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.
See more
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.

Safety

Adverse Reactions

Many of the adverse reactions in the LUTATHERA arm were grade 1 or 2.1

Adverse Reactions Occurring at a Higher Incidence in the LUTATHERA Arm (Between-Arm Difference of ≥5% [All Grades] or ≥2% [Grade 3/4])1
 
LUTATHERA With Long-Acting
Octreotide (30 mg) 
(n=111)
Long-Acting
Octreotide (60 mg)
(n=112)
Adverse Reactiona All
Grades,
%
Grade
3/4,
%
All
Grades,
%
Grade
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 failureb 13 3 4 1
Radiation-related urinary tract
adverse reactionsc
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

aNational Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 only displays adverse reactions occurring at a higher incidence in patients treated with LUTATHERA (between-arm difference of ≥5% [all grades] or ≥2% [grade 3/4]).

bIncludes the terms glomerular filtration rate decreased, acute kidney injury, acute prerenal failure, azotemia, renal disorder, renal failure, and renal impairment.

cIncludes the terms dysuria, micturition urgency, nocturia, pollakiuria, renal colic, renal pain, urinary tract pain, and urinary incontinence.

Adverse events that were considered by the investigator to be related to trial treatment occurred in 129 patients.2

  • 95 patients (86%) in the LUTATHERA arm and 34 patients (31%) in the control arm2
    • Premature withdrawal due to adverse reactions was more common in patients treated with octreotide alone vs LUTATHERA with octreotide (10 patients or 9% vs 7 patients or 6%, respectively) 

79% icon

of LUTATHERA patients
received a cumulative dose
>22.2 GBq (>600 mCi)
in NETTER-1.1

Laboratory Abnormalities

Laboratory Abnormalities Occurring at a Higher Incidence in the LUTATHERA Arm (Between-Arm Difference of ≥5% [All Grades] or ≥2% [Grade 3/4])1
 
LUTATHERA With Long-Acting
Octreotide (30 mg)
(n=111)
Long-Acting
Octreotide (60 mg)
(n=112)
Laboratory Abnormalityd,e All
Grades,
%
Grade
3/4,
%
All
Grades,
%
Grade
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

dValues are worst grade observed after randomization.

eNational Cancer Institute Common Technology Criteria for Adverse Events (CTCAE) Version 4.03 only displays laboratory abnormalities occurring at a higher incidence in patients treated with LUTATHERA (between-arm difference of ≥5% [all grades] or ≥2% [grade 3/4]).

Dose reduction and discontinuation

  • 6% (7 of 111) of patients required a dose reduction, and 13% (14 of 111) of patients discontinued LUTATHERA1
  • 5 patients discontinued due to renal-related events
  • 4 patients discontinued due to hematologic toxicities

The most common grade 3/4 adverse reactions with a higher incidence in the LUTATHERA arm were lymphopenia (44%), increased GGT (20%), vomiting (7%), nausea (5%), elevated AST (5%), increased ALT (4%), hyperglycemia (4%), and hypokalemia (4%).1

76% icon
of patients treated with
LUTATHERA and long-acting
octreotide received all
4 planned doses in NETTER-1.1

NETTER-1 Final Analysis

No new safety signals were reported in the 5-year, long-term follow-up3,f

Adverse Events During the long-term follow-up, only serious adverse events (SAEs) deemed related to treatment with LUTATHERA and AEs of special interest (hematotoxicity, cardiovascular events, and nephrotoxicity, regardless of causality) in the LUTATHERA arm were reported3
Grade ≥3 Treatment-Related SAEs During the Entire Study 7 (6%) of 111 patients treated in the LUTATHERA arm3
Incidence of Treatment-Related SAEs During the Long-Term Follow-Up Period

3 (3%) of 111 patients treated with LUTATHERA3

  • 2 (1.8%) patients experienced at least 1 grade ≥3 SAE (1 grade 5 MDS event)
  • 1 (0.9%) patient experienced an SAE leading to study discontinuation
MDS or Acute Leukemia

No new cases were reported during long-term follow-up3

  • MDS incidence from the Prescribing Information for LUTATHERA: In NETTER-1, with a median follow-up time of 76 months in the main study, MDS was reported in 2.3% of patients receiving LUTATHERA with long-acting octreotide compared with no patients receiving high-dose, long-acting octreotide1,3
  • In ERASMUS,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
Diffuse Large B-Cell Lymphoma

One patient developed diffuse large B-cell lymphoma during long-term follow-up that was deemed unrelated to treatment with LUTATHERA3

