Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Vertex Pharmaceuticals (Ireland) Limited, Unit 49, Block F2, Northwood Court, Santry, Dublin 9, D09 T665, Ireland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Contraindications to mobilisation and myeloablative conditioning medicinal products must be considered.
Warnings and precautions of mobilisation and myeloablative conditioning medicinal products must be considered.
The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the product, the batch number and the name of the treated patient must be kept for a period of 30 years after expiry date of the medicinal product.
Casgevy is intended solely for autologous use and must not under any circumstances be administered to other patients. Casgevy must not be administered if the information on the product labels and Lot information sheet (LIS) does not match the patient’s identity.
Although Casgevy is tested for sterility, mycoplasma and endotoxins, a risk of transmission of infectious agents exists. Healthcare professionals administering Casgevy must, therefore, monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed.
There is a potential for hypersensitivity reactions with Casgevy, including due to Cas9. Serious hypersensitivity reactions, including anaphylaxis may occur due to dimethyl sulfoxide (DMSO) or dextran 40 in Casgevy. Patients should be observed closely during and after infusion. Vital signs (blood pressure, heart rate, and oxygen saturation) and the occurrence of any symptoms should be monitored prior to the start of the infusion, and approximately every 30 minutes from when the first vial of Casgevy is infused until 2 hours after the last vial of Casgevy is infused.
Neutrophil engraftment failure is a potential risk in hematopoietic stem cell transplant, defined as not achieving neutrophil engraftment after Casgevy infusion and requiring use of unmodified rescue CD34+ cells. Patients must be monitored for absolute neutrophil counts (ANC) and infections must be managed according to standard guidelines and medical judgement. In the event of neutrophil engraftment failure, patients must be infused with rescue CD34+ cells (see section 4.8).
Longer median platelet engraftment times have been observed with Casgevy treatment compared to allogeneic HSC transplantation. There is an increased risk of bleeding until platelet engraftment is achieved.
Patients should be monitored for bleeding according to standard guidelines and medical judgement. Frequent platelet counts must be conducted until platelet engraftment and platelet recovery are achieved. Blood cell count determination and other appropriate testing must be performed whenever clinical symptoms suggestive of bleeding arise (see section 4.8).
Patients with SCD may require more cycles of mobilisation and apheresis compared to patients with TDT and are at higher risk of failure of sufficient mobilisation/apheresis. See section 4.2 for the recommended total CD34+ cell collection target. See section 5.1 for information regarding the average number of cycles of mobilisation and apheresis, and overall discontinuation rates.
No cases of myelodysplasia, leukaemia, or lymphoma have been reported in clinical studies with Casgevy. There is a theoretical risk of oncogenesis related to gene editing. Monitor patients at least annually (including complete blood count) for 15 years after treatment with Casgevy. If myelodysplasia, leukaemia, or lymphoma are detected, contact the local representative of the Marketing Authorisation Holder to determine appropriate samples for analysis.
No immune-mediated reactions were observed in clinical studies with Casgevy. It is unknown whether pre-formed antibodies to Cas9 including following recent Streptococcus pyogenes infection could result in immune-mediated reactions and/or clearance of cells with residual Cas9.
Patients treated with Casgevy must not donate blood, organs, tissues, and cells for transplantation.
Patients must be monitored annually (including complete blood counts) according to standard guidelines and medical judgement. Patients are expected to be enrolled in a long-term follow-up scheme in order to better understand the long-term safety and efficacy of Casgevy.
This medicinal product contains 5.3 mg to 70 mg sodium in each vial. This is equivalent to 0.3 to 4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
The drug-drug interaction of mobilisation and myeloablative conditioning medicinal products must be considered.
No formal drug interaction studies have been performed. Casgevy is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters.
Use of hydroxyurea/hydroxycarbamide must be discontinued at least 8 weeks prior to start of mobilisation and conditioning. There is no experience on the use of hydroxyurea/hydroxycarbamide after Casgevy infusion.
Discontinue the use of voxelotor and crizanlizumab at least 8 weeks prior to start of mobilisation and conditioning, as their interaction potential with mobilisation and myeloablative conditioning medicinal products is not known.
Iron chelators must be discontinued at least 7 days prior to initiation of myeloablative conditioning, due to potential interaction with the conditioning medicinal product. Some iron chelators are myelosuppressive. Avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after Casgevy infusion. Phlebotomy can be used instead of iron chelation, when appropriate.
