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.

Dosing and Administration

Premedication and Concomitant Medications

Somatostatin Analogs¹
4 weeks prior	Before initiating LUTATHERA treatment, discontinue long-acting SSAs (eg, long-acting octreotide) at least 4 weeks prior to initiating LUTATHERA. Administer short-acting octreotide as needed; discontinue at least 24 hours prior to initiating LUTATHERA.
4 to 24 hours after	During treatment with LUTATHERA, administer long-acting octreotide 30 mg IM between 4 to 24 hours after each dose of LUTATHERA. Do not administer long-acting octreotide within 4 weeks prior to each subsequent dose of LUTATHERA. Short-acting octreotide may be given for symptomatic management during treatment with LUTATHERA, but must be withheld at least 24 hours before each dose of LUTATHERA.
4 weeks after	Following treatment with LUTATHERA, continue long-acting octreotide 30 mg IM every 4 weeks after completing LUTATHERA until disease progression or for 18 months following treatment initiation at the discretion of the physician.

Antiemetics and Amino Acids

Patients treated with LUTATHERA in the NETTER-1 trial received an amino acid solution for renal protection.^1,2

Premedication with antiemetics should be administered prior to the start of the amino acid solution infusion¹
Initiate an IV infusion of a sterile amino acid solution containing L-lysine and L-arginine 30 minutes before the start of the LUTATHERA infusion. Use a 3-way valve to administer the amino acid solution using the same venous access as LUTATHERA or administer the amino acid solution through a separate venous access in the patient’s other arm. Continue the infusion during and for at least 3 hours after completion of the infusion of LUTATHERA¹
- – Do not decrease the dose of the amino acid solution if a reduced dose of LUTATHERA is administered¹
For more information about the amino acid solution, please refer to the full Prescribing Information for LUTATHERA

Hypersensitivity Prophylaxis

Premedicate patients who have had prior grade 1/2 hypersensitivity reactions to LUTATHERA. Do not re-challenge patients who experience grade 3/4 hypersensitivity reactions to LUTATHERA.¹

Antiemetics and the recommended IV infusion of a sterile amino acid solution should be initiated prior to administration of LUTATHERA. Monitor patients closely for signs and symptoms of hypersensitivity reactions, including anaphylaxis.¹

Treatment Regimen

Before initiating LUTATHERA: Discontinue long-acting SSAs (eg, long-acting octreotide) for at least 4 weeks prior to initiating LUTATHERA. Administer short-acting octreotide as needed; discontinue at least 24 hours prior to initiating LUTATHERA.¹

During LUTATHERA treatment: Administer long-acting octreotide 30 mg IM between 4 to 24 hours after each LUTATHERA dose. Do not administer long-acting octreotide within 4 weeks prior to each subsequent LUTATHERA dose. Short-acting octreotide may be given for symptomatic management during LUTATHERA treatment, but must be withheld for at least 24 hours before each LUTATHERA dose.¹

Following treatment with LUTATHERA, continue long-acting octreotide 30 mg IM every 4 weeks after completing LUTATHERA until disease progression or for 18 months following treatment initiation at the discretion of the physician.¹

Long-acting SSAs should be discontinued at least 4 weeks prior to initiating LUTATHERA.¹

Short-acting octreotide may be given for symptomatic management during treatment with LUTATHERA, but must be withheld for at least 24 hours before each dose of LUTATHERA.¹

LUTATHERA dosage should be modified based on hematologic, renal, hepatic, hypersensitivity, or other adverse reactions (see full Prescribing Information).¹

For reduced dose administration instructions, refer to section 2.5 (Preparation and Administration) of the full Prescribing Information

^aAdminister long-acting octreotide 30 mg IM between 4 to 24 hours after each dose of LUTATHERA. Do not administer long-acting octreotide within 4 weeks prior to each subsequent dose of LUTATHERA.¹

– The interval between infusions may be extended up to 16 weeks in the case of a dose modification due to an adverse reaction.¹ Permanently discontinue LUTATHERA in patients who experience grade 3/4 hypersensitivity reactions. Please see the Prescribing Information for additional information on dose modifications.

