Adverse reactions : תופעות לוואי

4.8     Undesirable Effects

Summary of the safety profile
Adverse reactions reported following treatment with LuNET-SRY in a single medical center in Israel were mostly associated with mild and transient bone-marrow/hematologic toxicities, manifesting as reductions in blood counts affecting all lineages. Two additional cases of mild renal toxicity (as indicated by reduction in the estimated glomerular filtration rate (eGFR)) have also been reported. No information was available on the frequency of nausea, vomiting, fatigue or decreased appetite following treatment with LuNET-SRY.

The overall safety profile of [177Lu]DOTA-TATE is based on pooled data from patients from clinical studies (NETTER-1 phase III and Erasmus phase I/II Dutch patients) and from compassionate use programs.


The most common adverse reactions in patients receiving [177Lu]DOTA-TATE treatment were nausea and vomiting, which occurred at the beginning of the infusion in 58.9% and 45.5% of patients, respectively. The causality of nausea/vomiting is confounded by the emetic effect of the concomitant amino acid solution infusion administered for renal protection.

Due to the bone marrow toxicity of [177Lu]DOTA-TATE, the most expected adverse reactions were related to hematological toxicity: thrombocytopenia (25%), lymphopenia (22.3%), anemia (13.4%) and pancytopenia (10.2%).

Other very common adverse reactions reported include fatigue (27.7%) and decreased appetite (13.4%).

At the time of the NETTER-1 final analysis, after a median follow-up duration of 76 months in each study arm, the safety profile remained consistent with that previously reported.


Tabulated list of adverse reactions

The adverse reactions are listed in Table 3 according to the frequency and the MedDRA System Organ Class (SOC). The frequencies are categorized as follows: 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) and not known (cannot be estimated from the available data).

Table 3.       Frequency of adverse reactions reported from clinical studies and post-marketing surveillance MedDRA System Organ Class         Very common         Common                       Uncommon                               Not known (SOC)
Infections and infestations                                                        Conjunctivitis Respiratory tract infection
Cystitis
Pneumonia
Herpes zoster
Ophthalmic herpes zoster
Influenza
Staphylococcal infections
Streptococcal bacteremia
Neoplasms benign, malignant                           Refractory cytopenia with    Acute myeloid leukaemia and unspecified (including                            multilineage dysplasia       Acute leukaemia cysts and polyps)                                     (myelodysplastic syndrome)   Chronic myelomonocytic leukaemia 
Blood and lymphaticsystem         Thrombocytopenia2   Leukopenia5                  Refractory cytopenia with unilineage disorders                         Lymphopenia3        Neutropenia6                 dysplasia Anemia4                                          Nephrogenic anemia
Pancytopenia                                     Bone marrow failure
Thrombocytopenic purpura
Immune system disorders                                                            Hypersensitivity                       Angioedema Endocrine disorders                                   Secondary hypothyroidism     Hypothyroidism Diabetes mellitus
Carcinoid crisis
Hyperparathyroidism
Metabolism and nutrition          Decreased           Hyperglycemia                Hypoglycemia disorders                         appetite            Dehydration                  Hypernatremia Hypomagnesaemia              Hypophosphatemia
Hyponatremia                 Tumor lysis syndrome
Hypercalcemia
Hypocalcaemia
Hypoalbuminemia
Metabolic acidosis
Psychiatric disorders                                 Sleep disorders              Anxiety Hallucination
Disorientation
Nervous system disorders                              Dizziness                    Formication Dysgeusia                    Hepatic encephalopathy
Headache10                   Paraesthesia
Lethargy                     Parosmia
Syncope                      Somnolence
Spinal cord compression
Eye disorders                                                                      Eye disorders Ear and labyrinthdisorders                                                         Vertigo Cardiac disorders                                     Electrocardiogram QT         Atrial fibrillation prolonged                    Palpitations
Myocardial infarction
Angina pectoris
Cardiogenic shock
Vascular disorders                                    Hypertension7                Vasodilatation Flushing                     Peripheral coldness
Hot flush                    Pallor
Hypotension                  Orthostatic hypotension
Phlebitis
Respiratory, thoracic and                             Dyspnea                      Oropharyngeal pain mediastinal disorders                                                              Pleural effusion Sputum increased
Choking sensation


