Lutathera (Lutetium Lu 177 Dotatate)

Injection: 370 MBq/mL (10 mCi/mL) of lutetium Lu 177 dotatate as a clear and colorless to slightly yellow solution in a single-dose vial.

• Risk From Radiation Exposure
  : Minimize radiation exposure during and after treatment with LUTATHERA consistent with institutional good radiation safety practices and patient management procedures. (
  2.1     Important Safety Instructions

  LUTATHERA is a radiopharmaceutical; handle with appropriate safety measures to minimize radiation exposure

  [see Warnings and Precautions ]

  . Use waterproof gloves and effective radiation shielding when handling LUTATHERA. Radiopharmaceuticals, including LUTATHERA, should be used by or under the control of healthcare providers 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

  [see Use in Specific Populations ]

  .

  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 where cardiopulmonary resuscitation medication and equipment are available

  [see Warnings and Precautions ]

  .
  ,
  5.1     Risk From Radiation Exposure

  LUTATHERA contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. These risks of radiation associated with the use of LUTATHERA are greater in pediatric patients than in adults

  [see Use in Specific Populations ]

  .

  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 Dosage and Administration , Clinical Pharmacology ]

  .
  )
• Myelosuppression
  : Monitor blood cell counts. Withhold dose, reduce dose, or permanently discontinue based on the severity. (
  2.4     Dosage Modifications for Adverse Reactions

  Recommended dose modifications of LUTATHERA for adverse reactions are provided in Table 2.

  Table 2. Recommended Dosage Modifications of LUTATHERA for Adverse Reactions

  aGrading of severity is defined in the most current Common Terminology Criteria for Adverse Events (CTCAE). bIncluding allergic reaction and anaphylaxis. cNo dose modification required for hematological toxicities Grade 3 or Grade 4 solely due to lymphopenia.
  Adverse reaction	Severity of adverse reactiona	Dose modification
  Thrombocytopenia [see Warnings and Precautions ]	First occurrence of Grade 2, 3, or 4	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.
  	Recurrent Grade 2, 3, or 4	Permanently discontinue LUTATHERA.
  Anemia and Neutropenia [see Warnings and Precautions ]	First occurrence of Grade 3 or 4	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.
  	Recurrent Grade 3 or 4	Permanently discontinue LUTATHERA.
  Renal Toxicity [see Warnings and Precautions ]	First occurrence of: Creatinine clearance less than 40 mL/min; calculated using Cockcroft-Gault formula with actual body weight, or 40% increase from baseline serum creatinine, or 40% decrease from baseline creatinine clearance; calculated using Cockcroft-Gault formula with actual body weight.	Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with 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.
  	Recurrent renal toxicity	Permanently discontinue LUTATHERA.
  Hepatotoxicity [see Warnings and Precautions ]	First occurrence of: Bilirubinemia greater than 3 times the upper limit of normal (Grade 3 or 4), or Serum albumin less than 30 g/L with international normalized ratio (INR) > 1.5.	Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with 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.
  	Recurrent hepatotoxicity	Permanently discontinue LUTATHERA.
  Hypersensitivity Reactionsb [see Warnings and Precautions ]	First occurrence of Grade 3 or 4	Permanently discontinue LUTATHERA.
  Any Other Adverse Reactionsc [see Adverse Reactions ]	First occurrence of Grade 3 or 4	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) as next dose. Permanently discontinue LUTATHERA for Grade 3 or higher adverse reactions requiring a dosing interval beyond 16 weeks.
  	Recurrent Grade 3 or 4	Permanently discontinue LUTATHERA.
  ,
  5.2     Myelosuppression

  In NETTER-1, myelosuppression occurred more frequently in patients receiving LUTATHERA with long-acting octreotide compared to patients receiving high-dose long-acting octreotide (all Grades/Grade 3 or 4): anemia (81%/0) versus (54%/1%); thrombocytopenia (53%/1%) versus (17%/0); and neutropenia (26%/3%) versus (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 nineteen 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

  [see Dosage and Administration ]

  .
  )
• Secondary Myelodysplastic Syndrome (MDS) and Leukemia
  : Median time to onset: MDS is 29 months; acute leukemia is 55 months. (
  5.3     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 to no patients receiving high-dose long-acting octreotide.

