Lutetium Lu 177 Dotatate

1 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.

2 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. Permanently discontinue LUTATHERA for Grade 3 or higher adverse reactions requiring a dosing interval beyond 16 weeks. Recurrent Grade 3 or 4 Permanently discontinue LUTATHERA. 2.5 Preparation and Administration Preparation Instructions Use aseptic technique and radiation shielding when handling or administering the LUTATHERA solution. Use tongs when handling the vial to minimize radiation exposure. Inspect the product visually under a shielded screen for particulate matter and discoloration prior to administration. Discard the vial if particulates and/or discoloration are present. Do not inject the LUTATHERA solution directly into any other intravenous solution. Confirm the amount of radioactivity of LUTATHERA delivered to the patient with an appropriate dose calibrator prior to and after each LUTATHERA administration. Dispose of any unused medicinal product or waste material in accordance with local and federal laws. Administration Instructions Prior to administration, flush the intravenous catheter used for LUTATHERA administration with ≥ 10 mL of 0.9% Sodium Chloride Injection, USP to ensure patency and to minimize the risk of extravasation. Manage cases of extravasation as per institutional guidelines. The gravity method, peristaltic pump method, or the syringe pump method may be used for the administration of the recommended dosage. Do not administer LUTATHERA as an intravenous bolus. When using the gravity or peristaltic pump method, infuse LUTATHERA directly from its original container. Use the peristaltic pump or syringe pump method when administering a reduced dose of LUTATHERA following a dosage modification for an adverse reaction. When using the gravity method for a reduced dose, adjust the LUTATHERA dose before the administration to avoid the delivery of an incorrect volume of LUTATHERA. Intravenous Methods of Administration Instructions for the Gravity Method Insert a 2.5 cm, 20-gauge needle (short needle) into the LUTATHERA vial and connect via a catheter to 500 mL 0.9% Sodium Chloride Injection, USP (used to transport the LUTATHERA solution during the infusion). Ensure that the short needle does not touch the LUTATHERA solution in the vial and do not connect this short needle directly to the patient. Do not allow the 0.9% Sodium Chloride Injection, USP to flow into the LUTATHERA vial prior to the initiation of the LUTATHERA infusion and do not inject the LUTATHERA solution directly into the 0.9% Sodium Chloride Injection, USP. Insert a second needle that is 9 cm, 18-gauge (long needle) into the LUTATHERA vial ensuring that this long needle touches and is secured to the bottom of the LUTATHERA vial during the entire infusion. Connect the long needle to the patient by an intravenous catheter that is pre-filled with 0.9% Sodium Chloride Injection, USP and that is used for the LUTATHERA infusion into the patient. Use a clamp or an infusion pump to regulate the flow of the 0.9% Sodium Chloride Injection, USP via the short needle into the LUTATHERA vial at a rate of 50 mL/hour to 100 mL/hour for 5 to 10 minutes and then 200 mL/hour to 300 mL/hour for an additional 25 to 30 minutes (the 0.9% Sodium Chloride Injection, USP entering the vial through the short needle will carry the LUTATHERA solution from the vial to the patient via the intravenous catheter connected to the long needle over a total duration of 30 to 40 minutes). During the infusion, ensure that the level of solution in the LUTATHERA vial remains constant. Disconnect the vial from the long needle line and clamp the 0.9% Sodium Chloride Injection, USP line once the level of radioactivity is stable for at least five minutes. Follow the infusion with an intravenous flush of 25 mL of 0.9% Sodium Chloride Injection, USP through the intravenous catheter to the patient. Instructions for the Peristaltic Pump Method Insert a filtered 2.5 cm, 20-gauge needle (short venting needle) into the LUTATHERA vial. Ensure that the short needle does not touch the LUTATHERA solution in the vial and do not connect this short needle directly to the patient or to the peristaltic pump. Insert a second needle that is 9 cm, 18 gauge (long needle) into the LUTATHERA vial ensuring that the long needle touches and is secured to the