The safety of immunisation with live viral vaccines during or following Casgevy treatment has not been studied. As a precautionary measure, vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of the conditioning regimens, during Casgevy treatment, and until haematological recovery following treatment.
A negative serum pregnancy test must be confirmed prior to the start of each mobilisation cycle and re-confirmed prior to myeloablative conditioning. There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with Casgevy. Women of childbearing potential and men capable of fathering a child must use effective method of contraception from start of mobilisation through at least 6 months after administration of myeloablative conditioning. Please also refer to the Summary of Product Characteristics for the myeloablative conditioning medicinal product.
There are no clinical data from the use of exagamglogene autotemcel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with exagamglogene autotemcel to assess whether it can cause foetal harm when administered to a pregnant woman. It is not known whether exagamglogene autotemcel has the potential to be transferred to the foetus. Casgevy must not be administered during pregnancy because of the risk associated with myeloablative conditioning. Pregnancy after Casgevy infusion should be discussed with the treating physician (see guidance on contraception, above).
It is unknown whether exagamglogene autotemcel is excreted in human milk or transferred to the breast-feeding child. There are no data available.
Refer to the Summary of Product Characteristics of the mobilisation and myeloablative conditioning medicinal product(s) for guidance on their use during breast-feeding. Because of the potential risks associated with myeloablative conditioning, breast-feeding should be discontinued during conditioning.
The decision to breast-feed after Casgevy treatment should be discussed with the treating physician, taking into account the benefit of breast-feeding for the child versus any potential adverse events from Casgevy or from the underlying maternal condition.
There are no data on the effects of exagamglogene autotemcel on human fertility. Effects on male and female fertility have not been evaluated in animal studies. Data are available on the risk of infertility with myeloablative conditioning. It is therefore advised to consider fertility preservation options such as cryopreservation of semen or ova before treatment if possible.
Casgevy has no influence on the ability to drive or use machines.
The effect of mobilisation and myeloablative conditioning medicinal products on the ability to drive or use machines must be considered.
The safety of Casgevy was evaluated in two open-label, single-arm studies (study 111 and study 121) and one long-term follow-up study (study 131), in which 97 adolescent and adult patients with TDT or SCD were treated with Casgevy.
Treatment with Casgevy was preceded by peripheral blood mobilisation with granulocyte colony-stimulating factor (G-CSF) and plerixafor in patients with TDT and plerixafor only in patients with SCD, followed by apheresis and myeloablative conditioning with busulfan.
The safety profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant after mobilisation and apheresis.
The median (min, max) duration of follow-up after being administered Casgevy was 22.8 (2.1, 51.1) months for patients with TDT (N=54), and 17.5 (1.2, 46.2) months for patients with SCD (N=43).
Serious adverse reactions attributed to Casgevy occurred in 2 (3.7%) patients with TDT: 1 (1.9%) patient with haemophagocytic lymphohistiocytosis, acute respiratory distress syndrome, idiopathic pneumonia syndrome, and headache; 1 (1.9%) patient with delayed engraftment and thrombocytopenia. No patient with SCD had serious adverse reactions attributed to Casgevy.
A life-threatening serious adverse reaction of cerebellar haemorrhage occurred in 1 (1.9%) patient with TDT and was attributed to busulfan myeloablative conditioning.
One (2.3%) patient with SCD died due to a COVID-19 infection and subsequent respiratory failure. The event was not related to Casgevy.
Adverse reactions are listed by MedDRA body system organ class and by frequency. Frequencies are defined as: very common (≥1/10) and common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Tables 1, 2, 3, and 4 are lists of adverse reactions attributed to mobilisation/apheresis with G-CSF and plerixafor, mobilisation/apheresis with plerixafor only, myeloablative conditioning with busulfan, and Casgevy, respectively, experienced by patients with TDT and SCD in clinical studies with Casgevy.
