreased platelets occurred throughout treatment with RYTELO, with 48% of patients experiencing Grade 3 or Grade 4 thrombocytopenia during cycles 1-3, 31% during cycles 4-6, 33% during cycles 7-12, and 24% during cycles 13 and beyond. Grade 3 or 4 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)].
. Neutropenia
RYTELO can cause neutropenia based on laboratory values. In the clinical trial, new or worsening Grade 3 or 4 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 3 or 4 decreased neutrophils was 4.6 weeks (range: 1 to 81 weeks) and median time to recovery from each occurrence of Grade 3 or 4 decreased neutrophils to Grade 2 or lower, or last value available, was 1.9 weeks (range: 0 to 16 weeks). Grade 3 or 4 decreased neutrophils occurred throughout treatment with RYTELO, with 65% of patients experiencing Grade 3 or Grade 4 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 3 or 4 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)].
. 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 3 or 4 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)].
. Embryo-Fetal Toxicity
Based on findings in animals, RYTELO can cause embryo-fetal harm when administered to a 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 a fetus. Advise females of reproductive potential to use effective contraception during treatment with RYTELO and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].