Data from FDA - Curated by EPG Health - Last updated 12 April 2018

Indication(s)

1 INDICATIONS AND USAGE LUTATHERA is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults. LUTATHERA is a radiolabeled somatostatin analog indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None.
Adverse reactions
6 ADVERSE REACTIONS The following serious 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)] Neuroendocrine Hormonal Crisis [see Warnings and Precautions ( 5.6)] 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 Advanced Accelerator Applications USA, Inc. at 1-844-863-1930 or [email protected], 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 substudy 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)] . NETTER-1 The safety data described below are from NETTER-1, which randomized (1:1) patients with progressive, somatostatin receptor-positive midgut carcinoid tumors to receive 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. The median duration of follow-up was 24 months for patients receiving LUTATHERA with octreotide and 20 months for patients receiving high-dose octreotide. Table 4 and Table 5 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 GGT (20%), vomiting (7%), nausea and elevated AST (5% each), and increased ALT, hyperglycemia and hypokalemia (4% each). Table 4. Adverse Reactions Occurring in ≥ 5% (All Grades) of Patients Receiving LUTATHERA with Octreotide in NETTER-1 Adverse Reaction 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)] LUTATHERA and Long-Acting Octreotide (30 mg) (N = 111) Long-Acting Octreotide (60 mg) (N = 112) All Grades % Grades 3-4 % All Grades % Grades 3-4 % Cardiac disorders Atrial fibrillation 5 1 0 0 Gastrointestinal disorders Nausea 65 5 12 2 Vomiting 53 7 9 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 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 Nervous system disorders Headache 17 0 5 0 Dizziness 17 0 8 0 Dysgeusia 8 0 2 0 Psychiatric disorders Anxiety 12 1 5 0 Renal and urinary disorders Renal failure Includes the terms: Glomerular filtration rate decreased, acute kidney injury, acute prerenal failure, azotemia, renal disorder, renal failure, renal impairment 12 3 3 1 Radiation-related urinary tract toxicity Includes the terms: Dysuria, micturition urgency, nocturia, pollakiuria, renal colic, renal pain, urinary tract pain and urinary incontinence 8 0 3 0 Respiratory, thoracic and mediastinal disorders Cough 11 1 6 0 Skin and subcutaneous tissue disorders Alopecia 12 0 2 0 Vascular disorders Flushing 14 1 9 0 Hypertension 12 2 7 2 Table 5. Laboratory Abnormalities Occurring in ≥ 5% (All Grades) of Patients Receiving LUTATHERA with Octreotide in NETTER-1 Values are worst grade observed after randomization Laboratory Abnormality 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)] LUTATHERA and Long-Acting Octreotide (30 mg) (N = 111) Long-Acting Octreotide (60 mg) (N = 112) All grades % Grade 3-4 % All grades % Grade 3-4 % Hematology Lymphopenia 90 44 39 4 Anemia 81 0 54 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 29 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 54 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%).

