Dotatate

INDICATIONS AND USAGE LUTATHERA is indicated for the treatment of adult and pediatric patients 12 years and older with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors. LUTATHERA is a radiolabeled somatostatin analog indicated for the treatment of adult and pediatric patients 12 years and older with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors.

DOSAGE AND ADMINISTRATION Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA. ( 2.1 ) Administer 7.4 GBq (200 mCi) every 8 weeks (± 1 week) for a total of 4 doses. ( 2.2 ) Administer long-acting octreotide 30 mg intramuscularly 4 to 24 hours after each LUTATHERA dose and short-acting octreotide for symptomatic management. ( 2.3 ) Continue long-acting octreotide 30 mg intramuscularly every 4 weeks after completing LUTATHERA until disease progression or for 18 months following treatment initiation. ( 2.3 ) Administer antiemetics before recommended amino acid solution. ( 2.3 ) Initiate recommended intravenous amino acid solution 30 minutes before LUTATHERA infusion; continue during and for at least 3 hours after LUTATHERA infusion. Do not decrease dose of amino acid solution if LUTATHERA dose is reduced. ( 2.3 ) 2.1 Important Safety Instructions LUTATHERA is a radiopharmaceutical; handle with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions ( 5.1 )] . Use waterproof gloves and effective radiation shielding when handling LUTATHERA. Radiopharmaceuticals, including LUTATHERA, should be used by or under the control of healthcare providers who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals. Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA [see Use in Specific Populations ( 8.1 , 8.3 )] . Monitor patients closely for signs and symptoms of hypersensitivity reactions during and following the LUTATHERA administration for a minimum of 2 hours in a setting where cardiopulmonary resuscitation medication and equipment are available [see Warnings and Precautions ( 5.6 )] . 2.2 Recommended Dosage The recommended LUTATHERA dosage for adult and pediatric patients 12 years and older is 7.4 GBq (200 mCi) every 8 weeks (± 1 week) for a total of 4 doses. Administer premedications and concomitant medications as recommended [see Dosage and Administration ( 2.3 )] . 2.3 Premedications and Concomitant Medications Somatostatin Analogs Before initiating LUTATHERA treatment: Discontinue long-acting somatostatin analogs (e.g., long-acting octreotide) at least 4 weeks prior to initiating LUTATHERA. Administer short-acting octreotide as needed; discontinue at least 24 hours prior to initiating LUTATHERA [see Drug Interactions ( 7.1 )] . During LUTATHERA treatment: Administer long-acting octreotide 30 mg intramuscularly between 4 to 24 hours after each LUTATHERA dose. Do not administer long-acting octreotide within 4 weeks prior to each subsequent LUTATHERA dose. Short-acting octreotide may be given for symptomatic management during LUTATHERA treatment but must be withheld at least 24 hours before each LUTATHERA dose. Following LUTATHERA treatment: Continue long-acting octreotide 30 mg intramuscularly every 4 weeks after completing LUTATHERA until disease progression or for 18 months following treatment initiation at the discretion of the physician. Antiemetics Administer antiemetics before the recommended amino acid solution. Amino Acid Solution Initiate an intravenous infusion of a sterile amino acid solution containing L-lysine and L-arginine (Table 1) 30 minutes before the start of the LUTATHERA infusion. Use a three-way valve to administer the amino acid solution using the same venous access as LUTATHERA or administer the amino acid solution through a separate venous access in the patient’s other arm. Continue the amino acid solution infusion during and for at least 3 hours after completion of the LUTATHERA infusion. Do not decrease the dose of the amino acid solution if a reduced dose of LUTATHERA is administered [see Warnings and Precautions ( 5.4 )] . Table 1. Amino Acid Solution Item Specification a equivalent to 14.4 to 20 g L-lysine. b equivalent to 14.9 to 20.7 g L-arginine. L-lysine HCl Between 18 and 25 g a L-arginine HCl Between 18 and 25 g b Volume 1 to 2 L Osmolality < 1200 mOsmol/kg Hypersensitivity Prophylaxis Premedicate patients who have had prior Grade 1 or 2 hypersensitivity reactions to LUTATHERA. Do not re-challenge patients who experience Grade 3 or 4 hypersensitivity reactions to LUTATHERA [see Warnings and Precautions ( 5.6 )] . 2.4 Dosage Modifications for Adverse Reactions Recommended dose modifications of LUTATHERA for adverse reactions are provided in Table 2. Table 2. Recommended Dosage Modifications of LUTATHERA for Adverse Reactions a Grading of severity is defined in the most current Common Terminology Criteria for Adverse Events (CTCAE). b Including allergic reaction and anaphylaxis. c No dose modification required for hematological toxicities Grade 3 or Grade 4 solely due to lymphopenia. Adverse reaction Severity of adverse reaction a Dose modification Thrombocytopenia [see Warnings and Precautions ( 5.2 )] First occurrence of Grade 2, 3, or 4 Withhold dose until complete or partial resolution (Grade 0 to 1). Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 2, 3, or 4 thrombocytopenia, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for Grade 2 or higher thrombocytopenia requiring a dosing interval beyond 16 weeks. Recurrent Grade 2, 3, or 4 Permanently discontinue LUTATHERA. Anemia and Neutropenia [see Warnings and Precautions ( 5.2 )] First occurrence of Grade 3 or 4 Withhold dose until complete or partial resolution (Grade 0, 1, or 2). Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 3 or 4 anemia or neutropenia, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for Grade 3 or higher anemia or neutropenia requiring a dosing interval beyond 16 weeks. Recurrent Grade 3 or 4 Permanently discontinue LUTATHERA. Renal Toxicity [see Warnings and Precautions ( 5.4 )] First occurrence of: Creatinine clearance less than 40 mL/min; calculated using Cockcroft-Gault formula with actual body weight, or 40% increase from baseline serum creatinine, or 40% decrease from baseline creatinine clearance; calculated using Cockcroft-Gault formula with actual body weight. Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with resolution or return to baseline. If reduced dose does not result in renal toxicity, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for renal toxicity requiring a dosing interval beyond 16 weeks. Recurrent renal toxicity Permanently discontinue LUTATHERA. Hepatotoxicity [see Warnings and Precautions ( 5.5 )] First occurrence of: Bilirubinemia greater than 3 times the upper limit of normal (Grade 3 or 4), or Serum albumin less than 30 g/L with international normalized ratio (INR) > 1.5. Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with resolution or return to baseline. If reduced LUTATHERA dose does not result in hepatotoxicity, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for hepatotoxicity requiring a dosing interval beyond 16 weeks. Recurrent hepatotoxicity Permanently discontinue LUTATHERA. Hypersensitivity Reactions b [see Warnings and Precautions ( 5.6 )] First occurrence of Grade 3 or 4 Permanently discontinue LUTATHERA. Any Other Adverse Reactions c [see Adverse Reactions ( 6.1 )] First occurrence of Grade 3 or 4 Withhold dose until complete or partial resolution (Grade 0 to 2). Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 3 or 4 toxicity, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanentl

WARNINGS AND PRECAUTIONS Risk From Radiation Exposure : Minimize radiation exposure during and after treatment with LUTATHERA consistent with institutional good radiation safety practices and patient management procedures. ( 2.1 , 5.1 ) Myelosuppression : Monitor blood cell counts. Withhold dose, reduce dose, or permanently discontinue based on the severity. ( 2.4 , 5.2 ) Secondary Myelodysplastic Syndrome (MDS) and Leukemia : Median time to onset: MDS is 29 months; acute leukemia is 55 months. ( 5.3 ) Renal Toxicity : Advise patients to hydrate and to urinate frequently before, on the day of and the day after administration of LUTATHERA. Monitor serum creatinine and calculated creatinine clearance. Withhold dose, reduce dose, or permanently discontinue based on the severity. ( 2.3 , 2.4 , 5.4 ) Hepatotoxicity : Monitor transaminases, bilirubin, serum albumin and INR. ( 2.4 , 5.5 ) Hypersensitivity Reactions : Monitor patients closely for signs and symptoms of hypersensitivity reactions, including anaphylaxis. Permanently discontinue LUTATHERA based on severity. ( 2.3 , 2.4 , 5.6 ) Neuroendocrine Hormonal Crisis : Monitor for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms. ( 5.7 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.8 , 8.1 , 8.3 ) Risk of Infertility : LUTATHERA may cause infertility. ( 5.9 , 8.3 ) 5.1 Risk From Radiation Exposure LUTATHERA contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. These risks of radiation associated with the use of LUTATHERA are greater in pediatric patients than in adults [see Use in Specific Populations ( 8.4 )] . Radiation can be detected in the urine for up to 30 days following LUTATHERA administration. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with LUTATHERA consistent with institutional good radiation safety practices, patient management procedures, Nuclear Regulatory Commission patient-release guidance, and instructions to the patient for follow-up radiation protection at home [see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.3 )] . 5.2 Myelosuppression In NETTER-1, myelosuppression occurred more frequently in patients receiving LUTATHERA with long-acting octreotide compared to patients receiving high-dose long-acting octreotide (all Grades/Grade 3 or 4): anemia (81%/0) versus (54%/1%); thrombocytopenia (53%/1%) versus (17%/0); and neutropenia (26%/3%) versus (11%/0). 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. Among these 15 patients, 5 improved to Grade 1, 9 to Grade 2, and 1 to Grade 3. Monitor blood cell counts. Withhold dose, reduce dose, or permanently discontinue LUTATHERA based on the severity of myelosuppression [see Dosage and Administration ( 2.4 )] . 