bottom of the LUTATHERA vial during the entire infusion. Connect the long needle and a 0.9% Sodium Chloride Injection, USP to a 3-way stopcock valve via appropriate tubing. Connect the output of the 3-way stopcock valve to tubing installed on the input side of the peristaltic pump according to manufacturer’s instructions. Prime the line by opening the 3-way stopcock valve and pumping the LUTATHERA solution through the tubing until it reaches the exit of the valve. Prime the intravenous catheter that will be connected to the patient by opening the 3-way stopcock valve to the 0.9% Sodium Chloride Injection, USP and pumping the 0.9% Sodium Chloride Injection, USP until it exits the end of the catheter tubing. Connect the primed intravenous catheter to the patient and set the 3-way stopcock valve such that the LUTATHERA solution is in line with the peristaltic pump. Infuse an appropriate volume of LUTATHERA solution over a 30-40 min period to deliver the desired radioactivity. When the desired LUTATHERA radioactivity has been delivered, stop the peristaltic pump and then change the position of the 3-way stopcock valve so that the peristaltic pump is in line with the 0.9% Sodium Chloride Injection, USP. Restart the peristaltic pump and infuse an intravenous flush of 25 mL of 0.9% Sodium Chloride Injection, USP through the intravenous catheter to the patient. Instructions for the Syringe Pump Method Withdraw an appropriate volume of LUTATHERA solution to deliver the desired radioactivity by using a disposable syringe fitted with a syringe shield and a disposable sterile needle that is 9 cm, 18 gauge (long needle). To aid the withdrawal of the solution, a filtered 2.5 cm, 20-gauge needle (short venting needle) can be used to reduce the resistance from the pressurized vial. Ensure that the short needle does not touch the LUTATHERA solution in the vial. Fit the syringe into the shielded pump and include a 3-way stopcock valve between the syringe and an intravenous catheter pre-filled with 0.9% Sodium Chloride Injection, USP and used for LUTATHERA administration to the patient. Infuse an appropriate volume of LUTATHERA solution over a 30-40 min period to deliver the desired radioactivity. When the desired LUTATHERA radioactivity has been delivered, stop the syringe pump and then change the position of the 3-way stopcock valve to flush the syringe with 25 mL of 0.9% Sodium Chloride Injection, USP. Restart the syringe pump. After the flush of the syringe has been completed, perform an intravenous flush with 25 mL of 0.9% Sodium Chloride Injection, USP through the intravenous catheter to the patient. 2.6 Radiation Dosimetry The maximum penetration of lutetium-177 in tissue is 2.2 mm and the mean penetration is 0.67 mm. The mean and standard deviation (SD) of the estimated radiation absorbed doses for adults receiving LUTATHERA are shown in Table 3. The mean and SD of the estimated radiation absorbed doses for pediatric patients 12 years and older receiving LUTATHERA are shown in Table 4. Table 3. Estimated Radiation Absorbed Dose for LUTATHERA in Adults in NETTER-1 a N = 18 (two patients excluded because the liver absorbed dose was biased by the uptake of the liver metastases). b N = 9 (female patients only). c Red marrow dosimetry estimates were determined using blood radioactivity. d N = 11 (male patients only). Absorbed dose per unit activity (Gy/GBq) (N = 20) Calculated absorbed dose for 4 x 7.4 GBq (29.6 GBq cumulative activity) (Gy) Organ Mean SD Mean SD Adrenals 0.037 0.016 1.1 0.5 Brain 0.027 0.016 0.8 0.5 Breasts 0.027 0.015 0.8 0.4 Gallbladder wall 0.042 0.019 1.2 0.6 Heart wall 0.032 0.015 0.9 0.4 Kidneys 0.654 0.295 19.4 8.7 Liver a 0.299 0.226 8.9 6.7 Lower large intestine wall 0.029 0.016 0.9 0.5 Lungs 0.031 0.015 0.9 0.4 Muscle 0.029 0.015 0.8 0.4 Osteogenic cells 0.151 0.268 4.5 7.9 Ovaries b 0.031 0.013 0.9 0.4 Pancreas 0.038 0.016 1.1 0.5 Red marrow c 0.035 0.029 1.0 0.8 Skin 0.027 0.015 0.8 0.4 Small intestine 0.031 0.015 0.9 0.5 Spleen 0.846 0.804 25.1 23.8 Stomach wall 0.032 0.015 0.9 0.5 Testes d 0.026 0.018 0.8 0.5 Thymus 0.028 0.015 0.8 0.5 Thyroid 0.027 0.016 0.8 0.5 Total body 0.052 0.027 1.6 0.8 Upper large intestine wall 0.032 0.015 0.9 0.4 Urinary bladder wall 0.437 0.176 12.8 5.3 Uterus b 0.032 0.013 1.0 0.4 Table 4. Estimated Radiation Absorbed Dose for LUTATHERA in Pediatric Patients 12 Years and