Molecular mass: 1,609.55 g/mol
No studies on animal reproductive function have been conducted with lutetium (177Lu) oxodotreotide. Radionuclide procedures carried out on pregnant women also involve radiation dose to the foetus. The use of lutetium (177Lu) oxodotreotide is contraindicated during established or suspected pregnancy or when pregnancy has not been excluded due to the risk associated with the ionizing radiation. Pregnant women should be advised of the risk to a foetus.
It is unknown whether lutetium (177Lu) oxodotreotide is excreted in breast milk. A risk to the suckling child associated with ionising radiation cannot be excluded. Breast-feeding should be avoided during treatment with this medicinal product. If treatment with lutetium (177Lu) oxodotreotide during breast-feeding is necessary, the child must be weaned.
When an administration of radiopharmaceuticals to a woman of childbearing potential is intended, it is important to determine whether or not she is pregnant. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. If in any doubt about her potential pregnancy (if the woman has missed a period, if the period is very irregular, etc.), alternative techniques not using ionising radiation (if there are any) should be offered to the patient. Before the use of lutetium (177Lu) oxodotreotide, pregnancy should be excluded using an adequate/validated test.
Lutetium (177Lu) oxodotreotide can cause fetal harm when administered to a pregnant woman. During treatment with lutetium (177Lu) oxodotreotide and for a minimum of the following 6 months after the end of the treatment, appropriate measures must be taken to avoid pregnancy; this applies to patients of both genders.
No animal studies have been performed to determine the effects of lutetium (177Lu) oxodotreotide on the fertility of either gender. Ionizing radiations of lutetium (177Lu) oxodotreotide may potentially have temporary toxic effects on female and male gonads. Genetic consultation is recommended if the patient wishes to have children after treatment. Cryopreservation of sperm or eggs can be discussed as an option to patients before the treatment.
Lutetium (177Lu) oxodotreotide has no or negligible influence on the ability to drive and use machines. Nevertheless, the general condition of the patient and the possible adverse reactions to treatment must be taken into account before driving or using machines.
The overall safety profile of lutetium (177Lu) oxodotreotide is based on pooled data from patients from clinical trials (NETTER-1 phase III and Erasmus phase I/II Dutch patients) and from compassionate use programs.
The most common adverse reactions in patients receiving lutetium (177Lu) oxodotreotide 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 acids infusion administered for renal protection.
Due to the bone marrow toxicity of lutetium (177Lu) oxodotreotide, 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%).
The adverse reactions are listed in Table 5 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 5. Frequency of adverse reactions reported from clinical trials and from post-marketing surveillance:
| MedDRA System Organ Class (SOC) | Very common | Common | Uncommon |
|---|---|---|---|
| Infections and infestations | Conjunctivitis Respiratory tract infection Cystitis Pneumonia Herpes zoster Ophthalmic herpes zoster Influenza Staphylococcal infections Streptococcal bacteraemia | ||
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Refractory cytopenia with multilineage dysplasia (Myelodysplastic syndrome) | Acute myeloid leukaemia Acute leukaemia Chronic myelomonocytic leukaemia | |
| Blood and lymphatic system disorders | Thrombocytopenia2 Lymphopenia3 Anaemia4Pancytopenia | Leukopenia5 Neutropenia6 | Refractory cytopenia with unilineage dysplasia Nephrogenic anaemia Bone marrow failure Thrombocytopenic purpura |
| Immune system disorders | Hypersensitivity | ||
| Endocrine disorders | Secondary hypothyroidism | Hypothyroidism Diabetes mellitus Carcinoid crisis Hyperparathyroidism | |
| Metabolism and nutrition disorders | Decreased appetite | Hyperglycaemia Dehydration Hypomagnesaemia Hyponatremia | Hypoglycaemia Hypernatremia Hypophosphatemia Tumor lysis syndrome Hypercalcaemia Hypocalcaemia Hypoalbuminaemia Metabolic acidosis |
| Psychiatric disorders | Sleep disorders | Anxiety Hallucination Disorientation | |
| Nervous system disorders | Dizziness Dysgeusia Headache10 Lethargy Syncope | Formication Hepatic encephalopathy Paraesthesia Parosmia Somnolence Spinal cord compression | |
| Eye disorders | Eye disorders | ||
| Ear and labyrinth disorders | Vertigo | ||
| Cardiac disorders | Electrocardiogram QT prolonged | Atrial fibrillation Palpitations Myocardial infarction Angina pectoris Cardiogenic shock | |
| Vascular disorders | Hypertension7 Flushing Hot flush Hypotension | Vasodilatation Peripheral coldness Pallor Orthostatic hypotension Phlebitis | |
| Respiratory, thoracic and mediastinal disorders | Dyspnoea | Oropharyngeal pain Pleural effusion Sputum increased Choking sensation | |
| Gastrointestinal disorders | Nausea Vomiting | Abdominal distension Diarrhoea Abdominal pain Constipation Abdominal pain upper Dyspepsia Gastritis | Dry mouth Flatulence Ascities Gastrointestinal pain Stomatitis Haematochezia Abdominal discomfort Intestinal obstruction Colitis Pancreatitis acute Rectal haemorrhage Melaena Abdominal pain lower Haematemesis Haemorrhagic ascites Ileus |
| Hepatobiliary disorders | Hyperbilirubinaemia9 | Pancreatic enzymes decreased Hepatocellular injury Cholestasis Hepatic congestion Hepatic failure | |
| Skin and subcutaneous tissue disorders | Alopecia | Rash Dry skin Swelling face Hyperhidrosis Pruritus generalized | |
| Musculoskeletal and connective tissue disorders | Musculoskeletal pain8 Muscle spasms | ||
| Renal and urinary disorders | Acute kidney injury Haematuria Renal failure Proteinuria | Leukocyturia Urinary incontinence Glomerular filtration rate decreased Renal disorder Acute prerenal failure Renal impairment | |
| General disorders and administration site conditions | Fatigue1 | Injection site reaction11 Oedema peripheral Administration site pain Chills Influenza like illness | Injection site mass Chest discomfort Chest pain Pyrexia Malaise Pain Deaths Feeling abnormal |
| Investigations | Blood creatinine increased GGT* increased ALAT** increased ASAT*** increased Blood ALP**** increased | Blood potassium decreased Blood urea increased Glycosylated haemoglobin increased Haematocrit decreased Protein urine Weight decreased Blood creatine phosphokinase increased Blood lactate dehydrogenase increased Blood catecholamines c-reactive protein increased | |
| Injury, poisoning and procedural complications | Clavicle fracture | ||
| Surgical and medical procedures | Transfusion | Abdominal cavity drainage 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 amino transferase
*** Aspartate amino transferase
**** Alkaline phosphatase
Bone marrow toxicity (myelo-/hematotoxicity) 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 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 lutetium (177Lu) oxodotreotide treatment.
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 lutetium (177Lu) oxodotreotide-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 lutetium (177Lu) oxodotreotide in patients with mild and moderate renal impairment. The use of lutetium (177Lu) oxodotreotide is contraindicated in patients with severe kidney failure.
Hormonal crises related to bioactive substances release (probably due to lysis of the neuroendocrine tumour cells) have rarely been observed and resolved after appropriate medical treatment.
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