Lutathera Drug Information
Generic name: LUTETIUM LU 177 DOTATATE
Uses of 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 & Administration of Lutathera
| aequivalent to 14.4 to 20 g L-lysine. bequivalent to 14.9 to 20.7 g L-arginine. | |
|---|---|
| L-lysine HCl | Between 18 and 25 ga |
| L-arginine HCl | Between 18 and 25 gb |
| Volume | 1 to 2 L |
| Osmolality | < 1200 mOsmol/kg |
Side Effects of Lutathera
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 . Adult Population NETTER-1 The safety data of LUTATHERA with octreotide was evaluated in NETTER-1 . Patients with progressive, somatostatin receptor-positive midgut carcinoid tumors received LUTATHERA
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) . Among patients receiving LUTATHERA with octreotide, 79% received a cumulative dose >
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. 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. 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
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 ≥
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
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.
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
Warnings & Cautions for Lutathera
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 . 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 .
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 .
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.
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 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 . Patients with baseline renal impairment may be at increased risk of toxicity due to increased radiation exposure .
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 .
Hypersensitivity Reactions Hypersensitivity reactions, including angioedema, occurred in patients treated with
LUTATHERA . 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 . Permanently discontinue LUTATHERA in patients who experience Grade 3 or 4 hypersensitivity reactions .
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.
Embryo-Fetal Toxicity
Based on its mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman . 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 . 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 .
Risk of Infertility
LUTATHERA may cause infertility in males and females. The recommended cumulative dose of
GBq of
LUTATHERA results in a radiation absorbed dose to the testes and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy .
Drug Interactions with Lutathera
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 .
Glucocorticoids Glucocorticoids can induce down-regulation of subtype 2 somatostatin receptors (SSTR2).
Avoid repeated administration of high doses of glucocorticoids during treatment with LUTATHERA.
Pregnancy Safety for Lutathera
Pregnancy Risk Summary Based on its mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman . 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. Advise pregnant women of the potential 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.
Pediatric Use of Lutathera
Pediatric Use Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors The safety and effectiveness of LUTATHERA have been established in pediatric patients 12 years and older with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Use of LUTATHERA for this indication is supported by evidence from an adequate and well-controlled study of LUTATHERA in adults with additional safety, pharmacokinetic, and dosimetry data in pediatric patients aged 12 years and older with somatostatin receptor-positive tumors, including 4 pediatric patients with GEP-NETs . The risks of radiation exposure associated with LUTATHERA are greater in pediatric patients than in adult patients due to longer life expectancy. Continued follow-up is recommended for evaluation of long-term effects. There was no clinically relevant difference in lutetium Lu 177 dotatate exposure in pediatric patients aged 13 to 16 years versus adult patients . The pharmacokinetic profile and safety of LUTATHERA in pediatric patients 12 years and older with baseline renal impairment have not been studied.
The safety and effectiveness of LUTATHERA have not been established in pediatric patients younger than 12 years old with somatostatin receptor-positive GEP-NETs.
Clinical Studies of Lutathera
Progressive, Well-Differentiated Advanced or Metastatic Somatostatin Receptor-Positive Midgut Carcinoid Tumors
The efficacy of LUTATHERA in patients with progressive, well-differentiated, locally advanced/inoperable or metastatic somatostatin receptor-positive midgut carcinoid tumors was established in NETTER-1 (NCT01578239), a randomized, multicenter, open-label, active-controlled trial. Key eligibility criteria included Ki67 index ≤ 20%, Karnofsky performance status ≥ 60, confirmed presence of somatostatin receptors on all lesions (OctreoScan uptake ≥ normal liver), creatinine clearance ≥ 50 mL/min, no prior treatment with peptide receptor radionuclide therapy (PRRT), and no prior external beam radiation therapy to more than 25% of the bone marrow. At the time of the primary analysis, 229 patients were randomized (1:1) to receive either LUTATHERA
GBq (200 mCi) every 8 weeks (±1 week) for up to 4
administrations (maximum cumulative dose of
GBq) or high-dose long-acting octreotide (defined as 60 mg by intramuscular injection
every 4 weeks). Patients in the LUTATHERA arm also received long-acting octreotide 30 mg as an intramuscular injection 4 to 24 hours after each LUTATHERA dose and every 4 weeks after completion of LUTATHERA treatment until disease progression or until week 76 of the study. Patients in both arms could receive short-acting octreotide for symptom management; however, short-acting octreotide was withheld at least 24 hours before each LUTATHERA dose. Randomization was stratified by OctreoScan tumor uptake score (Grade 2, 3, or 4) and the length of time that patients had been on the most recent constant dose of octreotide prior to randomization (≤ 6 or > 6 months). The major efficacy outcome measure was progression-free survival (PFS) as determined by a blinded independent review committee (IRC) per RECIST v1.1. Additional efficacy outcome measures were overall response rate (ORR) by IRC, duration of response (DoR) by IRC, and overall survival (OS). Demographic and baseline disease characteristics were balanced between the treatment arms.
