Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Evive Biotechnology Ireland LTD, 20 Kildare Street, Dublin 2, D02 T3V7, Ireland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered medicinal product should be clearly recorded.
Granulocyte colony-stimulating factor (G-CSF) can promote growth of myeloid cells in vitro and similar effects may be seen on some non-myeloid cells in vitro.
The safety and efficacy of efbemalenograstim alfa have not been investigated in patients with myelodysplastic syndrome, chronic myelogenous leukaemia, or acute myeloid leukaemia. Therefore, it should not be used in such patients.
The safety and efficacy of efbemalenograstim alfa have not been investigated in patients receiving high dose chemotherapy. This medicinal product should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens.
Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk (see section 4.8).
The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary infiltrates, and deterioration in pulmonary function along with increased neutrophil count may be preliminary signs of acute respiratory distress syndrome (ARDS). In such circumstances, efbemalenograstim alfa should be discontinued at the discretion of the physician and the appropriate treatment should be administered (see section 4.8).
Glomerulonephritis has been reported in patients receiving G-CSF (e.g. filgrastim and pegfilgrastim). Generally, events of glomerulonephritis resolved after dose reduction or withdrawal of G-CSF. Urinalysis monitoring is recommended.
Capillary leak syndrome has been reported after G-CSF administration and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care (see section 4.8).
Generally asymptomatic cases of splenomegaly have been reported after administration of efbemalenograstim alfa. Cases of splenic rupture, including some fatal cases, have been reported following administration of G-CSF (see section 4.8). Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in patients reporting left upper abdominal pain or shoulder tip pain.
Treatment with efbemalenograstim alfa alone does not preclude thrombocytopenia and anaemia because full dose myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring of platelet count and haematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic agents which are known to cause severe thrombocytopenia.
Sickle cell crises have been associated with the use of G-CSF in patients with sickle cell trait or sickle cell disease (see section 4.8). Therefore, physicians should use caution when prescribing efbemalenograstim alfa in patients with sickle cell trait or sickle cell disease, clinical parameters and laboratory status should be monitored appropriately and attentively by the physician for the possible association of this medicinal product with splenic enlargement and vaso-occlusive crisis.
White blood cell (WBC) counts of 100 × 109/L or greater have been observed in patients receiving G-CSF. No adverse events directly attributable to this degree of leukocytosis have been reported. Such elevation in white blood cells is transient, being typically seen 24 to 48 hours after administration and is consistent with the pharmacodynamic effects of this medicinal product. Consistent with the clinical effects and the potential for leukocytosis, a WBC count should be performed at regular intervals during therapy. If leukocyte counts exceed 50 × 109/L after the expected nadir, this medicinal product should be discontinued immediately.
Hypersensitivity, including serious allergic reactions, occurring on initial or subsequent treatment have been reported in patients treated with G-CSF. Efbemalenograstim alfa should be permanently discontinued in patients with clinically significant hypersensitivity. Efbemalenograstim alfa should not be administered to patients with a history of hypersensitivity to efbemalenograstim alfa. Caution should be exercised if using efbemalenograstim alfa in patients with a history of serious allergic reactions to other G-CSF products as the risk of cross-reactivity cannot be excluded. In such circumstances, efbemalenograstim alfa should be administered at the discretion of the physician with the appropriate assessment of risks and benefits. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days.
Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported rarely in association with G-CSF treatment. If the patient has developed SJS with the use of efbemalenograstim alfa, treatment with efbemalenograstim alfa must not be restarted in this patient at any time.
As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of antibodies against efbemalenograstim alfa is generally low. Binding antibodies do occur as expected with all biologics; however, they have not been associated with neutralising activity at present.
Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory markers (e.g. c-reactive protein and white blood cell count). In most cases aortitis was diagnosed by computed tomography (CT) scan and generally resolved after withdrawal of G-CSF (see also section 4.8).
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have been observed following the use of some G-CSF (e.g. pegfilgrastim) in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer (see section 4.8). Patients with breast and lung cancer should be monitored for signs and symptoms of MDS/AML.
The safety and efficacy of Ryzneuta for the mobilisation of blood progenitor cells in patients or healthy donors has not been adequately evaluated.
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging findings. This should be considered when interpreting bone-imaging results.
This medicinal product contains 50 mg sorbitol in each pre-filled syringe. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.
This medicinal product contains less than 1 mmol sodium (23 mg) per 20 mg dose, that is to say essentially ‘sodium-free’.
The needle cap of the pre-filled syringe contains dry natural rubber (latex), which may cause allergic reactions.
Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ efbemalenograstim alfa should be administered at least 24 hours after administration of cytotoxic chemotherapy, and at least 14 days before the next dose of chemotherapy. Concomitant use of Ryzneuta with chemotherapy (i.e. administration on the same day) has been shown to potentiate myelosuppression.
Possible interactions with other haematopoietic growth factors and cytokines have not been specifically investigated in clinical trials.
The potential for interaction with lithium, which also promotes the release of neutrophils, has not been specifically investigated. There is no evidence that such an interaction would be harmful.
The safety and efficacy of Ryzneuta have not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression, e.g. nitrosoureas.
There are no data from the use of efbemalenograstim alfa in pregnant women. Although studies in animals have not shown reproductive toxicity (see section 5.3), Ryzneuta is not recommended during pregnancy and in women of childbearing potential not using contraception.
There is insufficient information on the excretion of efbemalenograstim alfa in human milk; a risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Ryzneuta therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Efbemalenograstim alfa did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately 2.2 times higher than the recommended human dose (based on body surface area) (see section 5.3).
