Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Geron Netherlands B.V., Naritaweg 165, 1043 BW Amsterdam, Netherlands
Hypersensitivity to the active substance or to any of the excipients are listed in section 6.1.
Thrombocytopenia has been reported during treatment with Rytelo, including new or worsening Grade 3 or Grade 4 thrombocytopenia (see section 4.8). Complete blood cell counts should be monitored prior to each dose of Rytelo, weekly following administration of the first two doses, and for any case of Grade 3 or Grade 4 thrombocytopenia or as clinically indicated. Patients with Grade 3 or Grade 4 thrombocytopenia should be monitored for bleeding events as a precaution. The need for platelet transfusions should be assessed as clinically appropriate. Patients should be advised to report any signs or symptoms of bruising or bleeding immediately. The next dose should be delayed and resumed at the same or reduced dose as recommended (see section 4.2).
Neutropenia has been reported during treatment with Rytelo, including new or worsening Grade 3 or Grade 4 neutropenia (see section 4.8), and febrile neutropenia may occur. Complete blood cell counts should be monitored prior to each dose of Rytelo, weekly following administration of the first two doses, and for any case of Grade 3 or Grade 4 neutropenia. Patients with Grade 3 or Grade 4 neutropenia should be monitored for infections, including sepsis as a precaution. Granulocyte-colony stimulating factors and anti-infective therapies should be administered as clinically indicated. Patients should be advised to report any signs or symptoms of neutropenia, such as fever or infection immediately. The next dose should be delayed and resumed at the same or reduced dose as recommended (see section 4.2).
Infusion-related reactions have been reported during treatment with Rytelo and were generally mild or moderate in severity (see section 4.8). The most common symptoms were headache and back pain. Other notable adverse reactions were Grade 3 hypotension, hypertension, hypertensive crisis, and non-cardiac chest pain. Patients usually experienced an infusion-related reaction during or shortly after the end of the infusion.
Patients should receive premedication at least 30 minutes prior to dosing with Rytelo to reduce the risk of experiencing infusion-related reactions (see section 4.2). Patients should be monitored for adverse reactions for at least one hour after the infusion has been completed.
Manage symptoms of infusion-related reactions with supportive care and consider interrupting the infusion, decreasing the infusion rate, or discontinuing treatment based on the severity and frequency of occurrence as recommended (see section 4.2).
Based on findings in animals, Rytelo may cause embryo-foetal harm when administered to a pregnant woman. Administration of imetelstat to pregnant mice and rabbits during the period of organogenesis resulted in embryo-foetal mortality at maternal exposures (AUC) ≥3.4 times the human exposure at the recommended clinical dose (see section 5.3).
Pregnant women should be advised of the potential risk to a foetus. Women of child-bearing potential should be advised to use effective contraception during treatment with Rytelo and for at least 1 week after the last dose (see section 4.6).
This medicinal product contains 35 mg sodium (the dose of a patient weighing 80 kg) per dose or approximately 1.8% of the World Health Organization (WHO) recommended maximum daily intake of 2 g sodium for an adult.
Additional sodium will be introduced through a sodium-containing solution used for preparation for administration (see section 6.6). This should be considered in relation to the total sodium intake to the patient from all sources per day.
No interaction studies have been performed in humans (see section 5.2).
In vitro imetelstat is an inhibitor of BCRP, OAT1, OATP1B1 and OATP1B3 at concentrations similar to those reached on the day of imetelstat administration. The risk for an interaction, causing increased plasma concentrations of a co-administrated substrate, declines with the rapidly declining plasma concentrations of imetelstat and is likely not relevant on the following days of the dose interval.
The pregnancy status of females of reproductive potential should be verified before starting treatment with Rytelo (see section 4.2).
Women of childbearing potential should be advised to use effective contraception during treatment with Rytelo and for at least 1 week after the last dose.
There are no data on the use of imetelstat in pregnant women. Studies in animals have shown that imetelstat may cause embryonic or foetal loss (see section 5.3). Imetelstat is not recommended during pregnancy and in women of childbearing potential not using contraception.
It is unknown whether imetelstat is excreted in human milk.