5.3 Secondary Myelodysplastic Syndrome and Leukemia In NETTER-1, with a median follow-up time of 76 months in the main study, myelodysplastic syndrome (MDS) was reported in 2.3% of patients receiving LUTATHERA with long-acting octreotide compared to no patients receiving high-dose long-acting octreotide. In ERASMUS, 16 patients (2.0%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to onset was 29 months (9 to 45 months) for MDS and 55 months (32 to 125 months) for acute leukemia. 5.4 Renal Toxicity In ERASMUS, 8 patients (< 1%) developed renal failure 3 to 36 months following LUTATHERA. Two of these patients had underlying renal impairment or risk factors for renal failure (e.g., diabetes or hypertension) and required dialysis. Administer the recommended amino acid solution before, during and after LUTATHERA [see Dosage and Administration ( 2.3 )] to decrease the reabsorption of lutetium Lu 177 dotatate through the proximal tubules and decrease the radiation dose to the kidneys. Advise patients to hydrate and to urinate frequently before, on the day of, and the day after administration of LUTATHERA. Monitor serum creatinine and calculated creatinine clearance. Withhold dose, reduce dose, or permanently discontinue LUTATHERA based on the severity of renal toxicity [see Dosage and Administration ( 2.4 )] . Patients with baseline renal impairment may be at increased risk of toxicity due to increased radiation exposure [see Use in Specific Populations ( 8.6 )] . 5.5 Hepatotoxicity In ERASMUS, 2 patients (< 1%) were reported to have hepatic tumor hemorrhage, edema, or necrosis, with one patient experiencing intrahepatic congestion and cholestasis. Patients with hepatic metastasis may be at increased risk of hepatotoxicity due to radiation exposure. Monitor transaminases, bilirubin, serum albumin, and international normalized ratio (INR) during treatment. Withhold dose, reduce dose, or permanently discontinue LUTATHERA based on the severity of hepatotoxicity [see Dosage and Administration ( 2.4 )] . 5.6 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema, occurred in patients treated with LUTATHERA [see Adverse Reactions ( 6.2 )] . Monitor patients closely for signs and symptoms of hypersensitivity reactions, including anaphylaxis, during and following LUTATHERA administration for a minimum of 2 hours in a setting where cardiopulmonary resuscitation medication and equipment are available. Discontinue the infusion upon the first observation of any signs or symptoms consistent with a severe hypersensitivity reaction and initiate appropriate therapy. Premedicate patients with a history of Grade 1 or 2 hypersensitivity reactions to LUTATHERA before subsequent doses [see Dosage and Administration ( 2.3 )] . Permanently discontinue LUTATHERA in patients who experience Grade 3 or 4 hypersensitivity reactions [see Dosage and Administration ( 2.4 )] . 5.7 Neuroendocrine Hormonal Crisis Neuroendocrine hormonal crises, manifesting with flushing, diarrhea, bronchospasm and hypotension, occurred in < 1% of patients in ERASMUS and typically occurred during or within 24 hours following the initial LUTATHERA dose. Two (< 1%) patients were reported to have hypercalcemia. Monitor patients for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms of tumor-related hormonal release. Administer intravenous somatostatin analogs, fluids, corticosteroids, and electrolytes as indicated. 5.8 Embryo-Fetal Toxicity Based on its mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data on LUTATHERA use in pregnant women. No animal studies using lutetium Lu 177 dotatate have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, radioactive emissions, including those from LUTATHERA, can cause fetal harm. Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA [see Dosage and Administration ( 2.1 )] . Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LUTATHERA and for 7 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with LUTATHERA and for 4 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] . 5.9 Risk of Infertility LUTATHERA may cause infertility in males and females. The recommended cumulative dose of 29.6 GBq of LUTATHERA results in a radiation absorbed dose to the te

CONTRAINDICATIONS None. None. ( 4 )

DRUG INTERACTIONS Somatostatin Analogs : Somatostatin analogs competitively bind to the same somatostatin receptors as gallium Ga 68 dotatate and may affect imaging – image just prior to dosing with long-acting somatostatin analogs. ( 7.1 ) Glucocorticoids : Repeated administration of high doses of glucocorticoids prior to gallium Ga 68 dotatate administration may affect imaging. ( 7.2 ) 7.1 Somatostatin analogs Non-radioactive somatostatin analogs competitively bind to the same somatostatin receptors as gallium Ga 68 dotatate. Image patients with gallium Ga 68 dotatate PET just prior to dosing with long-acting analogs of somatostatin. Short-acting analogs of somatostatin can be used up to 24 hours before imaging with gallium Ga 68 dotatate. 7.2 Glucocorticoids Glucocorticoids can down-regulate somatostatin subtype 2 receptors (SSTR2). Repeated administration of high doses of glucocorticoids prior to gallium Ga 68 dotatate administration may result in false negative imaging.

