IMPORTANT SAFETY INFORMATION AND INDICATION

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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Radiation Exposure: Treatment with LUTATHERA contributes to a patient’s overall long-term cumulative radiation exposure and is associated with an increased risk for cancer. 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.

INDICATION

LUTATHERA^® (lutetium Lu 177 dotatate) is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.

Disease Progression

Monitor for Progression

Proactively Monitoring for Progression, Regardless of Recurrent or Worsening Symptoms

Proactive monitoring for disease progression is important when treating patients with GEP-NETs^1,2

Close monitoring may help you identify the appropriate time to consider different treatment options for patients who are progressing.⁸

Proactively Monitoring for Progression,
Regardless of Recurrent or Worsening Symptoms^2,8-10

Symptoms associated with NETs may be nonspecific or absent until more advanced stages of disease. Progression may not be correlated with symptoms, so proactive monitoring may determine the right time for a change of treatment.

Identify Appropriate Patients for LUTATHERA Early

Take Action With LUTATHERA After First-Line SSA Therapy

Many patients with GEP-NETs are diagnosed with late-stage disease. Time matters—consider LUTATHERA after first progression on an SSA before patients become ineligible.^2,11

Patient eligible for LUTATHERA	Patient not eligible for LUTATHERA
Emily	Maggie

Referred for LUTATHERA immediately after progressing on first-line SSA therapy	Referred for LUTATHERA after progressing on multiple therapies, but deemed ineligible for LUTATHERA due to development of renal failure requiring dialysis Not actual patients.

Patients with NETs, including GEP-NETs, are often left waiting to receive a diagnosis, which may delay treatment.^1,2

Patient Profiles

How to Identify Potential Patients for Treatment With LUTATHERA

After a patient with GEP-NET progresses following first-line SSA therapy, there may be multiple treatment options to consider for the next step. However, only certain patients may be appropriate candidates for treatment with LUTATHERA.¹²

Consider LUTATHERA for adults with SSTR-positive GEP-NETs, including foregut, midgut, and hindgut NETs. The table below outlines the characteristics of patients who were studied in the NETTER-1 clinical trial.¹²

Do any of your patients fit these criteria?

Category	Characteristics of Patients in the NETTER-1 Trial^12,13
Extent of disease	Operable	Inoperable
Location of disease	Metastatic	Locally advanced
Pace of growth	Stable	Progressive
Primary site	Midgut

Grade

Low

Intermediate

High

Differentiation	Well differentiated	Poorly differentiated
Hormone status	Functional	Nonfunctional
SSTR expression	Positive	Negative

Table Key

Included in clinical trial

Excluded from clinical trial

Recognizing the early signs of progression after first-line SSA therapy is important when determining when a change in treatment may be needed.^2,8,10

Early detection of progression and the initiation of LUTATHERA may help appropriate patients with GEP-NETs.^1,2

Next: Efficacy

CT, computed tomography; GEP-NETs, gastroenteropancreatic neuroendocrine tumors; MRI, magnetic resonance imaging; NETs, neuroendocrine tumors; SSA, somatostatin analog; SSTR, somatostatin receptor.

