Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The overall safety profile of Lutathera 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 programmes.

The most common adverse reactions in patients receiving Lutathera 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 administered for renal protection.

Due to the bone marrow toxicity of Lutathera, the most expected adverse reactions were related to haematological toxicity: thrombocytopenia (25%), lymphopenia (22.3%), anaemia (13.4%), 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 5 according to frequency and MedDRA System Organ Class (SOC). The frequencies are categorised 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 5 Frequency of adverse reactions reported from clinical studies and post-marketing surveillance

MedDRA System            Very common          Common                      Uncommon                      Not known Organ Class (SOC)
Infections and                                                            Conjunctivitis infestations                                                              Respiratory tract infection Cystitis
Pneumonia
Herpes zoster
Ophthalmic herpes zoster
Influenza
Staphylococcal infections
Streptococcal bacteraemia
Neoplasms benign,                             Refractory cytopenia with   Acute myeloid leukaemia malignant and                                 multilineage dysplasia      Acute leukaemia unspecified (including                        (myelodysplastic            Chronic myelomonocytic cysts and polyps)                             syndrome)                   leukaemia Blood and lymphatic      Thrombocytopenia2    Leukopenia5                 Refractory cytopenia with system disorders         Lymphopenia3         Neutropenia6                unilineage dysplasia Anaemia4                                         Nephrogenic anaemia
Pancytopenia                                     Bone marrow failure
Thrombocytopenic purpura
Immune system                                                             Hypersensitivity              Angioedema disorders
Endocrine disorders                           Secondary                   Hypothyroidism hypothyroidism              Diabetes mellitus
Carcinoid crisis
Hyperparathyroidism
Metabolism and           Decreased appetite   Hyperglycaemia              Hypoglycaemia nutrition disorders                           Dehydration                 Hypernatraemia Hypomagnesaemia             Hypophosphataemia
Hyponatraemia               Tumour lysis syndrome
Hypercalcaemia
Hypocalcaemia
Hypoalbuminaemia
Metabolic acidosis
Psychiatric disorders                         Sleep disorders             Anxiety Hallucination
Disorientation
Nervous system                                Dizziness                   Formication disorders                                     Dysgeusia                   Hepatic encephalopathy Headache10                  Paraesthesia
Lethargy                    Parosmia
Syncope                     Somnolence
Spinal cord compression
Eye disorders                                                             Eye disorders Ear and labyrinth                                                         Vertigo disorders
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                         Dyspnoea                    Oropharyngeal pain and mediastinal                                                           Pleural effusion disorders                                                                 Sputum increased Choking sensation
Gastrointestinal         Nausea               Abdominal distension        Dry mouth disorders                Vomiting             Diarrhoea                   Flatulence Abdominal pain              Ascites
Constipation                Gastrointestinal pain
Abdominal pain upper        Stomatitis

MedDRA System           Very common          Common                      Uncommon                          Not known Organ Class (SOC)
Dyspepsia                   Haematochezia
Gastritis                   Abdominal discomfort
Intestinal obstruction
Colitis
Pancreatitis acute
Rectal haemorrhage
Melaena
Abdominal pain lower
Haematemesis
Haemorrhagic ascites
Ileus
Hepatobiliary                                Hyperbilirubinaemia9        Pancreatic enzymes decreased disorders                                                                Hepatocellular injury Cholestasis
Hepatic congestion
Hepatic failure
Skin and subcutaneous                        Alopecia                    Rash tissue disorders                                                         Dry skin Swelling face
Hyperhidrosis
Pruritus generalised
Musculoskeletal and                          Musculoskeletal pain8 connective tissue                            Muscle spasms disorders
Renal and urinary                            Acute kidney injury         Leukocyturia disorders                                    Haematuria                  Urinary incontinence Renal failure               Glomerular filtration rate
Proteinuria                 decreased
Renal disorder
Acute pre-renal failure
Renal impairment
General disorders and   Fatigue1             Injection site reaction11   Injection site mass administration site                          Oedema peripheral           Chest discomfort conditions                                   Administration site pain    Chest pain Chills                      Pyrexia
Influenza-like illness      Malaise
Pain
Death
Feeling abnormal
Investigations                               Blood creatinine            Blood potassium decreased increased                   Blood urea increased
GGT* increased              Glycosylated haemoglobin
ALT** increased             increased
AST*** increased            Haematocrit decreased
Blood ALP****               Protein urine increased                   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 anaemia and haemoglobin 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 hyperbilirubinaemia
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

Myelosuppression
Mostly mild/moderate 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 - anaemia, 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 haematological pathologies, i.e. premalignant and malignant blood neoplasms (i.e.
myelodysplastic syndrome and acute myeloid leukaemia, respectively) have been reported following Lutathera treatment.

In NETTER-1, platelet nadir occurred at a median of 5.1 months following the first dose. Of the 59 patients who developed thrombocytopenia, 68% had platelet recovery to baseline or normal levels.
The median time to platelet recovery was 2 months. Fifteen of the nineteen patients in whom platelet recovery was not documented had post-nadir platelet counts.

Renal toxicity
Lutetium (177Lu) oxodotreotide is excreted by the kidney.

The long-term trend of progressive glomerular filtration function deterioration demonstrated in the clinical studies confirms that Lutathera-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 Lutathera in patients with mild or moderate renal impairment.
For additional details see section 4.2 (Error! Reference source not found. Table 3 and “Renal impairment” subsection) and section 4.4. The use of Lutathera is contraindicated in patients with kidney failure with creatinine clearance <30 mL/min (see section 4.3).

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

Reporting of suspected adverse reactions

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.
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 Novartis using the following email address: Safetydest.israel@novaris.com