Safety Information | LUTATHERA® (lutetium Lu 177 dotatate)

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 Reaction^a	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 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

^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 Abnormality^d,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-up^3,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 octreotide^1,3 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

patients

developed

MDS
Renal failure
Cardiac failure

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

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 gloves^1,5
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 covers^1,5
Use tongs when handling vial to minimize radiation exposure¹

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.

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.

Safety

Important Safety Information

Indication