Gastrointestinal disorders          Nausea                 Abdominal distension         Dry mouth Vomiting               Diarrhea                     Flatulence
Abdominal pain               Ascites
Constipation                 Gastrointestinal pain
Abdominal pain upper         Stomatitis
Dyspepsia                    Haematochezia
Gastritis                    Abdominal discomfort
Intestinal obstruction
Colitis
Pancreatitis acute
Rectal hemorrhage
Melena
Abdominal pain lower
Hematemesis
Hemorrhagic ascites
Ileus
Hepatobiliary disorders                                    Hyperbilirubinaemia9         Pancreatic enzymes decreased Hepatocellular injury
Cholestasis
Hepatic congestion
Hepatic failure
Skin and subcutaneous                                      Alopecia                     Rash tissue disorders                                                                        Dry skin Swelling face
Hyperhidrosis
Pruritus generalized
Musculoskeletal and                                        Musculoskeletal pain8 connective tissue disorders                                Muscle spasms Renal and urinary                                          Acute kidney injury          Leukocyturia disorders                                                  Hematuria                    Urinary incontinence Renal failure                Glomerular filtration rate decreased
Proteinuria                  Renal disorder
Acute pre-renal failure
Renal impairment
General disorders and               Fatigue1               Injection site reaction11    Injection site mass administration site conditions                             Edema peripheral             Chest discomfort Administration site pain     Chest pain
Chills                       Pyrexia
Influenza like illness       Malaise
Pain
Death
Feeling abnormal
Investigations                                             Blood creatinine increased   Blood potassium decreased GGT* increased               Blood urea increased
ALT** increased              Glycosylated hemoglobin increased
AST*** increased             Hematocrit decreased
Blood ALP**** increased      Protein urine
Weight decreased
Blood creatine phosphokinase increased
Blood lactate dehydrogenase increased
Blood catecholamines
C-reactive protein increased
Injury, poisoning and                                                                   Clavicle fracture procedural complications
Surgical and medical                                       Transfusion                  Abdominal cavity drainage procedures                                                                              Dialysis Gastrointestinal tube insertion
Stent placement
Abscess drainage
Bone marrow harvest
Polypectomy
Social circumstances                                                                    Physical disability 1
Includes asthenia and fatigue
2
Includes thrombocytopenia and platelet count decreased
3
Includes lymphopenia and lymphocyte count decreased
4
Includes anemia and hemoglobin decreased
5
Includes leukopenia and white blood cell count decreased
6
Includes neutropenia and neutrophil count decreased
7
Includes hypertension and hypertensive crisis
8
Includes arthralgia, pain in extremity, back pain, bone pain, flank pain, musculoskeletal chest pain and neck pain 9
Includes blood bilirubin increased and hyperbilirubinemia
10
Includes headache and migraine
11
Includes injection site reaction, injection site hypersensibility, injection site induration, injection site swelling *Gamma-glutamyltransferase
**Alanine aminotransferase
***Aspartate aminotransferase
****Alkaline phosphatase

Description of selected adverse reactions

Bone marrow toxicity
Bone marrow toxicity (myelo-/haematotoxicity) manifested with reversible/transient reductions in blood counts affecting all lineages (cytopenias in all combinations, i.e. pancytopenia, bicytopenias, isolated monocytopenias – anemia, neutropenia, lymphocytopenia, and thrombocytopenia). In spite of an observed significant selective B- cell depletion, no increase in the rate of infectious complications occurs after peptide receptor radionuclide therapy (PRRT). Cases of irreversible hematological pathologies, i.e. premalignant and malignant blood neoplasms (i.e.
myelodysplastic syndrome and acute myeloid leukemia, respectively) have been reported following [177Lu]DOTA- TATE treatment.

Nephrotoxicity

Lutetium-177-labeled oxodotreotide is excreted by the kidneys.
The long-term trend of progressive glomerular filtration function deterioration demonstrated in the clinical studies confirms that [177Lu]DOTA-TATE-related nephropathy is a chronic kidney disease that develops progressively over months or years after exposure. An individual benefit-risk assessment is recommended prior to treatment with LuNET-SRY in patients with mild or moderate renal impairment. For additional details see section 4.2 and section 4.4. The use of LuNET-SRY is contraindicated in patients with severe kidney failure (see section 4.3).

Hormonal crises
Hormonal crises related to release of bioactive substances (probably due to lysis of the neuroendocrine tumor cells) have rarely been observed and resolved after appropriate medical treatment (section 4.4).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/, and to S.R.Y Medical Services Ltd. via email to: contact@sryms.com.