Nephrotoxicity of Grade ≥3, Regardless of Causality

Reported in 6 (5%) of 111 patients in the LUTATHERA arm and 4 (4%) of 112 patients in the control arm during the study3

fCutoff date for final analysis was January 18, 2021.3

ERASMUS: Long-Term Safety

ERASMUS, A RETROSPECTIVE, LONG-TERM (MEDIAN FOLLOW-UP, >4 YEARS), OPEN-LABEL TRIAL
STUDY DESIGN Retrospective safety data are available from 1214 patients in ERASMUS, an international, single-institution, single-arm, open-label trial of patients with SSTR-positive tumors (neuroendocrine and other primaries).1
ADMINISTRATION

LUTATHERA 7.4 GBq (200 mCi) was administered every 6 to 13 weeks for up to 4 doses with or without octreotide. Retrospective medical record review was conducted on a subset of 811 patients to document serious adverse reactions.1

  • 81% of patients in the subset received a cumulative dose ≥22.2 GBq (≥600 mCi)

Serious adverse reactions1

2% of patients developed: MDS, Renal failure, Cardiac failure.
patients developed
  • MDS
  • Renal failure
  • Cardiac failure
1% of patients developed: acute leukemia, hypotension, myocardial infraction, neuroendocrine hormonal crisis.
patients developed
  • Acute leukemia
  • Hypotension
  • Myocardial infarction
  • Neuroendocrine hormonal crisis
  • Hepatotoxicity was also observed in ERASMUS, with 2 patients (<1%) reported to have hepatic tumor hemorrhage, edema, or necrosis, and 1 patient experiencing intrahepatic congestion and cholestasis. Patients with hepatic metastasis may be at increased risk of hepatotoxicity due to radiation exposure1
  • Monitor transaminases, bilirubin, and serum albumin during treatment. Withhold, reduce dose, or permanently discontinue LUTATHERA based on severity of hepatic impairment1

Please see warnings and precautions for myelosuppression, MDS, leukemia, renal toxicity, hypersensitivity reactions, and neuroendocrine hormonal crisis. Monitor blood cell counts. Withhold, reduce dose, or permanently discontinue based on severity of adverse reactions.1

ERASMUS long-term safety results build on the safety profile of LUTATHERA seen in NETTER-1.1

Warnings and Precautions

Events Reported in the NETTER-1 and ERASMUS Clinical Trials

RISK FROM RADIATION EXPOSURE
  • LUTATHERA contributes to a patient’s overall long-term radiation exposure. Long-term, cumulative radiation exposure is associated with an increased risk for cancer. Radiation can be detected in the urine for up to 30 days following administration of LUTATHERA1
  • 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 home1
MYELOSUPPRESSION
  • In NETTER-1, 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 or 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 weeks following the first dose1
  • Of the 59 patients who developed thrombocytopenia, 68% had platelet recovery to baseline or normal levels1
  • 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, reduce dose, or permanently discontinue based on severity of myelosuppression1
SECONDARY MDS AND LEUKEMIA
  • In NETTER-1, with a median follow-up time of 76 months in main study, MDS was reported in 2.3% of patients receiving LUTATHERA with long-acting octreotide compared with no patients receiving high-dose, long-acting octreotide1
  • In ERASMUS, 16 patients (2.0%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to the onset was 29 months (range, 9-45 months) for MDS and 55 months (range, 32-125 months) for acute leukemia1
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 dialysis1
  • Administer the recommended amino acid solution before, during, and after LUTATHERA to decrease reabsorption of LUTATHERA through the proximal tubules and decrease the radiation dose to the kidneys. Do not decrease the dose of the amino acid solution if the dose of LUTATHERA is reduced. Advise patients to urinate frequently during and after administration of LUTATHERA1
  • Monitor serum creatinine and calculated creatinine clearance. Withhold, reduce dose, or permanently discontinue LUTATHERA based on severity of renal toxicity1
  • Patients with baseline renal impairment may be at greater risk of toxicity; perform more frequent assessments of renal function in patients with mild or moderate impairment. LUTATHERA has not been studied in patients with severe renal impairment (CrCL <30 mL/min)1
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 exposure1
  • Monitor transaminases, bilirubin, and serum albumin during treatment. Withhold, reduce dose, or permanently discontinue LUTATHERA based on severity of hepatoxicity1
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 administration of LUTATHERA 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
HORMONAL CRISIS
  • Neuroendocrine hormonal crisis, 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 dose of LUTATHERA. Two (<1%) patients were reported to have hypercalcemia1
  • Monitor patients for flushing, diarrhea, hypotension, bronchoconstriction, or other signs and symptoms of tumor-related hormonal release. Administer intravenous SSAs, fluids, corticosteroids, and electrolytes as indicated1
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 the use of LUTATHERA in pregnant women. No animal studies using LUTATHERA 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 harm1
  • Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA1
  • 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 final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with LUTATHERA and for 4 months after the final dose1
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 testes and ovaries within the range in which temporary or permanent infertility can be expected following external beam radiotherapy1