Of the 229 patients, 82% were White, 4% were Black, 3% were Hispanic or Latino, 0.4% were Asian, 0.4% were Other, and 9% were not reported. The median age was 64 years (28 to 87 years); 51% were male, 74% had an ileal primary, and 96% had metastatic disease in the liver. The median Karnofsky performance score was 90 (60 to 100), 74% received a constant dose of octreotide for > 6 months and 12% received prior treatment with everolimus.
Sixty-nine percent of patients had Ki67 expression in ≤ 2% of tumor cells, 77% had CgA > 2 times the upper limit of normal (ULN), 65% had 5-HIAA > 2 times ULN, and 65% had alkaline phosphatase ≤ ULN. At the time of the final OS analysis, which occurred 66 months after the primary PFS analysis, 117 patients were randomized to the LUTATHERA arm and 114 patients were randomized to the octreotide arm. In the final OS analysis, there was no statistically significant difference in OS between the two treatment arms. Efficacy results for NETTER-1 are presented in Table 9 and Figure 1. Table 9. Efficacy Results in NETTER-1 Abbreviations: CI, confidence interval; IRC, independent radiology committee; NE, not evaluable; NR, not reached; ORR, overall response rate; PFS, progression-free survival. a Hazard ratio based on the unstratified Cox model. b Unstratified log rank test. c Fisher’s exact test.
LUTATHERA with long-acting Octreotide (30 mg) N = 116 Long-acting Octreotide (60 mg) N = 113 PFS by IRC Events (%) 27 (23%) 78 (69%) Progressive disease, n (%) 15 (13%) 61 (54%) Death, n (%) 12 (10%) 17 (15%) Median in months (95% CI) NR (18.4, NE)
Hazard ratio a (95% CI) 0.21 p-value b < 0.0001
ORR by IRC ORR, % (95% CI) 13% (7%, 19%) 4% (0.1%, 7%) Complete response rate, n (%) 1 (1%) 0 Partial response rate, n (%) 14 (12%) 4 (4%) p-value c 0.0148 Duration of response, median in months (95% CI) NR (2.8, NE) 1.9 (1.9, NE) Figure 1. Kaplan-Meier Curves for Progression-Free Survival in NETTER-1 Figure 1. Kaplan-Meier Curves for Progression-Free Survival in NETTER-1
Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors
The efficacy of LUTATHERA in patients with foregut, midgut, and hindgut gastroenteropancreatic neuroendocrine tumors (GEP-NETs) was assessed in 360 patients in the ERASMUS study. In ERASMUS, LUTATHERA was initially provided as expanded access under a general peptide receptor radionuclide therapy protocol at a single site in the Netherlands. A subsequent LUTATHERA-specific protocol written eight years after study initiation did not describe a specific sample size or hypothesis testing plan but allowed for retrospective data collection.
A total of 1214 patients received LUTATHERA in ERASMUS, of whom 578 patients had baseline tumor assessments. Of the 578 patients, 360 (62%) had GEP-NETs and long-term follow-up. Of these 360 patients, 145 (40%) had their tumors prospectively evaluated according to RECIST criteria.
LUTATHERA
GBq (200 mCi) was administered every 6 to 13 weeks for up
to 4 doses concurrently with the recommended amino acid solution. The major efficacy outcome was investigator-assessed ORR. The median age in the efficacy subset was 60 years (30 to 85 years), 51% were male, 71% had a baseline Karnofsky performance status ≥ 90, 51% had progressed within 12 months of treatment, and 7% had received prior chemotherapy. Fifty-two percent (52%) of patients received a concomitant somatostatin analog.
The median dose of LUTATHERA was
GBq (800 mCi).
The investigator-assessed ORR was 17% (95% CI: 13, 21) based on an analysis that required responders to have had prospective response assessments according to RECIST criteria. Three complete responses were observed (< 1%). Median DoR in the 60 responding patients was 35 months (95% CI: 17, 38).
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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