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12/15 ONC-1130276
This site is for US health care professionals only.
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This site is for US health care professionals only.
 * About GEP-NETs
 * Disease Progression
 * Efficacy
 * Safety
 * Dosing and Administration
 * Mechanism of Action
 * Access
 * Resources


IMPORTANT SAFETY INFORMATION AND INDICATION
 * About GEP-NETs
 * Disease Progression
 * Efficacy
 * Safety
 * Dosing and Administration
 * Mechanism of Action
 * Access
 * Resources


QUICK LINKS

 * Full Prescribing Information
 * Visit Patient Site
 * Find a Treatment Site
 * Contact Us

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
 * Laboratory Abnormalities
 * NETTER-1 Final Analysis
 * ERASMUS: Long-Term Safety
 * Warnings and Precautions
 * Radiation Safety
 * Radiation Exposure
 * Radiation Spill


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) 



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,d,e  
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%), increased AST (5%), increased ALT (4%), hyperglycemia (4%), and
hypokalemia (4%).1






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 leukemia1

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

patients developed
 * MDS
 * Renal failure
 * Cardiac failure

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, serum albumin, and the international
   normalized ratio (INR) during treatment. Withhold dose, reduce dose, or
   permanently discontinue LUTATHERA based on the severity of hepatotoxicity

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






ERASMUS long-term safety results help to further illustrate 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 3/4): 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 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 months1
 * – 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 31

 * Monitor blood cell counts. Withhold dose, reduce dose, or permanently
   discontinue LUTATHERA based on the 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 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 LUTATHERA1
 * Monitor serum creatinine and calculated creatinine clearance. Withhold dose,
   reduce dose, or permanently discontinue LUTATHERA based on the severity of
   renal toxicity1
 * 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
   disease1

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, serum albumin, and the INR during
   treatment. Withhold dose, reduce dose, or permanently discontinue LUTATHERA
   based on the severity of hepatotoxicity1

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
   therapy1
 * 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 reactions1

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 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 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 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, 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.

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 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






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 minus (β-) radiation with a maximum
energy of 0.498 MeV (79%) and photonic radiation (γ) of 0.208 MeV (11%) and
0.113 MeV (6.2%)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

AEs, adverse events; 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 analog; SSTR, somatostatin receptor.

References: 1. Lutathera. Prescribing information. 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. Accessed August 4, 2021.
https://www.cdc.gov/nceh/radiation/alara.html 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.
Accessed February 24, 2022. https://www.nrc.gov/docs/ML0827/ML082750235.pdf






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 3/4): 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.

 * About GEP-NETs
 * Disease Progression
 * Efficacy
 * Safety
 * Dosing and Administration
 * Mechanism of Action
 * Access
 * Resources


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