Radiation Safety

Important Safety Instructions1

LUTATHERA is a radiopharmaceutical; handle with appropriate safety measures to minimize radiation exposure. Use waterproof gloves and effective radiation shielding when handling LUTATHERA. Radiopharmaceuticals, including LUTATHERA, should be used by or under the control of health care professionals who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals. Their 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.

Monitor patients closely for signs and symptoms of hypersensitivity reactions during and after LUTATHERA administration for a minimum of 2 hours in a setting in which cardiopulmonary resuscitation medication and equipment are available.

ALARA Principle: Keeping Radiation Exposure as Low as Reasonably Achievable4

ALARA is the guiding principle of radiation safety. It means that even a small radiation dose should be avoided if there is no benefit to receiving it. It includes 3 basic protective measures:

Time
  Minimize time near a radiation source. Spend only the time needed to complete your job near the radiation source and then leave the area.
Distance
  Maximize distance from a radiation source. Stay as far away as you can from the radiation source.
Shielding
  Use appropriate shielding between yourself and a radiation source. Put appropriate materials between you and the radiation source. The appropriate materials will depend on what type of radiation the source emits.

Safety Procedures

You should follow these procedures in addition to your institution’s radiation safety guidelines whenever handling or administering LUTATHERA:

General handling and administration recommendations

  • Use waterproof gloves1,5
  • Use aseptic technique and radiation shielding1
  • Dispose of any unused medicinal product or waste material in accordance with local and federal laws1

Additional handling and administration recommendations

  • Wear gowns and shoe covers1,5
  • Use tongs when handling vial to minimize radiation exposure1

lutathera_hcp_icon_selection_of_new_treatment_01.jpg
Established radiation safety protocols guide the proper administration of LUTATHERA.

Radiation Exposure

Radiation Associated With LUTATHERA

TYPES OF RADIATION EMITTED LUTATHERA decays to stable hafnium (Hf 177), with a half-life of 6.647 days, by emitting beta radiation with a maximum energy of 0.498 MeV and photonic radiation (γ) of 0.208 MeV (11%) and 0.113 MeV (6.4%)1
PENETRATING RADIATION

The maximum radiation penetration in tissue is 2.2 mm, and the mean penetration is 0.67 mm1

PATIENT EXPOSURE

Patients are discharged from the treatment center only when radiation exposure to third parties does not exceed regulatory thresholds5

 

Radiation Exposure to HCPs and Caregivers Following Outpatient Treatment With Lutetium 177

Methods

Seventy-six patients with progressive, metastatic NETs received 4 cycles of 7.8 GBq of LUTATHERA at 8-week intervals in an outpatient setting at 1 treatment center. Four patients were treated sequentially on each therapy day in a 4-bed room in the hospital’s day procedure unit, with each patient remaining until radiation exposure was below the release limit. Radiation exposure to HCPs and caregivers was monitored by personal dosimeter.6

Radiation study results

HEALTH CARE PROFESSIONALS Mean whole-body exposures per therapy treatment day with 4 patients when administering LUTATHERA ranged from 6.8 μSv (nuclear medicine technologist) to 33.2 μSv (nurse). In the nearby staff office with a 50% staff occupancy, the mean exposure rate measured on 10 different therapy administration days was 1.6 μSv/h (range, 1.3–2.0 μSv/h), whereas that at the nursing station with 100% staff occupancy was 3.5 μSv/h (range, 2.9–4.0 μSv/h).6,g
CAREGIVERS

Mean total exposure during the day of therapy and at home for a period of up to 5 days was 90 µSv, with a median exposure of 40 μSv and range of 10 μSv to 470 μSv.6,g,h

Exposures to HCPs and caregivers were within the limits recommended by the International Commission on Radiological Protection.6

gFor reference, mean radiation exposure is 14.5 μSv on a 5.2-hour flight from Los Angeles to Honolulu.7

hTwenty-five caregivers were provided with electronic dosimeters.6

Radiation Spill

If a radiation spill occurs, you should always follow the guidance of your institution’s radiation safety department. The information below is guidance from the National Radiation Commission.8

FOR MINOR SPILLS8
NOTIFY Notify persons in the area that a spill has occurred.
PREVENT THE SPREAD Cover the spill with absorbent paper.
CLEANUP Use disposable gloves and absorbent paper. Carefully fold the absorbent paper with the clean side out and place in a labeled plastic bag for transfer to a radioactive waste container. Also put contaminated gloves and any other contaminated disposable material in the bag.
SURVEY With a low-range radiation detection survey meter, check the area around the spill. Also check your hands, clothing, and shoes for contamination.
REPORT Report the incident to the Radiation Safety Officer (RSO).
DOCUMENT Complete any necessary forms for documentation.

