RYTELO Solution for injection Ref.[110353] Active ingredients: Imetelstat

5.1. 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)].

5.2. 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)].

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 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)].

5.4. 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)].

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)]

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 [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 4 weeks. The median time on treatment with RYTELO was 8 months (range, 0 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 a 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 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:

Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.
^a Fatigue: asthenia, fatigue, and malaise.
^b Arthralgia/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.
^c COVID-19: asymptomatic COVID-19, COVID-19, COVID-19 pneumonia, and SARS-CoV-2 antibody test positive.
^d Urinary tract infection: cystitis, Escherichia urinary tract infection, renal abscess, and urinary tract infection.
^e Syncope: fall, pre-syncope, and syncope.
^f Infusion-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.
^g Atrial arrhythmia: atrial fibrillation and atrial flutter.
^h Fractures: femur fracture, hand fracture, hip fracture, humerus fracture, lumbar vertebral fracture, and thoracic vertebral fracture.

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.

Table 6. 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:

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 time
¹ The denominator used to calculate the rate varied from 97 to 118 based on the number of patients with a baseline value and at least one post-treatment value.
² The denominator used to calculate the rate varied from 50 to 59 based on the number of patients with a baseline value and at least one post-treatment value.

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.

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.

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)].

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

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.