  In ERASMUS, 16 patients (2.0%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to onset was 29 months (9 to 45 months) for MDS and 55 months (32 to 125 months) for acute leukemia.
  )
• Renal Toxicity
  : Advise patients to hydrate and to urinate frequently before, on the day of and the day after administration of LUTATHERA. Monitor serum creatinine and calculated creatinine clearance. Withhold dose, reduce dose, or permanently discontinue based on the severity. (
  2.3     Premedications and Concomitant Medications

  Somatostatin Analogs

  • Before initiating LUTATHERA treatment: Discontinue long-acting somatostatin analogs (e.g., 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
    [see Drug Interactions ]
    .
  • During LUTATHERA treatment: Administer long-acting octreotide 30 mg intramuscularly 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 at least 24 hours before each LUTATHERA dose.
  • Following LUTATHERA treatment: Continue long-acting octreotide 30 mg intramuscularly every 4 weeks after completing LUTATHERA until disease progression or for 18 months following treatment initiation at the discretion of the physician.

  Antiemetics

  Administer antiemetics before the recommended amino acid solution.

  Amino Acid Solution

  Initiate an intravenous infusion of a sterile amino acid solution containing L-lysine and L-arginine (Table 1) 30 minutes before the start of the LUTATHERA infusion. Use a three-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 amino acid solution infusion during and for at least 3 hours after completion of the LUTATHERA infusion. Do not decrease the dose of the amino acid solution if a reduced dose of LUTATHERA is administered

  [see Warnings and Precautions ]

  .

  Table 1. Amino Acid Solution

  Item	Specification
  aequivalent to 14.4 to 20 g L-lysine. bequivalent to 14.9 to 20.7 g L-arginine.
  L-lysine HCl	Between 18 and 25 ga
  L-arginine HCl	Between 18 and 25 gb
  Volume	1 to 2 L
  Osmolality	< 1200 mOsmol/kg

  Hypersensitivity Prophylaxis

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

  [see Warnings and Precautions ]

  .
  ,
  2.4     Dosage Modifications for Adverse Reactions

  Recommended dose modifications of LUTATHERA for adverse reactions are provided in Table 2.

  Table 2. Recommended Dosage Modifications of LUTATHERA for Adverse Reactions

  aGrading of severity is defined in the most current Common Terminology Criteria for Adverse Events (CTCAE). bIncluding allergic reaction and anaphylaxis. cNo dose modification required for hematological toxicities Grade 3 or Grade 4 solely due to lymphopenia.
  Adverse reaction	Severity of adverse reactiona	Dose modification
  Thrombocytopenia [see Warnings and Precautions ]	First occurrence of Grade 2, 3, or 4	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.
  	Recurrent Grade 2, 3, or 4	Permanently discontinue LUTATHERA.
  Anemia and Neutropenia [see Warnings and Precautions ]	First occurrence of Grade 3 or 4	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.
  	Recurrent Grade 3 or 4	Permanently discontinue LUTATHERA.
  Renal Toxicity [see Warnings and Precautions ]	First occurrence of: Creatinine clearance less than 40 mL/min; calculated using Cockcroft-Gault formula with actual body weight, or 40% increase from baseline serum creatinine, or 40% decrease from baseline creatinine clearance; calculated using Cockcroft-Gault formula with actual body weight.	Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with 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.
  	Recurrent renal toxicity	Permanently discontinue LUTATHERA.
  Hepatotoxicity [see Warnings and Precautions ]	First occurrence of: Bilirubinemia greater than 3 times the upper limit of normal (Grade 3 or 4), or Serum albumin less than 30 g/L with international normalized ratio (INR) > 1.5.	Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with 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.
  	Recurrent hepatotoxicity	Permanently discontinue LUTATHERA.
  Hypersensitivity Reactionsb [see Warnings and Precautions ]	First occurrence of Grade 3 or 4	Permanently discontinue LUTATHERA.
  Any Other Adverse Reactionsc [see Adverse Reactions ]	First occurrence of Grade 3 or 4	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) as next dose. Permanently discontinue LUTATHERA for Grade 3 or higher adverse reactions requiring a dosing interval beyond 16 weeks.
  	Recurrent Grade 3 or 4	Permanently discontinue LUTATHERA.
  ,
  5.4     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 (e.g., diabetes or hypertension) and required dialysis.

  Administer the recommended amino acid solution before, during and after LUTATHERA

  [see Dosage and Administration ]

  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 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

  [see Dosage and Administration ]

  .

  Patients with baseline renal impairment may be at increased risk of toxicity due to increased radiation exposure

  [see Use in Specific Populations ]

  .
  )
• Hepatotoxicity
  : Monitor transaminases, bilirubin, serum albumin and INR. (
  2.4     Dosage Modifications for Adverse Reactions

  Recommended dose modifications of LUTATHERA for adverse reactions are provided in Table 2.