 

FOR MAJOR SPILLS8
CLEAR THE AREA Notify all persons not involved in the spill to vacate the room.
PREVENT THE SPREAD Cover the spill with absorbent paper, but do not attempt to clean it up. To prevent the spread of contamination, limit the movement of all personnel who may be contaminated.
SHIELD THE SOURCE If possible, shield the spill. This should be done only if it can be done without further contamination or a significant increase in radiation exposure.
CLOSE THE ROOM Lock or otherwise secure the area to prevent entry.
CALL FOR HELP Notify the RSO immediately.
PERSONNEL DECONTAMINATION Remove contaminated clothing and flush contaminated skin with lukewarm water and then wash with mild soap. If contamination remains, induce perspiration by covering the area with plastic. Then wash the affected area again to remove any contamination that was released by the perspiration.
CLEANUP The RSO will supervise the cleanup of the spill and complete any necessary forms for documentation.

Careful cleanup should occur in the event of a radiation spill.

Next: Dosing and Administration

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CrCL, creatinine clearance; GGT, gamma-glutamyl transferase; HCPs, health care professionals; MDS, myelodysplastic syndrome; NETs, neuroendocrine tumors; SSA, somatostatin analogue; SSTR, somatostatin receptor.

References: 1. Lutathera [prescribing information]. Millburn, NJ: Advanced Accelerator Applications. 2. 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. 3. Strosberg JR, Caplin ME, Kunz PL, et al; NETTER-1 investigators. 177Lu-dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(12):1752-1763. 4. Centers for Disease Control and Prevention. ALARA - as low as reasonably achievable. https://www.cdc.gov/nceh/radiation/alara.html. Accessed August 4, 2021. 5. Hope TA, Abbott A, Colucci K, et al. NANETS/SNMMI procedure standard for somatostatin receptor–based peptide receptor radionuclide therapy with 177Lu-DOTATATE. J Nucl Med. 2019;60(7):937-943. 6. Calais PJ, Turner JH. Radiation safety of outpatient 177Lu-octreotate radiopeptide therapy of neuroendocrine tumors. Ann Nucl Med. 2014;28(6):531-539. 7. Friedberg W, Copeland K, Duke FE, O’Brien K III, Darden EB Jr. Radiation exposure during air travel: guidance provided by the Federal Aviation Administration for air carrier crews. Health Phys. 2000;79(5):591-595. 8. National Radiation Commission. Attachment 1, item 19, emergency procedure. https://www.nrc.gov/docs/ML0827/ML082750235.pdf. Accessed February 24, 2022.

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.

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 or 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 weeks 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, reduce dose, or permanently discontinue based on 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 reabsorption of lutetium Lu 177 dotatate through the proximal tubules and decrease the radiation dose to the kidneys. Do not decrease the dose of the amino acid solution if the dose of LUTATHERA is reduced. Advise patients to urinate frequently during and after administration of LUTATHERA. Monitor serum creatinine and calculated creatinine clearance. Withhold, reduce dose, or permanently discontinue LUTATHERA based on severity of renal toxicity. Patients with baseline renal impairment may be at greater risk of toxicity; perform more frequent assessments of renal function in patients with mild or moderate impairment. LUTATHERA has not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min).
  • 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, and serum albumin during treatment. Withhold, reduce dose, or permanently discontinue LUTATHERA based on severity of hepatic impairment.
  • 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 after LUTATHERA administration for a minimum of 2 hours in a setting in which cardiopulmonary resuscitation medication and equipment are available. Discontinue the infusion at 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 crisis, 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 analogues, fluids, corticosteroids, and electrolytes as indicated.
  • Embryo-Fetal Toxicity: LUTATHERA can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the final dose. Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA.
  • 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 to 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%), elevated 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 analogues competitively bind to somatostatin receptors and may interfere with the efficacy of LUTATHERA. Discontinue long-acting somatostatin analogues 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.

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

SPECIFIC POPULATIONS

Lactation: 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.

Please see full Prescribing Information.