Older in NETTER-P a Data are pooled for 8 pediatric patients with somatostatin receptor-positive (SSTR+) tumors, including 4 patients with GEP-NETs. b N = 5 (female patients only). c N = 7 (3 GEP-NET, 4 SSTR+ tumors). Pituitary dosimetry estimates were only performed when pituitary uptake was clearly observed on the planar images. Due to the small size of the pituitary gland, availability for quantification only from planar images and interference from activity in the nasal mucosa, estimates can be associated with a large uncertainty. Pituitary gland absorbed dose estimate includes absorbed dose contributions from activity within the pituitary only, dose contributions from other tissues are not included. d N = 3 (male patients only). e Red marrow dosimetry estimates were determined either using blood radioactivity or by imaging and scaling of a representative region of the lumbar spine. Absorbed dose per unit activity (Gy/GBq) (N = 8 a ) Calculated absorbed dose for 4 x 7.4 GBq (29.6 GBq cumulative activity) (Gy) Organ Mean SD Mean SD Adrenals 0.045 0.011 1.3 0.3 Brain 0.021 0.006 0.6 0.2 Breasts b 0.018 0.006 0.5 0.2 Esophagus 0.024 0.006 0.7 0.2 Eyes 0.021 0.006 0.6 0.2 Gallbladder wall 0.031 0.011 0.9 0.3 Heart wall 0.024 0.006 0.7 0.2 Kidneys 0.773 0.288 22.9 8.5 Left colon 0.265 0.081 7.8 2.4 Liver 0.216 0.231 6.4 6.8 Lungs 0.024 0.006 0.7 0.2 Osteogenic cells 0.046 0.019 1.4 0.6 Ovaries b 0.026 0.007 0.8 0.2 Pancreas 0.027 0.007 0.8 0.2 Pituitary c 1.053 0.348 31.2 10.3 Prostate d 0.026 0.006 0.8 0.2 Rectum 0.272 0.085 8.0 2.5 Red marrow (blood) e 0.027 0.005 0.8 0.2 Red marrow (image) e 0.055 0.026 1.6 0.8 Right colon 0.152 0.045 4.5 1.3 Salivary glands 0.036 0.017 1.1 0.5 Small intestine 0.046 0.013 1.3 0.4 Spleen 0.733 0.304 21.7 9.0 Stomach wall 0.027 0.007 0.8 0.2 Testes d 0.021 0.005 0.6 0.2 Thymus 0.022 0.006 0.7 0.2 Thyroid 0.022 0.006 0.6 0.2 Total body 0.042 0.010 1.2 0.3 Urinary bladder wall 0.573 0.088 17.0 2.6 Uterus b 0.031 0.008 0.9 0.2

6 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

12.3 Pharmacokinetics The pharmacokinetics (PK) of lutetium Lu 177 dotatate have been characterized in patients with progressive, somatostatin receptor-positive neuroendocrine tumors. The mean blood exposure (area under the curve) of lutetium Lu 177 dotatate at the recommended dose is 41 ng.h/mL [coefficient of variation (CV) 36%]. The mean maximum blood concentration (C max ) for lutetium Lu 177 dotatate is 10 ng/mL (CV 50%), which generally occurred at the end of the LUTATHERA infusion. Distribution The mean volume of distribution (V z ) for lutetium Lu 177 dotatate is 460 L (CV 54%). The non-radioactive lutetium Lu 175 dotatate is 43% bound to human plasma proteins. Within 4 hours after administration, lutetium Lu 177 dotatate distributes in kidneys, tumor lesions, liver, spleen, and, in some patients, pituitary gland and thyroid. The co-administration of amino acids reduced the median radiation dose to the kidneys by 47% (34% to 59%) and increased the mean beta-phase blood clearance of lutetium Lu 177 dotatate by 36%. Elimination The mean clearance (CL) is 4.5 L/h (CV 31%) and the mean terminal half-life is 71 (±28) hours for lutetium 177 dotatate. Metabolism Lutetium Lu 177 dotatate does not undergo hepatic metabolism. Excretion Lutetium Lu 177 dotatate is primarily eliminated renally with cumulative excretion of 44% within 5 hours, 58% within 24 hours, and 65% within 48 hours following LUTATHERA administration. Prolonged elimination of lutetium Lu 177 dotatate in the urine is expected; however, based on the half-life of lutetium-177 and terminal half-life of lutetium Lu 177 dotatate, greater than 99% of the administered radioactivity will be eliminated within 14 days after administration of LUTATHERA [see Warnings and Precautions ( 5.1 )] . Special Populations Pediatric Patients There were no clinically relevant differences in exposure of lutetium Lu 177 dotatate in pediatric patients 12 years and older compared to that of adult patients. Drug Interaction Studies In Vitro Studies CYP450 enzymes: The non-radioactive lutetium Lu 175 dotatate is not an inhibitor or inducer of cytochrome P450 (CYP) 1A2, 2B6, 2C9, 2C19 or 2D6 in vitro. Transporters: The non-radioactive lutetium Lu 175 dotatate is not an inhibitor of P-glycoprotein, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, or OATP1B3 in vitro.