^bContinue long-acting octreotide 30 mg IM every 4 weeks after completing LUTATHERA until disease progression or for 18 months following treatment initiation at the discretion of the physician.¹

The recommended dose for LUTATHERA is 7.4 GBq (200 mCi) every 8 weeks (± 1 week) for a total of 4 doses.¹

Infusion Schedule and Procedures

Pretreatment Antiemetic:

Premedication with antiemetics should be administered prior to the start of the amino acid solution infusion¹

Concomitant Amino Acid Infusion¹

Initiate an IV infusion of a sterile amino acid solution containing L-lysine and L-arginine 30 minutes before the start of the LUTATHERA infusion. Use a 3-way valve to administer the amino acid solution using the same venous access as LUTATHERA or administer the amino acid solution through a separate venous access in the patient’s other arm. Continue the infusion during and for at least 3 hours after the completion of the infusion of LUTATHERA¹
- – Do not decrease the dose of the amino acid solution if a reduced dose of LUTATHERA is administered¹

Amino Acid Solution
Characteristic¹	Specification
L-lysine HCI	Between 18 and 25 g^c
L-arginine HCI	Between 18 and 25 g^d
Volume	1 to 2 L
Osmolality	<1200 mOsmol/kg

^cEquivalent to 14.4 g to 20 g L-lysine.¹

^dEquivalent to 14.9 g to 20.7 g L-arginine.¹

Hypersensitivity Prophylaxis¹

Premedicate patients who have had prior grade 1/2 hypersensitivity reactions to LUTATHERA. Do not rechallenge patients who experience grade 3/4 hypersensitivity reactions to LUTATHERA

Administration of LUTATHERA Using the Gravity Method

7.4 GBq (200 mCi) of LUTATHERA is administered IV over 30 to 40 minutes with the gravity method¹

– Do not inject LUTATHERA directly into any other IV solution

The gravity method, peristaltic pump method, or the syringe pump method may be used for the administration of the recommended dosage. Use the peristaltic pump or syringe pump method when administering a reduced dose of LUTATHERA following a dosage modification for an adverse reaction. When using the gravity method for a reduced dose, adjust the LUTATHERA dose before the administration to avoid the delivery of an incorrect volume of LUTATHERA¹

– For instructions on how to use the gravity method, peristaltic pump method, or the syringe pump method to administer LUTATHERA, please refer to the full Prescribing Information

Patient Management

Patient Management Before and During Treatment With LUTATHERA

Prescribing Information Directions

Advise patients of the need for periodic laboratory tests to monitor for adverse events¹
Advise patients to hydrate and to urinate frequently before, on the day of, and the day after administration of LUTATHERA¹
Monitor patients for flushing, diarrhea, hypotension, bronchoconstriction, or other signs and symptoms of tumor-related hormonal release¹:
- – Administer IV somatostatin analogs
- – Fluids
- – Corticosteroids
- – Electrolytes as indicated
Pregnancy status must be verified in women of childbearing potential prior to initiating LUTATHERA¹
Patients should not breastfeed during treatment with LUTATHERA and for 2.5 months after the last infusion of LUTATHERA¹
Effective birth control should be used for patients receiving LUTATHERA and for:
- – Women of reproductive potential for 7 months following their last dose¹
- – Men with a female partner of reproductive potential for 4 months following their last dose¹
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
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 therapy¹

General Recommendations^e

Laboratory values should be checked shortly before the treatment is ordered (typically 2 weeks before each cycle)²
These may include BUN, creatinine, albumin, ALP, AST, ALT, total bilirubin, WBC count with differential, hemoglobin, and platelet counts²

^eThese are general recommendations provided by representatives from the NANETS and the SNMMI who collaborated to develop a practical consensus guideline for the administration of lutetium Lu 177 dotatate. This guidance is not required per the LUTATHERA package insert and is designed to provide practical guidance on how to safely treat patients with this therapy.²

