Betibeglogene autotemcel interacts in the following cases:
There are no data on the effects of betibeglogene 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 cryopreserve semen or ova before treatment if possible.
Patients with TDT experience iron overload due to chronic red blood cell (RBC) transfusions that can lead to end organ damage. HSC transplantation with myeloablative conditioning is not appropriate for patients with TDT who have evidence of severely elevated iron in the heart i.e., patients with cardiac T2* <10 msec by magnetic resonance imaging (MRI). MRI of the liver should be performed on all patients prior to myeloablative conditioning. It is recommended that patients with MRI results demonstrating liver iron content ≥15 mg/g undergo liver biopsy for further evaluation. If the liver biopsy demonstrates bridging fibrosis, cirrhosis, or active hepatitis, HSC transplantation with myeloablative conditioning is not appropriate.
A negative serum pregnancy test must be confirmed prior to the start of mobilisation and re-confirmed prior to conditioning procedures and before medicinal product administration.
No clinical data on exposed pregnancies are available.
Reproductive and developmental toxicity studies with betibeglogene autotemcel were not performed. Betibeglogene autotemcel must not be used during pregnancy because of myeloablative conditioning. It is unknown whether betibeglogene autotemcel transduced cells have the potential to be transferred in utero to a foetus.
There is no opportunity for germline transmission of the βA-T87Q-globin gene after treatment with betibeglogene autotemcel, therefore the likelihood that an offspring would have general somatic expression of the βA-T87Q-globin gene is considered negligible.
It is unknown whether betibeglogene autotemcel is excreted in human milk. The effect of administration of betibeglogene autotemcel to mothers on their breast-fed children has not been studied.
Betibeglogene autotemcel must not be administered to women who are breast-feeding.
There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with betibeglogene autotemcel. Women of childbearing potential and men capable of fathering a child must use a reliable method of contraception (intra-uterine device or combination of hormonal and barrier contraception) from start of mobilisation through at least 6 months after administration of betibeglogene autotemcel. Consult the SmPC of the myeloablative conditioning agent for information on the need for effective contraception in patients who undergo conditioning.
There are no data on the effects of betibeglogene 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 cryopreserve semen or ova before treatment if possible.
Betibeglogene autotemcel has no influence on the ability to drive or use machines.
The effect of the mobilisation agents and the myeloablative conditioning agent on the ability to drive or use machines must be considered.
The safety of betibeglogene autotemcel was evaluated in 45 patients with TDT. The only serious adverse reaction attributed to betibeglogene autotemcel was thrombocytopenia (2.2%). Given the small patient population and size of cohorts, adverse reactions in the table below do not provide a complete perspective on the nature and frequency of these events.
Adverse reactions are listed by MedDRA body system organ class and by frequency convention. 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, and 3 are lists of adverse reactions attributed to mobilisation/apheresis, myeloablative conditioning, and betibeglogene autotemcel, respectively, experienced by patients with TDT in clinical trials with betibeglogene autotemcel.
Table 1. Adverse reactions attributed to mobilisation/apheresis:
| System Organ Class (SOC) | Very Common (≥10%) | Common (≥1% - <10%) |
|---|---|---|
| Blood and lymphatic system disorders | Thrombocytopenia | Splenomegaly, Leukocytosis |
| Metabolism and nutrition disorders | Hypocalcaemia | Hypokalaemia, Hypomagnesaemia |
| Psychiatric disorders | Agitation | |
| Nervous system disorders | Headache, Peripheral sensory neuropathy | Dizziness, Head discomfort, Paraesthesia |
| Cardiac disorders | Cardiac flutter | |
| Vascular disorders | Hypotension | |
| Respiratory, thoracic and mediastinal disorders | Hypoxia, Epistaxis | |
| Gastrointestinal disorders | Nausea | Vomiting, Lip swelling, Abdominal pain, Abdominal pain upper, Paraesthesia oral |
| Skin and subcutaneous tissue disorders | Rash, Hyperhidrosis | |
| Musculoskeletal and connective tissue disorders | Bone pain | Back pain, Musculoskeletal discomfort |
| General disorders and administration site conditions | Pyrexia, Influenza like illness, Chest discomfort, Chest pain, Injection site reaction, Catheter site haemorrhage, Catheter site bruise, Injection site bruising, Fatigue, Non-cardiac chest pain, Catheter site pain, Injection site pain, Puncture site pain, Pain | |
| Investigations | Blood magnesium decreased | |
| Injury, poisoning and procedural complications | Citrate toxicity, Contusion, Procedural pain |
Table 2. Adverse reactions attributed to myeloablative conditioning:
| SOC | Very Common (≥10%) | Common (≥1% - <10%) |
|---|---|---|