References: 1. Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, et al. Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Ann Oncol. 2010;21(9):1794-1803. 2. Sackstein PE, O’Neil DS, Neuget AI, Chabot J, Fojo T. Epidemiologic trends in neuroendocrine tumors: an examination of incidence rates and survival of specific patient subgroups over the past 20 years. Semin Oncol. 2018;45(4):249-258. 3. Toumpanakis C, Garland J, Marelli L, et al. Long-term results of patients with malignant carcinoid syndrome receiving octreotide LAR. Aliment Pharmacol Ther. 2009;30(7):733-740. 4. Cancer.net. Neuroendocrine tumors: statistics. Accessed February 24, 2022. https://www.cancer.net/cancer-types/neuroendocrine-tumors/statistics 5. Vinik AI, Woltering EA, Warner RRP, et al. NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas. 2010;39(6):713-734. 6. Panzuto F, Falconi M, Nasoni S, et al. Staging of digestive endocrine tumours using helical computed tomography and somatostatin receptor scintigraphy. Ann Oncol. 2003;14(4):586-591. 7. Dromain C, de Baere T, Lumbroso J, et al. Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging. J Clin Oncol. 2005;23(1):70-78. 8. Merino-Casabiel X, Aller J, Arbizu J, et al. Consensus document on the progression and treatment response criteria in gastroenteropancreatic neuroendocrine tumors. Clin Transl Oncol. 2018;20(12):1522-1528. 9. Wolin EM, Leyden J, Goldstein G, Kolarova T, Hollander R, Warner RRP. Patient-reported experience of diagnosis, management, and burden of neuroendocrine tumors: results from a large patient survey in the United States. Pancreas. 2017;46(5):639-647. 10. Ter-Minassian M, Zhang S, Brooks NV, et al. Association between tumor progression endpoints and overall survival in patients with advanced neuroendocrine tumors. Oncologist. 2017;22(2):165-172. 11. Hope TA, Bodei L, Chan JA, et al. NANETS/SNMMI consensus statement on patient selection and appropriate use of ¹⁷⁷Lu- DOTATATE peptide receptor radionuclide therapy. J Nucl Med. 2020;61(2):222-227. 12. Lutathera. Prescribing information. Advanced Accelerator Applications. 13. Strosberg J, El-Haddad G, Wolin E, et al; for the NETTER-1 trial investigators. Phase 3 trial of ¹⁷⁷Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135.

INDICATION

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Radiation Exposure: Treatment with LUTATHERA contributes to a patient’s overall long-term cumulative radiation exposure and is associated with an increased risk for cancer. 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 the NETTER-1 clinical trial, myelosuppression occurred more frequently in patients receiving LUTATHERA with long-acting octreotide compared with patients receiving high-dose long-acting octreotide (all grades/grade 3/4): anemia (81%/0 vs 54%/1%), thrombocytopenia (53%/1% vs 17%/0), and neutropenia (26%/3% vs 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 19 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 with no patients receiving high-dose long-acting octreotide. In ERASMUS, a phase 2 clinical study, 16 patients (2.0%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to onset was 29 months (range, 9-45 months) for MDS and 55 months (range, 32-125 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 (eg, 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 on 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; perform more frequent assessments of renal function in patients with baseline mild or moderate impairment. LUTATHERA has not been studied in patients with baseline severe renal impairment (creatinine clearance <30 mL/min) or those with end-stage renal disease.
Hepatotoxicity: In ERASMUS, 2 patients (<1%) were reported to have hepatic tumor hemorrhage, edema, or necrosis, with 1 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 the international normalized ratio 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 in which 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 1/2 hypersensitivity reactions to LUTATHERA before subsequent doses. Permanently discontinue LUTATHERA in patients who experience grade 3/4 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: LUTATHERA can cause fetal harm when administered to a pregnant woman. Verify the 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. Radiation absorbed by testes and ovaries from the recommended cumulative LUTATHERA dose falls within the range in which temporary or permanent infertility can be expected following external beam radiotherapy.

ADVERSE REACTIONS

The most common grade 3/4 adverse reactions (≥4% with a higher incidence in the LUTATHERA arm) observed in NETTER-1 were lymphopenia (44%), increased gamma-glutamyl transferase (20%), vomiting (7%), nausea (5%), increased aspartate aminotransferase (5%), increased alanine aminotransferase (4%), hyperglycemia (4%), and hypokalemia (4%).

In ERASMUS, the following serious adverse reactions have been observed with a median follow-up time of >4 years after treatment with LUTATHERA: myelodysplastic syndrome (2%), acute leukemia (1%), renal failure (2%), hypotension (1%), cardiac failure (2%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%). Patients should be counseled and monitored in accordance with the LUTATHERA Prescribing Information.

DRUG INTERACTIONS

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 can induce downregulation of subtype 2 somatostatin receptors. Avoid repeated administration of high doses of glucocorticoids during treatment with LUTATHERA.

SPECIFIC POPULATIONS

Lactation: Because of the potential risk for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LUTATHERA and for 2.5 months after the last dose.

Please see full Prescribing Information.