Preparing your patient for treatment with LUTATHERA

The treatment center will provide patients with detailed instructions regarding their treatment procedures, including preparation and ways to avoid or minimize radiation exposure to household contacts

Dose Modifications

Recommended Dosage Modifications of LUTATHERA for Adverse Reactions¹
Adverse Reaction	Thrombocytopenia
Severity of Adverse Reaction^f	First occurrence of grade 2, 3, or 4
Dose Modification	Withhold dose until complete or partial resolution (grade 0 to 1) Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in grade 2, 3, or 4 thrombocytopenia, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose Permanently discontinue LUTATHERA for grade 2 or higher thrombocytopenia requiring a dosing interval beyond 16 weeks For recurrent grade 2, 3, or 4 thrombocytopenia, permanently discontinue LUTATHERA
Adverse Reaction	Anemia and neutropenia
Severity of Adverse Reaction^f	First occurrence of grade 3 or 4
Dose Modification	Withhold dose until complete or partial resolution (grade 0, 1, or 2) Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in grade 3 or 4 anemia or neutropenia, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose Permanently discontinue LUTATHERA for grade 3 or higher anemia or neutropenia requiring a dosing interval beyond 16 weeks For recurrent grade 3 or 4 anemia and neutropenia, permanently discontinue LUTATHERA
Adverse Reaction	Renal toxicity
Severity of Adverse Reaction^f	First occurrence of: Creatinine clearance <40 mL/min; calculate using Cockcroft-Gault with actual body weight, or 40% increase in baseline serum creatinine, or 40% decrease in baseline creatinine clearance; calculate using Cockcroft-Gault with actual body weight
Dose Modification	Withhold dose until complete resolution or return to baseline Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete resolution or return to baseline. If reduced dose does not result in renal toxicity, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose Permanently discontinue LUTATHERA for renal toxicity requiring a dosing interval beyond 16 weeks For recurrent renal toxicity, permanently discontinue LUTATHERA
Adverse Reaction	Hepatotoxicity
Severity of Adverse Reaction^f	First occurrence of: Bilirubinemia >3 times the upper limit of normal (grade 3 or 4), or Serum albumin <30 g/L with international normalized ratio (INR) > 1.5
Dose Modification	Withhold dose until complete resolution or return to baseline Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete resolution or return to baseline. If reduced LUTATHERA dose does not result in hepatotoxicity, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose Permanently discontinue LUTATHERA for hepatotoxicity requiring a dosing interval beyond 16 weeks For recurrent hepatotoxicity, permanently discontinue LUTATHERA
Adverse Reaction	Hypersensitivity reactions^g
Severity of Adverse Reaction^f	First occurrence of grade 3 or 4
Dose Modification	Permanently discontinue LUTATHERA
Adverse Reaction	Any other adverse reaction^h
Severity of Adverse Reaction^f	First occurrence of grade 3 or 4
Dose Modification	Withhold dose until complete or partial resolution (grade 0 to 2) Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in grade 3 or 4 toxicity, administer LUTATHERA at 7.4 GBq (200 mCi) for next dose Permanently discontinue LUTATHERA for grade 3 or higher adverse reactions that require a dosing interval beyond 16 weeks For recurrent grade 3 or 4 adverse reactions, permanently discontinue LUTATHERA

^fGrading of severity is defined in the most current Common Terminology Criteria for Adverse Events (CTCAE).¹
^gIncluding allergic reaction and anaphylaxis.¹
^hNo dose modification required for hematological toxicities of grade 3 or grade 4 solely due to lymphopenia.

For instructions on how to use the gravity method to administer LUTATHERA, please refer to the full Prescribing Information.

Next: Mechanism of Action

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; GBb, gigabecquerel; HCI, hydrochloride; IM, intramuscular; IV, intravenous; mCi, millicurie; NANETS, North American Neuroendocrine Tumor Society; SNMMI, Society of Nuclear Medicine and Molecular Imaging; SSA, somatostatin analog; WBC, white blood cell.

References: 1. Lutathera. Prescribing information. Advanced Accelerator Applications. 2. 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;60:937-943.

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.