| Infections and infestations | Neutropenic sepsis, Systemic infection, Staphylococcal infection, Pneumonia, Lower respiratory tract infection, Urinary tract infection, Mucosal infection, Cellulitis, Vaginal infection, Rash pustular, Folliculitis, Gingivitis, Vulvovaginal candidiasis | |
| Blood and lymphatic system disorders | Febrile neutropenia, Neutropenia, Thrombocytopenia, Leukopenia, Anaemia | Lymphopenia, Leukocytosis, Monocyte count decreased, Neutrophilia, Mean cell haemoglobin concentration increased |
| Endocrine disorders | Primary hypogonadism | |
| Metabolism and nutrition disorders | Decreased appetite | Hypocalcaemia, Hypokalaemia, Metabolic acidosis, Fluid overload, Fluid retention, Hypomagnesaemia, Hyponatraemia, Hypophosphataemia, Hyperphosphataemia |
| Psychiatric disorders | Insomnia | Anxiety |
| Nervous system disorders | Headache | Dizziness, Lethargy, Dysgeusia, Ageusia, Memory impairment |
| Eye disorders | Conjunctival haemorrhage | |
| Ear and labyrinth disorders | Vertigo | |
| Cardiac disorders | Cardiac failure congestive, Atrial fibrillation | |
| Vascular disorders | Hypotension, Haematoma, Hot flush | |
| Respiratory, thoracic and mediastinal disorders | Epistaxis, Pharyngeal inflammation | Hypoxia, Pulmonary mass, Dyspnoea, Pleural effusion, Rales, Upper-airway cough syndrome, Cough, Laryngeal pain, Hiccups, Oropharyngeal pain |
| Gastrointestinal disorders | Stomatitis, Vomiting, Nausea, Diarrhoea, Gingival bleeding, Constipation, Abdominal pain, Anal inflammation | Anal haemorrhage, Gastritis, Gastrointestinal inflammation, Abdominal distension, Abdominal pain upper, Anal fissure, Dyspepsia, Dysphagia, Oesophagitis, Haemorrhoids, Proctalgia, Lip dry |
| Hepatobiliary disorders | Veno-occlusive liver disease, Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood bilirubin increased | Cholecystitis, Cholelithiasis, Hepatomegaly, Jaundice, Transaminases increased, Gamma-glutamyltransferase increased |
| Skin and subcutaneous tissue disorders | Alopecia, Pruritus, Skin hyperpigmentation | Petechiae, Ecchymosis, Pain of skin, Palpable purpura, Pigmentation disorder, Pruritus generalised, Purpura, Sweat gland disorder, Urticaria, Dry skin, Rash |
| Musculoskeletal and connective tissue disorders | Bone pain, Myalgia, Pain in extremity, Back pain | |
| Renal and urinary disorders | Haematuria, Pollakiuria | |
| Reproductive system and breast disorders | Vaginal haemorrhage | Ovarian failure, Menstruation irregular, Premature menopause, Blood follicle stimulating hormone increased, Blood testosterone decreased |
| General disorders and administration site conditions | Pyrexia, Fatigue, Mucosal inflammation | Face oedema, Hypothermia, Feeling cold, Pain, Xerosis |
| Investigations | C-reactive protein increased, Aspergillus test positive, Blood potassium decreased, Weight decreased, Blood alkaline phosphatase decreased, Blood magnesium decreased, Forced expiratory flow decreased, Protein total decreased, Blood albumin decreased, Reticulocyte count decreased, Reticulocyte percentage decreased | |
| Injury, poisoning and procedural complications | Transfusion reaction, Skin abrasion |
Table 3. Adverse reactions attributed to betibeglogene autotemcel:
| SOC | Very Common (≥10%) | Common (≥1% - <10%) |
|---|---|---|
| Blood and lymphatic system disorders | Thrombocytopenia, Leukopenia, Neutropenia | |
| Vascular disorders | Hot flush | |
| Respiratory, thoracic and mediastinal disorders | Dyspnoea | |
| Gastrointestinal disorders | Abdominal pain | |
| Musculoskeletal and connective tissue disorders | Pain in extremity | |
| General disorders and administration site conditions | Non-cardiac chest pain |
Bleeding is a potential complication of thrombocytopenia subsequent to myeloablative conditioning and treatment with betibeglogene autotemcel. The majority of all reported bleeding events were nonserious. A risk of bleeding exists before platelet engraftment and may continue after platelet engraftment in patients who have continued thrombocytopenia.
Following platelet engraftment, all patients maintained platelet levels of ≥20 × 109/L. Median (min, max) times to unsupported platelet counts of ≥50 × 109/L and ≥100 × 109/L were 51 (20, 268) days (N=45) and 63.5 (20, 1231) days (N=42), respectively.
Serious events of hepatic VOD occurred in 11.1% of patients following myeloablative conditioning; 80% of these patients did not receive prophylaxis for VOD. All patients who experienced VOD received treatment with defibrotide and recovered. Patients with TDT may be at an increased risk of VOD following myeloablative conditioning compared with other patient populations.
Pre-medication for infusion reactions was managed at physician discretion. Infusion related reactions to betibeglogene autotemcel were observed in 13.3% of patients and occurred on the day of betibeglogene autotemcel infusion. All reactions resolved and the majority were mild. Events included abdominal pain, dyspnoea, hot flush, and non-cardiac chest pain in 11.1%, 2.2%, 2.2%, and 2.2% of patients, respectively.
According to available data, the frequency, type, and severity of adverse reactions in adolescents 12-17 years of age are similar to adults with the exception that VOD and pyrexia occurred more frequently in adolescents.
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