Ryzneuta has no or negligible influence on the ability to drive and use machines.
The most frequently reported adverse reactions were bone pain (very common [≥1/10]). Back pain, arthralgia and pain in extremity were reported commonly (≥1/100 to <1/10). Musculoskeletal pain was generally of mild to moderate severity, transient and could be controlled in most patients with standard analgesics.
Serious angioedema occurred on subsequent treatment with efbemalenograstim alfa (uncommon [≥1/1 000 to <1/100]).
Splenomegaly, generally asymptomatic, is uncommon. Splenic rupture, including some fatal cases, has been reported following administration of G-CSF (see section 4.4).
Uncommon pulmonary adverse reactions such as pulmonary oedema occurred on treatment with efbemalenograstim alfa. Other pulmonary adverse reactions including interstitial pneumonia, pulmonary infiltrates and pulmonary fibrosis have been reported following administration of G-CSF. Cases of respiratory failure or ARDS have been reported following administration of G-CSF, which may be fatal (see section 4.4).
Isolated cases of sickle cell crises have been associated with the use of G-CSF in patients with sickle cell trait or sickle cell disease (see section 4.4).
Capillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported in cancer patients undergoing chemotherapy following administration of G-CSFs; see section 4.4 and section “Description of selected adverse reactions” below.
The safety of efbemalenograstim alfa has been evaluated based on the results from clinical trials. Adverse reactions are divided into groups according to the MedDRA system organ class (SOC) and into frequency groups using the following convention: 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 order of decreasing seriouness.
Table 1. List of adverse reactions:
| MedDRA system organ class | Adverse reactions | ||
|---|---|---|---|
| Very common (≥1/10) | Common (≥1/100 to <1/10) | Uncommon (≥1/1 000 to <1/100) | |
| Infections and infestations | Herpes infection2 | ||
| Blood and lymphatic system disorders | Leukopenia, Neutropenia, Thrombocytopenia, Anaemia, Splenomegaly | ||
| Metabolism and nutrition disorders | Hyperglycaemia, Decreased appetite | ||
| Nervous system disorders | Headache1 | Dizziness, Taste disorder2, Muscle spasticity, Peripheral neuropathy2, Somnolence | |
| Eye disorders | Lacrimation increased | ||
| Ear and labyrinth disorders | Vertigo1 | ||
| Cardiac disorders | Tachycardia, Palpitations | ||
| Vascular disorders | Vasculitis, Hot flush | ||
| Respiratory, thoracic and mediastinal disorders | Pulmonary oedema, Epistaxis, Oropharyngeal pain, Cough, Dyspnoea, Nasal dryness | ||
| Gastrointestinal disorders | Nausea1, Diarrhoea1, Vomiting1 | Stomatitis, Dry mouth, Dyspepsia, Abdominal pain, Dysphagia | |
| Skin and subcutaneous tissue disorders | Alopecia, Urticaria1, Dermatitis allergic, Rash, Dermatitis, Erythema, Toxic skin eruption, Rash maculo- papular, Pruritus, Eczema, Dry skin, Skin disorder, Angioedema, Cold sweat, Night sweats, Onychalgia | ||
| Musculoskeletal and connective tissue disorders | Bone pain | Back pain, Arthralgia, Pain in extremity | Myalgia, Osteoarthropathy, Musculoskeletal discomfort, Neck pain |
| General disorders and administration site conditions | Asthenia1, Fatigue1, Pyrexia1 | Injection site reactions2, Peripheral swelling, Chills, Thirst | |
| Investigations | White blood cell count increased1, Alanine aminotransferase increased1, Aspartate aminotransferase increased1 | Neutrophil count increased, Blood creatinine increased, Gamma-glutamyltransferase increased, Weight increased | |
The frequency category was estimated from a statistical calculation based upon 488 patients receiving Ryzneuta in four clinical trials.
1 See section “Description of selected adverse reactions” below.
2 Includes multiple adverse reaction terms.
Nausea, vomiting, diarrhoea, asthenia, fatigue, pyrexia, vertigo and headaches were commonly observed in patients receiving chemotherapy.
One case of serious urticaria was reported after efbemalenograstim alfa treatment.
White blood cell count increased was commonly reported after efbemalenograstim alfa treatment. Leukocytosis (white blood cell counts ˃100 × 109/L) have been reported following the administration of G-CSF; (see section 4.4).
Increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST) have been commonly observed in patients after receiving efbemalenograstim alfa following cytotoxic chemotherapy. These elevations are transient and return to baseline.
Certain adverse reactions have not yet been observed in efbemalenograstim alfa clinical studies, but are generally accepted as being attributable to G-CSF and derivatives:
An increased risk of MDS/AML has been observed in an epidemiological study following the use of some G-CSF in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer (see section 4.4).
Hypersensitivity reactions have been reported after G-CSF administration (see section 4.4).
Cases of capillary leak syndrome have been reported after G-CSF administration and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Capillary leak syndrome generally occurred in patients with advanced malignant disease, sepsis, taking multiple chemotherapy medicinal products or undergoing apheresis (see section 4.4).
Aortitis may occur following the administration of G-CSF (see section 4.4).
Stevens-Johnson syndrome, Sweet’s syndrome (acute febrile neutrophilic dermatosis) may occur following the administration of G-CSF (see section 4.4).
Glomerulonephritis may occur following administration of G-CSF (see section 4.4).
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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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