Table 1. Adverse reactions attributed to mobilisation/apheresis in patients with TDT receiving G-CSF and plerixafor (N=59):
| System organ class (SOC) | Very common | Common |
|---|---|---|
| Blood and lymphatic system disorders | Leukocytosis, thrombocytopenia | |
| Metabolism and nutrition disorders | Hypokalaemia | |
| Nervous system disorders | Headache | |
| Respiratory, thoracic and mediastinal disorders | Oropharyngeal pain | |
| Gastrointestinal disorders | Nausea | Abdominal pain, vomiting, diarrhoea, oral hypoaesthesia |
| Musculoskeletal and connective tissue disorders | Musculoskeletal pain* | |
| General disorders and administration site conditions | Pain, pyrexia |
* Musculoskeletal pain included back pain, bone pain, musculoskeletal chest pain, neck pain, non-cardiac chest pain, pain in extremity.
Table 2. Adverse reactions attributed to mobilisation/apheresis in patients with SCD receiving plerixafor (N=58):
| System organ class (SOC) | Very common | Common |
|---|---|---|
| Blood and lymphatic system disorders | Sickle cell anaemia with crisis | |
| Metabolism and nutrition disorders | Hyperphosphataemia, hypomagnesaemia | |
| Nervous system disorders | Headache | |
| Respiratory, thoracic and mediastinal disorders | Acute chest syndrome | |
| Gastrointestinal disorders | Abdominal pain*, nausea, Vomiting | Diarrhoea |
| Musculoskeletal and connective tissue disorders | Musculoskeletal pain† | Arthralgia |
| General disorders and administration site conditions | Pain, fatigue |
* Abdominal pain included abdominal pain upper.
† Musculoskeletal pain included back pain, bone pain, chest pain, neck pain, non-cardiac chest pain, and pain in extremity.
Table 3. Adverse reactions attributed to myeloablative conditioning with busulfan in patients with TDT and SCD (N=97)*:
| System organ class (SOC) | Very common | Common |
|---|---|---|
| Infections and infestations | Pneumonia, sepsis, klebsiella | |
| Blood and lymphatic system disorders | Thrombocytopenia, febrile neutropenia, neutropenia, anaemia, lymphopenia†, leukopenia | Pancytopenia, reticulocytopenia, splenomegaly |
| Metabolism and nutrition disorders | Decreased appetite, hypokalaemia, hyperphosphataemia, hypomagnesaemia, fluid retention, hypophosphataemia | Hypoalbuminaemia, hypocalcaemia |
| Nervous system disorders | Headache | Cerebellar haemorrhage, hydrocephalus, peripheral sensory neuropathy, peripheral neuropathy, neuralgia, dysgeusia |
| Eye disorders | Vision blurred, dry eye | |
| Cardiac disorders | Tachycardia | |
| Vascular disorders | Hypotension, hot flush | |
| Respiratory, thoracic and mediastinal disorders | Epistaxis, oropharyngeal pain | Respiratory failure, idiopathic pneumonia syndrome, hypoxia, dyspnoea, cough |
| Gastrointestinal disorders | Mucositis‡, nausea, vomiting, abdominal pain§, diarrhoea, constipation, gastritis | Colitis, dyspepsia, gingival bleeding, gastrooesophageal reflux disease, haematemesis, oesophagitis, dysphagia, gastrointestinal inflammation, haematochezia, mouth ulceration |
| Hepatobiliary disorders | Venoocclusive liver disease, hyperbilirubinaemia, alanine aminotransferase increased | Aspartate aminotransferase increased, hepatomegaly, gamma-glutamyltransferase increased |
| Skin and subcutaneous tissue disorders | Pigmentation disorder#, skin exfoliation, alopecia, petechiae, dry skin, rash** | Pruritus, erythema |
| Musculoskeletal and connective tissue disorders | Musculoskeletal pain†† | Arthralgia |
| Renal and urinary disorders | Dysuria, haematuria | |
| Reproductive system and breast disorders | Amenorrhoea, intermenstrual bleeding, vulvovaginal pain, dysmenorrhoea, menstruation irregular, premature menopause | |
| General disorders and administration site conditions | Pyrexia, fatigue | Pain |
| Investigations | Weight decreased | International normalised ratio increased, C-reactive protein increased, weight increased |
| Injury, poisoning procedural complications | Delayed engraftment, subcutaneous haematoma, skin abrasion, skin laceration |
* Frequency is based on the highest incidence from study 111 in patients with TDT or from study 121 in patients with SCD.
† Lymphopenia included CD4 lymphocytes decreased and lymphocyte count decreased.
‡ Mucositis included anal inflammation, mucosal inflammation, pharyngeal inflammation, and stomatitis.