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Verify pregnancy status in females of reproductive potential prior to initiating LUTATHERA. ( 2.1) Administer 7.4 GBq (200 mCi) every 8 weeks 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 up to 18 months following treatment initiation. ( 2.3) Premedicate with antiemetics 30 minutes before recommended amino acid solution. ( 2.3) Initiate recommended intravenous amino acid solution 30 minutes before LUTATHERA infusion; continue during and for 3 hours after LUTATHERA infusion. Do not reduce dose of amino acid solution if LUTATHERA dose is reduced. ( 2.3) Modify LUTATHERA dose based on adverse reactions. ( 2.4) Prepare and administer as recommended. ( 2.5) 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 physicians 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)] . 2.2 Recommended Dosage The recommended LUTATHERA dose is 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses. Administer pre- and concomitant medications and administer LUTATHERA as recommended [see Dosage and Administration ( 2.3, 2.5) ]. 2.3 Premedication and Concomitant Medications Somatostatin Analogs Before initiating LUTATHERA: Discontinue long-acting somatostatin analogs (e.g., long-acting octreotide) for 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 of each subsequent LUTATHERA dose. Short-acting octreotide may be given for symptomatic management during LUTATHERA treatment, but must be withheld for 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 up to 18 months following treatment initiation. Antiemetic Administer antiemetics 30 minutes before the recommended amino acid solution. Amino Acid Solution Initiate an intravenous amino acid solution containing L-lysine and L-arginine (Table 1) 30 minutes before administering LUTATHERA. Use a three-way valve to administer amino acids using the same venous access as LUTATHERA or administer amino acids through a separate venous access in the patient’s other arm. Continue the infusion during, and for at least 3 hours after LUTATHERA infusion. Do not decrease the dose of the amino acid solution if the dose of LUTATHERA is reduced [see Warnings and Precautions ( 5.4)] . Table 1. Amino Acid Solution Item Specification Lysine HCl content Between 18 g and 24 g Arginine HCl content Between 18 g and 24 g Volume 1.5 L to 2.2 L Osmolarity < 1050 mOsmol 2.4 Dose Modifications for Adverse Reactions Recommended dose modifications of LUTATHERA for adverse reactions are provided in Table 2. Table 2. Recommended Dose Modifications of LUTATHERA for Adverse Reactions Adverse Reaction Severity of Adverse Reaction National Cancer Institute, Common Toxicity Criteria for Adverse Events, version 4.03 Dose Modification Thrombocytopenia [see Warnings and Precautions (5.2)] 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) for next dose. Permanently discontinue LUTATHERA for Grade 2 or higher thrombocytopenia requiring a treatment delay of 16 weeks or longer. Recurrent Grade 2, 3 or 4 Permanently discontinue LUTATHERA. Anemia and Neutropenia [see Warnings and Precautions (5.2)] 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) for next dose. Permanently discontinue LUTATHERA for Grade 3 or higher anemia or neutropenia requiring a treatment delay of 16 weeks or longer. Recurrent Grade 3 or 4 Permanently discontinue LUTATHERA. Renal Toxicity [see Warnings and Precautions (5.4)] Defined as: Creatinine clearance less than 40 mL/min; calculate using Cockcroft Gault with actual body weight, or 40% increase in baseline serum creatinine, or 40% decrease in baseline creatinine clearance; calculate using Cockcroft Gault with actual body weight. Withhold dose until complete resolution. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete resolution. If reduced dose does not result in renal toxicity, administer LUTATHERA at 7.4 GBq (200 mCi) for next dose. Permanently discontinue LUTATHERA for renal toxicity requiring a treatment delay of 16 weeks or longer. Recurrent renal toxicity Permanently discontinue LUTATHERA. Hepatotoxicity [see Warnings and Precautions (5.5)] Defined as: Bilirubinemia greater than 3 times the upper limit of normal (Grade 3 or 4), or Hypoalbuminemia less than 30 g/L with a decreased prothrombin ratio less than 70%. Withhold dose until complete resolution. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete resolution. If reduced LUTATHERA dose does not result in hepatotoxicity, administer LUTATHERA at 7.4 GBq (200 mCi) for next dose. Permanently discontinue LUTATHERA for hepatotoxicity requiring a treatment delay of 16 weeks or longer. Recurrent hepatotoxicity Permanently discontinue LUTATHERA. Other Non-Hematologic Toxicity 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) for next dose. Permanently discontinue LUTATHERA for Grade 3 or higher toxicity requiring treatment delay of 16 weeks or longer. Recurrent Grade 3 or 4 Permanently discontinue LUTATHERA. 