There is no data on the presence of imetelstat in human milk, the effects on the breastfed child, or the effects on milk production. A risk to the breast-feeding child cannot be excluded. Because of the potential for adverse reactions in breast-fed children, women should be advised not to breastfeed during treatment with Rytelo and for 1 week after the last dose.
Based on findings in animals, imetelstat may impair fertility in females of reproductive potential (see section 5.3). No human data on the effect of imetelstat on fertility are available.
Rytelo may have a minor influence on the ability to drive and use machines. The ability to react when performing these tasks may be impaired due to the potential effects of asthenia and infusion-related reactions, such as malaise, chest pain, and hypertensive crisis following treatment administration (see section 4.8).
Patients should be advised to use caution until any symptoms affecting their ability to drive or operate machines have resolved.
The most common adverse reactions with Rytelo were thrombocytopenia (94%), leukopenia (93%), neutropenia (92%), aspartate aminotransferase (AST) increased (48%), alanine aminotransferase (ALT) increased (42%), alkaline phosphatase (ALP) increased (41%), asthenia (26%) and headache (16%).
The most commonly reported severe adverse reactions (Grade ≥ 3) were neutropenia (69%) and thrombocytopenia (63%).
The most commonly reported serious adverse reactions were sepsis (1.7%), urinary tract infection (1.7%), atrial fibrillation (1.1%), oesophageal varices haemorrhage (1.1%), syncope (1.1%), and thrombocytopenia (1.1%).
The frequency of treatment discontinuation due to adverse reactions was 13%. The most common adverse reactions leading to treatment discontinuation were thrombocytopenia (6.3%) and neutropenia (6.3%).
The frequency of dose reduction or dose delay due to adverse reactions is 65%. The most common adverse reactions leading to dose modification or interruption were neutropenia (51%) and thrombocytopenia (45%).
The frequencies of adverse reactions are based on pooled data from the clinical trials in 175 patients with low to intermediate-1 risk MDS, transfusion-dependent anaemia and were either relapsed or refractory to or ineligible for ESA treatment and treated with imetelstat at the recommended dose. Patients were treated with Rytelo for a median of 7.8 months.
The adverse reactions are listed below by MedDRA system organ class and by frequency within each system organ class, with the most frequent adverse reactions listed first. Frequencies were defined as: very common (≥1/10); common (≥1/100 to ˂1/10); uncommon (≥1/1 000 to ˂1/100); rare (≥1/10 000 to ˂1/1 000); very rare (˂1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in decreasing order of seriousness.
Table 5. Adverse reactions in low to intermediate-1 risk MDS patients treated with Rytelo in Phase 2 and 3 MDS3001 study:
| System organ class | Adverse reaction | Frequency (all grades) | All grades (N=175) | Grades ≥ 3 (N=175) |
|---|---|---|---|---|
| Infections and infestations | Urinary tract infectiona | Very common | 12% | 2.3% |
| Sepsisb | Common | 4.0% | 4.0% | |
| Blood and lymphatic system disorders | Thrombocytopeniac | Very common | 94% | 63% |
| Neutropeniac | Very common | 92% | 69% | |
| Leukopeniac | Very common | 93% | 56% | |
| Immune system disorders | Infusion-related reactionsd | Common | 8.6% | 3.4% |
| Nervous system disorders | Headache | Very common | 16% | 1.7% |
| Syncopee | Common | 4.6% | 1.7% | |
| Cardiac disorders | Atrial fibrillationf | Common | 3.4% | 1.1% |
| Vascular disorders | Haematoma | Common | 5.7% | 0.6% |
| Respiratory, thoracic and mediastinal disorders | Epistaxis | Common | 5.1% | 0 |
| Gastrointestinal disorders | Gastrointestinal bleedingg | Common | 6.3% | 1.7% |
| Hepatobiliary disorders | Aspartate aminotransferase increasedc | Very common | 48% | 2.3% |
| Alanine aminotransferase increasedc | Very common | 42% | 4.0% | |
| Alkaline phosphatase increasedc | Very common | 41% | 0 | |
| Skin and subcutaneous tissue disorders | Pruritus | Common | 5.1% | 0 |
| Musculoskeletal and connective tissue disorders | Arthralgia | Common | 6.9% | 0 |
| Renal and urinary disorders | Haematuria | Common | 4.6% | 1.1% |
| General disorders and administration site conditions | Astheniah | Very common | 26% | 0.6% |
a Urinary tract infection includes urinary tract infection, Escherichia urinary tract infection, and cystitis.