  Table 2. Recommended Dosage Modifications of LUTATHERA for Adverse Reactions

  aGrading of severity is defined in the most current Common Terminology Criteria for Adverse Events (CTCAE). bIncluding allergic reaction and anaphylaxis. cNo dose modification required for hematological toxicities Grade 3 or Grade 4 solely due to lymphopenia.
  Adverse reaction	Severity of adverse reactiona	Dose modification
  Thrombocytopenia [see Warnings and Precautions ]	First occurrence of Grade 2, 3, or 4	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.
  	Recurrent Grade 2, 3, or 4	Permanently discontinue LUTATHERA.
  Anemia and Neutropenia [see Warnings and Precautions ]	First occurrence of Grade 3 or 4	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.
  	Recurrent Grade 3 or 4	Permanently discontinue LUTATHERA.
  Renal Toxicity [see Warnings and Precautions ]	First occurrence of: Creatinine clearance less than 40 mL/min; calculated using Cockcroft-Gault formula with actual body weight, or 40% increase from baseline serum creatinine, or 40% decrease from baseline creatinine clearance; calculated using Cockcroft-Gault formula with actual body weight.	Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with 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.
  	Recurrent renal toxicity	Permanently discontinue LUTATHERA.
  Hepatotoxicity [see Warnings and Precautions ]	First occurrence of: Bilirubinemia greater than 3 times the upper limit of normal (Grade 3 or 4), or Serum albumin less than 30 g/L with international normalized ratio (INR) > 1.5.	Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with 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.
  	Recurrent hepatotoxicity	Permanently discontinue LUTATHERA.
  Hypersensitivity Reactionsb [see Warnings and Precautions ]	First occurrence of Grade 3 or 4	Permanently discontinue LUTATHERA.
  Any Other Adverse Reactionsc [see Adverse Reactions ]	First occurrence of Grade 3 or 4	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) as next dose. Permanently discontinue LUTATHERA for Grade 3 or higher adverse reactions requiring a dosing interval beyond 16 weeks.
  	Recurrent Grade 3 or 4	Permanently discontinue LUTATHERA.
  ,
  5.5     Hepatotoxicity

  In ERASMUS, 2 patients (< 1%) were reported to have hepatic tumor hemorrhage, edema, or necrosis, with one 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 international normalized ratio (INR) during treatment. Withhold dose, reduce dose, or permanently discontinue LUTATHERA based on the severity of hepatotoxicity

  [see Dosage and Administration ]

  .
  )
• Hypersensitivity Reactions
  : Monitor patients closely for signs and symptoms of hypersensitivity reactions, including anaphylaxis. Permanently discontinue LUTATHERA based on severity. (
  2.3     Premedications and Concomitant Medications

  Somatostatin Analogs

  • Before initiating LUTATHERA treatment: Discontinue long-acting somatostatin analogs (e.g., 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
    [see Drug Interactions ]
    .
  • During LUTATHERA treatment: Administer long-acting octreotide 30 mg intramuscularly 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 at least 24 hours before each LUTATHERA dose.
  • Following LUTATHERA treatment: Continue long-acting octreotide 30 mg intramuscularly every 4 weeks after completing LUTATHERA until disease progression or for 18 months following treatment initiation at the discretion of the physician.

  Antiemetics

  Administer antiemetics before the recommended amino acid solution.

  Amino Acid Solution

  Initiate an intravenous infusion of a sterile amino acid solution containing L-lysine and L-arginine (Table 1) 30 minutes before the start of the LUTATHERA infusion. Use a three-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 amino acid solution infusion during and for at least 3 hours after completion of the LUTATHERA infusion. Do not decrease the dose of the amino acid solution if a reduced dose of LUTATHERA is administered

  [see Warnings and Precautions ]

  .

  Table 1. Amino Acid Solution

  Item	Specification
  aequivalent to 14.4 to 20 g L-lysine. bequivalent to 14.9 to 20.7 g L-arginine.
  L-lysine HCl	Between 18 and 25 ga
  L-arginine HCl	Between 18 and 25 gb
  Volume	1 to 2 L
  Osmolality	< 1200 mOsmol/kg

  Hypersensitivity Prophylaxis

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

  [see Warnings and Precautions ]

  .
  ,
  2.4     Dosage Modifications for Adverse Reactions

  Recommended dose modifications of LUTATHERA for adverse reactions are provided in Table 2.