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions ( 5.2 )] Secondary Myelodysplastic Syndrome and Leukemia [see Warnings and Precautions ( 5.3 )] Renal Toxicity [see Warnings and Precautions ( 5.4 )] Hepatotoxicity [see Warnings and Precautions ( 5.5 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] Neuroendocrine Hormonal Crisis [see Warnings and Precautions ( 5.7 )] Most common Grade 3-4 adverse reactions (≥ 4% with a higher incidence in LUTATHERA arm) are lymphopenia, increased GGT, vomiting, nausea, increased AST, increased ALT, hyperglycemia and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in WARNINGS AND PRECAUTIONS reflect exposure to LUTATHERA in 111 patients with advanced, progressive midgut neuroendocrine tumors (NETTER-1). Safety data in WARNINGS AND PRECAUTIONS were also obtained in an additional 22 patients in a non-randomized pharmacokinetic sub-study of NETTER-1 and in a subset of patients (811 of 1214) with advanced somatostatin receptor-positive tumors enrolled in ERASMUS [see Warnings and Precautions ( 5 )] . Adult Population NETTER-1 The safety data of LUTATHERA with octreotide was evaluated in NETTER-1 [see Clinical Studies ( 14.1 )] . Patients with progressive, somatostatin receptor-positive midgut carcinoid tumors received LUTATHERA 7.4 GBq (200 mCi) administered every 8 to 16 weeks concurrently with the recommended amino acid solution and with long-acting octreotide (30 mg administered by intramuscular injection within 24 hours of each LUTATHERA dose) (N = 111), or high-dose octreotide (defined as long-acting octreotide 60 mg by intramuscular injection every 4 weeks) (N = 112) [see Clinical Studies ( 14.1 )] . Among patients receiving LUTATHERA with octreotide, 79% received a cumulative dose > 22.2 GBq (> 600 mCi) and 76% of patients received all four planned doses. Six percent (6%) of patients required a dose reduction and 13% of patients discontinued LUTATHERA. Five patients discontinued LUTATHERA for renal-related events and 4 discontinued for hematological toxicities. Table 5 and Table 6 summarize the incidence of adverse reactions and laboratory abnormalities, respectively. The most common Grade 3-4 adverse reactions occurring with a greater frequency among patients receiving LUTATHERA with octreotide compared to patients receiving high-dose octreotide include: lymphopenia (44%), increased gamma-glutamyltransferase (GGT) (20%), vomiting (7%), nausea and increased aspartate aminotransferase (AST) (5% each), and increased alanine aminotransferase (ALT), hyperglycemia and hypokalemia (4% each). Table 5. Adverse Reactions Occurring at Higher Incidence in Patients Receiving LUTATHERA with Long-Acting Octreotide Compared to High-Dose Long-Acting Octreotide (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4) a a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Only displays adverse reactions occurring at a higher incidence in LUTATHERA-treated patients [between arm difference of ≥ 5% (all Grades) or ≥ 2% (Grades 3-4)]. b Includes the terms: Glomerular filtration rate decreased, acute kidney injury, acute prerenal failure, azotemia, renal disorder, renal failure, renal impairment. c Includes the terms: Dysuria, micturition urgency, nocturia, pollakiuria, renal colic, renal pain, urinary tract pain and urinary incontinence. Adverse reaction a LUTATHERA with long-acting Octreotide (30 mg) (N = 111) Long-acting Octreotide (60 mg) (N = 112) All Grades % Grades 3-4 % All Grades % Grades 3-4 % Gastrointestinal disorders Nausea 65 5 12 2 Vomiting 53 7 10 0 Abdominal pain 26 3 19 3 Diarrhea 26 3 18 1 Constipation 10 0 5 0 General disorders Fatigue 38 1 26 2 Peripheral edema 16 0 9 1 Pyrexia 8 0 3 0 Metabolism and nutrition disorders