§ Abdominal pain included abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and epigastric discomfort.
# Pigmentation disorder included nail pigmentation, skin hyperpigmentation, and skin hypopigmentation.
** Rash included dermatitis, rash erythematous, rash macular, rash maculo-papular, and rash papular.
†† Musculoskeletal pain included back pain, bone pain, chest pain and pain in extremity.
Table 4. Adverse reactions attributed to Casgevy in patients with TDT and SCD (N=97):
| System organ class (SOC) | Very common | Common |
|---|---|---|
| Blood and Lymphatic system disorders | Lymphopenia†,‡ | Thrombocytopenia†, neutropenia†, anaemia†, leukopenia† |
| Immune system disorders | Haemophagocytic lymphohistiocytosis | |
| Metabolism and nutrition disorders | Hypocalcaemia† | |
| Nervous system disorders | Headache†, paraesthesia | |
| Cardiac disorders | Tachycardia† | |
| Respiratory, thoracic and mediastinal disorders | Acute respiratory distress syndrome, idiopathic pneumonia syndrome†, epistaxis† | |
| Skin and subcutaneous tissue disorders | Rash†,§, petechiae† | |
| General disorders and administration site conditions | Chills†, pyrexia† | |
| Injury, poisoning and procedural complications | Delayed engraftment†, infusion related reactions# |
* Frequency is based on the highest incidence from study 111 in patients with TDT or from study 121 in patients with SCD.
† At least one event was also attributed to busulfan myeloablative conditioning.
‡ Lymphopenia included CD4 lymphocytes decreased and lymphocyte count decreased.
§ Rash included dermatitis.
# Infusion related reactions included chills, sinus tachycardia, and tachycardia.
Platelet engraftment was defined as 3 consecutive measurements of platelet counts ≥20 × 109/L in patients with TDT and 3 consecutive measurements of platelet counts ≥50 × 109/L in patients with SCD, obtained on 3 different days after Casgevy infusion without administration of platelet transfusions for 7 days. All patients achieved platelet engraftment.
In study 111, the median (min, max) time to platelet engraftment in patients with TDT was 44 (20, 200) days (n=53), with one remaining patient achieving platelet engraftment after the time of the interim analysis. The median (min, max) time to platelet engraftment was 45 (20, 199) days in adolescent patients and 40 (24, 200) days in adult patients. Patients without a spleen had an earlier median time to platelet engraftment than patients with an intact spleen. Median (min, max) time to platelet engraftment was 34.5 (20, 78) days in patients without a spleen and 46 (27, 200) days in patients with an intact spleen.
In study 121, the median (min, max) time to platelet engraftment for patients with SCD was 35 (23, 126) days (n=43). The median (min, max) time to platelet engraftment was 44.5 (23, 81) days in adolescent patients and 32 (23, 126) days in adult patients.
There was no association observed between bleeding events and time to platelet engraftment after Casgevy treatment.
Neutrophil engraftment was defined as 3 consecutive measurements of absolute neutrophil count (ANC) ≥500 cells/µL on 3 different days after Casgevy infusion, without use of the unmodified rescue CD34+ cells. All patients achieved neutrophil engraftment, and no patients received rescue CD34+ cells.
In study 111, the median (min, max) time to neutrophil engraftment in patients with TDT was 29 (12, 56) days (n=54). The median (min, max) time to neutrophil engraftment was 31 (19, 56) days in adolescent patients and 29 (12, 40) days in adult patients.
In study 121, the median (min, max) time to neutrophil engraftment in patients with SCD was 27 (15, 40) days (n=43). The median (min, max) time to neutrophil engraftment was 28 (24, 40) days in adolescent patients and 26 (15, 38) days in adult patients.
There was no association observed between infections and time to neutrophil engraftment.
The safety of Casgevy was evaluated in 31 adolescent patients aged 12 to less than 18 years with TDT or SCD. The median (min, max) age of adolescent TDT patients was 14 (12, 17) years, and for SCD patients was 15 (12, 17) years. The median (min, max) duration of follow-up was 19.6 (2.1, 26.6) months for adolescent TDT patients and 14.7 (2.5, 18.7) months for adolescent SCD patients. The safety profile was generally consistent among adolescent and adult patients. Engraftment times were similar in adolescent and adult patients.
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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