  Table 2. Recommended Dosage Modifications of LUTATHERA for Adverse Reactions

  aGrading of severity is defined in the most current Common Terminology Criteria for Adverse Events (CTCAE). bIncluding allergic reaction and anaphylaxis. cNo dose modification required for hematological toxicities Grade 3 or Grade 4 solely due to lymphopenia.
  Adverse reaction	Severity of adverse reactiona	Dose modification
  Thrombocytopenia [see Warnings and Precautions ]	First occurrence of Grade 2, 3, or 4	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.
  	Recurrent Grade 2, 3, or 4	Permanently discontinue LUTATHERA.
  Anemia and Neutropenia [see Warnings and Precautions ]	First occurrence of Grade 3 or 4	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.
  	Recurrent Grade 3 or 4	Permanently discontinue LUTATHERA.
  Renal Toxicity [see Warnings and Precautions ]	First occurrence of: Creatinine clearance less than 40 mL/min; calculated using Cockcroft-Gault formula with actual body weight, or 40% increase from baseline serum creatinine, or 40% decrease from baseline creatinine clearance; calculated using Cockcroft-Gault formula with actual body weight.	Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with 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.
  	Recurrent renal toxicity	Permanently discontinue LUTATHERA.
  Hepatotoxicity [see Warnings and Precautions ]	First occurrence of: Bilirubinemia greater than 3 times the upper limit of normal (Grade 3 or 4), or Serum albumin less than 30 g/L with international normalized ratio (INR) > 1.5.	Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with 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.
  	Recurrent hepatotoxicity	Permanently discontinue LUTATHERA.
  Hypersensitivity Reactionsb [see Warnings and Precautions ]	First occurrence of Grade 3 or 4	Permanently discontinue LUTATHERA.
  Any Other Adverse Reactionsc [see Adverse Reactions ]	First occurrence of Grade 3 or 4	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) as next dose. Permanently discontinue LUTATHERA for Grade 3 or higher adverse reactions requiring a dosing interval beyond 16 weeks.
  	Recurrent Grade 3 or 4	Permanently discontinue LUTATHERA.
  ,
  5.6     Hypersensitivity Reactions

  Hypersensitivity reactions, including angioedema, occurred in patients treated with LUTATHERA

  [see Adverse Reactions ]

  . 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 where 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 or 2 hypersensitivity reactions to LUTATHERA before subsequent doses

  [see Dosage and Administration ]

  . Permanently discontinue LUTATHERA in patients who experience Grade 3 or 4 hypersensitivity reactions

  [see Dosage and Administration ]

  .
  )
• Neuroendocrine Hormonal Crisis
  : Monitor for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms. (
  5.7     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
  : Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus and to use effective contraception. (
  5.8     Embryo-Fetal Toxicity

  Based on its mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman

  [see Clinical Pharmacology ]

  . There are no available data on LUTATHERA use in pregnant women. No animal studies using lutetium Lu 177 dotatate have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, radioactive emissions, including those from LUTATHERA, can cause fetal harm.

  Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA

  [see Dosage and Administration ]

  .

  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

  [see Use in Specific Populations ]

  .
  ,
  8.1     Pregnancy

  Risk Summary

  Based on its mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman

  [see Clinical Pharmacology ]

  . There are no available data on LUTATHERA use in pregnant women. No animal studies using lutetium Lu 177 dotatate have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, radioactive emissions, including those from LUTATHERA, can cause fetal harm. Advise pregnant women of the potential risk to a fetus.

  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
  ,
  8.3     Females and Males of Reproductive Potential

  Based on mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations ]

  .

  Pregnancy Testing

  Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA

  [see Use in Specific Populations ]

  .

  Contraception

  Females

  Advise females of reproductive potential to use effective contraception during treatment with LUTATHERA and for 7 months after the last dose.

  Males

  Advise males with female partners of reproductive potential to use effective contraception during treatment with LUTATHERA and for 4 months after the last dose

  [see Clinical Pharmacology , Nonclinical Toxicology ]

  .

  Infertility

  The recommended cumulative dose of 29.6 GBq of LUTATHERA results in a radiation absorbed dose to the testes and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy

  [see Dosage and Administration ]

  .
  )
• Risk of Infertility
  : LUTATHERA may cause infertility. (
  5.9     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 where temporary or permanent infertility can be expected following external beam radiotherapy

  [see Dosage and Administration , Use in Specific Populations ]

  .
  , 
  8.3     Females and Males of Reproductive Potential

  Based on mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations ]

  .

  Pregnancy Testing

  Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA

  [see Use in Specific Populations ]

  .

  Contraception

  Females

  Advise females of reproductive potential to use effective contraception during treatment with LUTATHERA and for 7 months after the last dose.

  Males

  Advise males with female partners of reproductive potential to use effective contraception during treatment with LUTATHERA and for 4 months after the last dose

  [see Clinical Pharmacology , Nonclinical Toxicology ]

  .

  Infertility

  The recommended cumulative dose of 29.6 GBq of LUTATHERA results in a radiation absorbed dose to the testes and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy

  [see Dosage and Administration ]

  .
  )