Decreased appetite 21 0 11 3 Nervous system disorders Headache 17 0 5 0 Dizziness 17 0 8 0 Dysgeusia 8 0 2 0 Vascular disorders Flushing 14 1 9 0 Hypertension 12 2 7 2 Musculoskeletal and connective tissue disorders Back pain 13 2 10 0 Pain in extremity 11 0 5 0 Myalgia 5 0 0 0 Neck pain 5 0 0 0 Renal and urinary disorders Renal failure b 13 3 4 1 Radiation-related urinary tract adverse reactions c 8 0 3 0 Psychiatric disorders Anxiety 12 1 5 0 Skin and subcutaneous tissue disorders Alopecia 12 0 2 0 Respiratory, thoracic and mediastinal disorders Cough 11 1 6 0 Cardiac disorders Atrial fibrillation 5 1 0 0 Table 6. Laboratory Abnormalities Occurring at Higher Incidence in Patients Receiving LUTATHERA with Long-Acting Octreotide Compared to High-Dose Long-Acting Octreotide (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4) a,b a Values are worst grade observed after randomization. b National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Only displays laboratory abnormalities occurring at a higher incidence in LUTATHERA-treated patients [between arm difference of ≥ 5% (all Grades) or ≥ 2% (Grades 3-4)]. Laboratory abnormality b LUTATHERA with long-acting Octreotide (30 mg) (N = 111) Long-acting Octreotide (60 mg) (N = 112) All Grades % Grades 3-4 % All Grades % Grades 3-4 % Hematology Lymphopenia 90 44 39 5 Anemia 81 0 55 1 Leukopenia 55 2 20 0 Thrombocytopenia 53 1 17 0 Neutropenia 26 3 11 0 Renal/Metabolic Creatinine increased 85 1 73 0 Hyperglycemia 82 4 67 2 Hyperuricemia 34 6 30 6 Hypocalcemia 32 0 14 0 Hypokalemia 26 4 21 2 Hyperkalemia 19 0 11 0 Hypernatremia 17 0 7 0 Hypoglycemia 15 0 8 0 Hepatic GGT increased 66 20 67 16 Alkaline phosphatase increased 65 5 55 9 AST increased 50 5 35 0 ALT increased 43 4 34 0 Blood bilirubin increased 30 2 28 0 ERASMUS Safety data are available from 1214 patients in ERASMUS, an international, single-institution, single-arm, open-label trial of patients with somatostatin receptor-positive tumors (neuroendocrine and other primaries). Patients received LUTATHERA 7.4 GBq (200 mCi) administered every 6 to 13 weeks with or without octreotide. Retrospective medical record review was conducted on a subset of 811 patients to document serious adverse reactions. Eighty-one (81%) percent of patients in the subset received a cumulative dose ≥ 22.2 GBq (≥ 600 mCi). With a median follow-up time of more than 4 years, the following rates of serious adverse reactions were reported: myelodysplastic syndrome (2%), acute leukemia (1%), renal failure (2%), hypotension (1%), cardiac failure (2%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%). Pediatric Population NETTER-P Safety data are available from 9 pediatric patients in NETTER-P (NCT04711135), an international, multi-center, single-arm, open-label trial of patients with somatostatin receptor-positive tumors, including 4 patients with GEP-NETs. Patients received LUTATHERA 7.4 GBq (200 mCi) administered every 8 weeks concurrently with the recommended amino acid solution. Adverse reactions observed in NETTER-P were similar to those observed in adults treated with LUTATHERA. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of LUTATHERA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders : hypersensitivity reactions, including angioedema

Mechanism of Action Lutetium Lu 177 dotatate binds to somatostatin receptors with highest affinity for subtype 2 somatostatin receptors (SSTR2). Upon binding to somatostatin receptor expressing cells, including malignant somatostatin receptor-positive tumors, the compound is internalized. The beta-minus emission from lutetium-177 induces cellular damage by formation of free radicals in somatostatin receptor-positive cells and in neighboring cells.