2.5 Preparation and Administration Use aseptic technique and radiation shielding when administering the LUTATHERA solution. Use tongs when handling vial to minimize radiation exposure. Do not inject LUTATHERA directly into any other intravenous solution. Confirm the amount of radioactivity of LUTATHERA in the radiopharmaceutical vial with an appropriate dose calibrator prior to and after LUTATHERA administration. Inspect the product visually for particulate matter and discoloration prior to administration under a shielded screen. Discard vial if particulates or discoloration are present. Administration Instructions Insert a 2.5 cm, 20 gauge needle (short needle) into the LUTATHERA vial and connect via a catheter to 500 mL 0.9% sterile sodium chloride solution (used to transport LUTATHERA 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 sodium chloride solution to flow into the LUTATHERA vial prior to the initiation of the LUTATHERA infusion and do not inject LUTATHERA directly into the sodium chloride solution. 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 prefilled with 0.9% sterile sodium chloride and that is used exclusively for the LUTATHERA infusion into the patient. Use a clamp or pump to regulate the flow of the sodium chloride solution 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 sodium chloride solution entering the vial through the short needle will carry the LUTATHERA from the vial to the patient via the catheter connected to the long needle over a total duration of 30 to 40 minutes). Do not administer LUTATHERA as an intravenous bolus. 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 saline 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% sterile sodium chloride. Dispose of any unused medicinal product or waste material in accordance with local and federal laws. 2.6 Radiation Dosimetry The mean and standard deviation (SD) of the estimated radiation absorbed doses for adults receiving LUTATHERA are shown in Table 3. The maximum penetration in tissue is 2.2 mm and the mean penetration is 0.67 mm. Table 3. Estimated Radiation Absorbed Dose for LUTATHERA in NETTER-1 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 N=18 (two patients excluded because the liver absorbed dose was biased by the uptake of the liver metastases) 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 N=9 (female patients only) 0.031 0.013 0.9 0.4 Pancreas 0.038 0.016 1.1 0.5 Red Marrow 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 N=11 (male patients only) 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 0.032 0.013 1.0 0.4
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2) 8.1 Pregnancy Risk Summary Based on its mechanism of action, LUTATHERA can cause fetal harm [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, all radiopharmaceuticals, including LUTATHERA, have the potential to cause fetal harm. Advise pregnant women of the risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary There are no data on the presence of lutetium Lu 177 dotatate in human milk, or its effects on the breastfed infant or milk production. No lactation studies in animals were conducted. Because of the potential risk for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with LUTATHERA and for 2.5 months after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA [see Use in Specific Populations ( 8.1)] . Contraception Females LUTATHERA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)] . Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the final dose of LUTATHERA. Males Based on its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during and for 4 months following the final dose of LUTATHERA [see Clinical Pharmacology ( 12.1) and Nonclinical Toxicology ( 13.1)] . Infertility The recommended cumulative dose of 29.6 GBq of LUTATHERA results in a radiation absorbed dose to the testis and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy [see Dosage and Administration ( 2.6)] . 8.4 Pediatric Use The safety and effectiveness of LUTATHERA have not been established in pediatric patients. 8.5 Geriatric Use Of the 1325 patients treated with LUTATHERA in clinical trials, 438 patients (33%) were 65 years and older. The response rate and number of patients with a serious adverse event were similar to that of younger subjects. 8.6 Renal Impairment No dose adjustment is recommended for patients with mild to moderate renal impairment; however, patients with mild or moderate renal impairment may be at greater risk of toxicity. Perform more frequent assessments of renal function in patients with mild to moderate impairment. The safety of LUTATHERA in patients with severe renal impairment (creatinine clearance < 30 mL/min by Cockcroft-Gault) or end-stage renal disease has not been studied. 8.7 Hepatic Impairment No dose adjustment is recommended for patients with mild or moderate hepatic impairment. The safety of LUTATHERA in patients with severe hepatic impairment (total bilirubin > 3 times upper limit of normal and any AST) has not been studied.

Interactions

7 DRUG INTERACTIONS Somatostatin Analogs: Discontinue long-acting analogs for at least 4 weeks and short-acting octreotide at least 24 hours prior to each LUTATHERA dose. ( 2.3, 7.1) 7.1 Somatostatin Analogs Somatostatin and its analogs competitively bind to somatostatin receptors and may interfere with the efficacy of LUTATHERA. Discontinue long-acting somatostatin analogs at least 4 weeks and short-acting octreotide at least 24 hours prior to each LUTATHERA dose. Administer short- and long-acting octreotide during LUTATHERA treatment as recommended [see Dosage and Administration ( 2.3)] .

More information

Category Value
Authorisation number NDA208700
Agency product number AE221IM3BB
Orphan designation No
Product NDC 69488-003
Date Last Revised 09-02-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Advanced Accelerator Applications USA, Inc