b Sepsis includes sepsis, enterococcal sepsis, escherichia sepsis, neutropenic sepsis, and urosepsis.
c Thrombocytopenia (platelet count decreased), neutropenia (neutrophil count decreased), leukopenia (white blood cell count decreased), AST increased, ALP increased, and ALT increased are based on laboratory values.
d Infusion-related reactions include abdominal pain, abdominal pain upper, arthralgia, asthenia, back pain, bone pain, chest pain, diarrhoea, discomfort, dyspnoea, erythema, flushing, headache, hyperhidrosis, hypertension, hypertensive crisis, hypotension, illness, malaise, nausea, non-cardiac chest pain, oedema peripheral, palmar erythema, pruritus, pyrexia, spinal pain, urticaria, and vomiting. Only events considered related to infusion-related reactions are included.
e Syncope includes loss of consciousness, presyncope, and syncope.
f Atrial fibrillation includes atrial fibrillation and atrial flutter.
g Gastrointestinal bleeding includes anal haemorrhage, gastric haemorrhage, gastrointestinal haemorrhage, haematochezia, haemorrhoidal haemorrhage, intestinal haemorrhage, rectal haemorrhage, and oesophageal varices haemorrhage.
h Asthenia includes asthenia and fatigue.
Thrombocytopenia occurred in 94.3% of patients receiving imetelstat. Incidences of Grade 3 or Grade 4 thrombocytopenia were 62.9%. Median time to first onset of ≥ Grade 3 events was 5 (range: 1.7, 89.7) weeks. Median duration of thrombocytopenia for ≥ Grade 3 events was 1.4 (range: 0.1, 15.0) weeks (see sections 4.2 and 4.4). Thrombocytopenia (treatment-emergent adverse events of any Grade) led to dose reduction or cycle delay in 24.6% and 44.6% of patients, respectively. Treatment was permanently discontinued in 6.3% of patients.
Neutropenia occurred in 92.0% of patients receiving imetelstat. Incidences of Grade 3 or Grade 4 neutropenia were 69.1%. Median time to first onset of ≥ Grade 3 events was 4.3 (range: 1.0, 118.6) weeks. Median duration of neutropenia for ≥ Grade 3 events was 2.0 (range:0.0, 16.7) weeks (see sections 4.2 and 4.4). Neutropenia (treatment-emergent adverse events of any Grade) led to dose reduction or cycle delay in 36.6% and 50.3% of patients, respectively. Treatment was permanently discontinued in 6.3% of patients.
Infusion-related reactions occurred in 8.6% of patients receiving imetelstat. Incidences of Grade 3 or Grade 4 infusion-related reactions were 3.4%. Infusion-related reactions were generally mild or moderate in severity. The most common infusion-related reactions were headache (3.4%) and back pain (2.3%). Other notable infusion-related reactions were Grade 3 events of hypotension (0.6%), hypertension (0.6%), hypertensive crisis (0.6%), and non-cardiac chest pain (0.6%). Infusion-related reactions usually occurred during or shortly after the end of the infusion (see sections 4.2 and 4.4). Infusion-related reactions led to dose reduction or cycle delay in 0.6% of patients or in temporary interruption or termination of the infusion in 5.7% of patients. Treatment was permanently discontinued in 0.6% of patients.
AST increased, ALT increased, and ALP increased occurred in 48.0%, 41.7%, and 41.1% of patients receiving imetelstat, respectively. Incidences of Grade 3 or Grade 4 events were 2.3%, 4.0%, and 0%, respectively. Median time to first onset of Grade ≥ 3 events was 30.4 (range: 25.9, 63.1) weeks for AST increased and 32.0 (range: 1.0, 84.1) weeks for ALT increased. Median duration of Grade ≥ 3 events was 1.2 (range: 0.4, 2.4) weeks for AST increased and 1.5 (range: 0.7, 4.0) weeks for ALT increased. Events (treatment-emergent adverse events of any Grade) led to cycle delay in 1.7% of patients for AST increased and 0.6% for ALT increased. No event led to discontinuation of treatment.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.