Rytelo

Rytelo
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kosar Doraghi, M.D. [2]

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Black Box Warning

Warnings: Thrombocytopenia See full prescribing information for complete Boxed Warning. 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. 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. Infusion-Related Reactions: Premedicate before infusion. Interrupt, decrease the rate of infusion, or permanently discontinue RYTELO based on severity. Embryo-Fetal Toxicity: Can cause embryo-fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception

Overview

Rytelo is an oligonucleotide telomerase inhibitor that is FDA approved for the treatment of oligonucleotide telomerase inhibitor 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).. There is a Black Box Warning for this drug as shown here. Common adverse reactions include 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.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

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. For injection: 47 mg powder in a single-dose vial for reconstitution. For injection: 188 mg powder in a single-dose vial for reconstitution

Off-Label Use and Dosage (Adult)

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Rytelo FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Contraindications

There is limited information regarding Rytelo Contraindications in the drug label.

Warnings

Warnings: Thrombocytopenia See full prescribing information for complete Boxed Warning. 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. 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. Infusion-Related Reactions: Premedicate before infusion. Interrupt, decrease the rate of infusion, or permanently discontinue RYTELO based on severity. Embryo-Fetal Toxicity: Can cause embryo-fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception

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. 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. Infusion-Related Reactions: Premedicate before infusion. Interrupt, decrease the rate of infusion, or permanently discontinue RYTELO based on severity. Embryo-Fetal Toxicity: Can cause embryo-fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception

Adverse Reactions

Clinical Trials Experience

• Thrombocytopenia
• Neutropenia
• Infusion-Related Reactions

Postmarketing Experience

There is limited information regarding Rytelo Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Rytelo Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Based on findings in animal studies, RYTELO can cause embryo-fetal harm when administered to a pregnant woman.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rytelo in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Rytelo during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Rytelo in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Rytelo in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Rytelo in geriatric settings.

Gender

There is no FDA guidance on the use of Rytelo with respect to specific gender populations.

Race

There is no FDA guidance on the use of Rytelo with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Rytelo in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Rytelo in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Rytelo in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Rytelo in patients who are immunocompromised.

Administration and Monitoring

Administration

RYTELO is administered at 7.1 mg/kg via a 2-hour intravenous infusion every 4 weeks. Discontinue treatment if there is no reduction in red blood cell transfusion burden after 24 weeks or if severe toxicity occurs.

• Recommended Premedications

Administer the following 30 minutes before dosing to prevent infusion reactions:

• Diphenhydramine (25-50 mg) IV or orally
• Hydrocortisone (100-200 mg) IV or orally
• Dosage Modifications for Adverse Reactions
• Grade 3 and 4 Adverse Reactions

First dose reduction: 5.6 mg/kg Second dose reduction: 4.4 mg/kg Non-Hematologic Adverse Reactions

• Infusion-Related Reactions:

Grade 2 or 3: Interrupt infusion; restart at 50% rate. Third occurrence may require discontinuation. Grade 4: Discontinue permanently. Other Adverse Reactions (elevated LFTs): Grade 3 or 4: Delay until recovery; restart at a lower dose or discontinue after the third occurrence.

• Preparation and Administration

Reconstitution: Calculate dose based on body weight. Adjust vials to room temperature and reconstitute with 0.9% Sodium Chloride Injection.

• Ensure solution is clear and free of particulates before use.

Dilution: Prepare a 500 mL infusion bag with reconstituted solution, ensuring it is well-mixed.

• Storage: Room temperature: Use within 18 hours.

Refrigerated: Use within 48 hours. Administration: Administer via 2-hour IV infusion.

Monitoring

There is limited information regarding Rytelo Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Rytelo and IV administrations.

Overdosage

There is limited information regarding Rytelo overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Rytelo Pharmacology in the drug label.

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.

Structure

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. The structural formula for imetelstat sodium is:

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).

Pharmacodynamics

Higher imetelstat exposure is associated with higher incidence of Grade 3 and 4 thrombocytopenia in patients with MDS.

Pharmacokinetics

• Plasma Concentrations

The geometric mean (CV%) maximum concentration (Cmax) of imetelstat is 18.3 µM (27.3%), and the area under the concentration-time curve from time 0 to 28 days (AUC0-28) is 114.2 hµM (43.2%). Imetelstat does not accumulate between treatment cycles.

• Distribution

Following a single intravenous dose of 7.1 mg/kg of RYTELO administered over 2 hours in patients with MDS, the geometric mean (CV%) volume of distribution is approximately 14.1 L (27.2%). In vitro human plasma protein binding is greater than 94%.

• Elimination

The geometric mean (CV%) apparent plasma half-life of imetelstat is approximately 4.9 hours (43.2%) at the approved recommended dosage.

• Metabolism

Imetelstat is expected to be metabolized by nucleases to nucleotides of various lengths.

• Specific Populations

No 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 > 1× to 1.5× ULN and any AST), or moderate hepatic impairment (total bilirubin > 1.5× to 3× ULN and any AST). The effects of severe renal impairment (CLcr 15 to <30 mL/min), end-stage renal disease, or severe hepatic impairment (total bilirubin > 3× ULN and any AST) have not been established.

• In Vitro Studies

Imetelstat is not an inhibitor or inducer of CYP450 enzymes. It is an inhibitor of OATP1B1 and OATP1B3.

• Immunogenicity

Seventeen percent (28/166) of evaluable patients with low- or intermediate-1 risk MDS tested positive for imetelstat anti-drug antibodies, with a median onset of 38 weeks following the study drug dosage of RYTELO for a median duration of treatment of 35 weeks in Phase 2 and Phase 3 of the IMerge study. There was no clinically significant effect of anti-drug antibodies on the pharmacokinetics, safety, or efficacy of RYTELO among the study participants who developed anti-drug antibodies.

Nonclinical Toxicology

There is limited information regarding Rytelo Nonclinical Toxicology in the drug label.

Clinical Studies

Myelodysplastic Syndromes (MDS) The efficacy of RYTELO was evaluated in a 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 ≥ 4 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 a 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. Efficacy was established after a 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 weeks (56 days) period, and during any consecutive 24 weeks (168 days) period, respectively, from randomization until the start of subsequent anti-cancer therapy (if any).

Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients with MDS Who Received RYTELO with a Difference Between Arms of >2% Compared to Placebo in IMerge

How Supplied

Storage

Store vials refrigerated at 2°C to 8°C (36°F to 46°F) in original carton.

• Do not freeze.

NDC 82959-112-01

RYTELO™ (imetelstat) for Injection

47 mg/vial

For intravenous infusion after reconstitution and dilution.

Single-Dose Vial. Discard Unused Portion.

NDC 82959-111-01 Rx Only

RYTELO™ (imetelstat) for Injection

188 mg/vial

For intravenous infusion after reconstitution and dilution.

Dispense the enclosed Medication Guide to each patient.

Single-Dose Vial. Discard Unused Portion.

1 Vial geron®

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Rytelo Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Rytelo interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Rytelo Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Rytelo Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.