------------------------WARNINGS AND PRECAUTIONS-----------------------
`• 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, 5.1)
`• Myelosuppression: Monitor blood cell counts. Withhold, reduce dose, or
`permanently discontinue based on severity. (2.4, 5.2)
`• Secondary Myelodysplastic Syndrome (MDS) and Leukemia: Median time
`to onset: MDS is 29 months; acute leukemia is 55 months. (5.3)
`• Renal Toxicity: Advise patients to urinate frequently during and after
`administration of LUTATHERA. Monitor serum creatinine and calculated
`creatinine clearance. Withhold, reduce dose, or permanently discontinue
`based on severity. (2.3, 2.4, 5.4)
`• Hepatotoxicity: Monitor transaminases, bilirubin and serum albumin. (2.4,
`5.5)
`• Hypersensitivity Reactions: Monitor patients closely for signs and
`symptoms of hypersensitivity reactions, including anaphylaxis.
`Permanently discontinue LUTATHERA based on severity. (2.3, 2.4, 5.6)
`• Neuroendocrine Hormonal Crisis: Monitor for flushing, diarrhea,
`hypotension, bronchoconstriction or other signs and symptoms. (5.7)
`• 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, 8.1, 8.3)
`• Risk of Infertility: LUTATHERA may cause infertility. (5.9, 8.3)
`-------------------------------ADVERSE REACTIONS------------------------------
`Most common Grade 3-4 adverse reactions (≥ 4% with a higher incidence in
`LUTATHERA arm) are lymphopenia, increased GGT, vomiting, nausea,
`increased AST, increased ALT, hyperglycemia and hypokalemia. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`Pharmaceutical Corporation at 1-888-669-6682 or FDA at 1-800-FDA-
`1088 or www.fda.gov/medwatch.
`-------------------------------DRUG INTERACTIONS------------------------------
`Somatostatin Analogs: Discontinue long-acting analogs at least 4 weeks and
`short-acting octreotide at least 24 hours prior to each LUTATHERA dose. (2.3,
`7.1)
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`Lactation: Advise not to breastfeed. (8.2)
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`
`
`
`
` Revised: 6/2022
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`LUTATHERA safely and effectively. See full prescribing information for
`LUTATHERA.
`LUTATHERA® (lutetium Lu 177 dotatate) injection, for intravenous use
`Initial U.S. Approval: 2018
`---------------------------RECENT MAJOR CHANGES---------------------------
`Dosage and Administration (2.1, 2.3, 2.4, 2.5, 2.6)
`6/2022
`Warnings and Precautions (5.3, 5.5, 5.6, 5.8)
`6/2022
`----------------------------INDICATIONS AND USAGE---------------------------
`LUTATHERA is a radiolabeled somatostatin analog indicated for the
`treatment of somatostatin receptor-positive gastroenteropancreatic
`neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut
`neuroendocrine tumors in adults. (1)
`------------------------DOSAGE AND ADMINISTRATION----------------------
`• Verify pregnancy status of females of reproductive potential prior to
`initiating LUTATHERA. (2.1)
`• Administer 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses. (2.2)
`• Administer long-acting octreotide 30 mg intramuscularly 4 to 24 hours
`after each LUTATHERA dose and short-acting octreotide for
`symptomatic management. (2.3)
`• Continue long-acting octreotide 30 mg intramuscularly every 4 weeks
`after completing LUTATHERA until disease progression or for up to 18
`months following treatment initiation. (2.3)
`• Administer antiemetics before recommended amino acid solution. (2.3)
`Initiate recommended intravenous amino acid solution 30 minutes before
`•
`LUTATHERA infusion; continue during and for at least 3 hours after
`LUTATHERA infusion. Do not decrease dose of amino acid solution if
`LUTATHERA dose is reduced. (2.3)
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`Injection: 370 MBq/mL (10 mCi/mL) in single-dose vial. (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`None. (4)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Important Safety Instructions
`2.2
`Recommended Dosage
`2.3
`Premedication and Concomitant Medications
`2.4
`Dosage Modifications for Adverse Reactions
`2.5
`Preparation and Administration
`2.6
`Radiation Dosimetry
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1
`Risk From Radiation Exposure
`5.2 Myelosuppression
`5.3
`Secondary Myelodysplastic Syndrome and Leukemia
`5.4
`Renal Toxicity
`5.5
`Hepatotoxicity
`5.6
`Hypersensitivity Reactions
`5.7
`Neuroendocrine Hormonal Crisis
`5.8
`Embryo-Fetal Toxicity
`5.9
`Risk of Infertility
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`7.1
`Somatostatin Analogs
`7.2
`Corticosteroids
`USE IN SPECIFIC POPULATIONS
`
`6
`
`7
`
`8
`
`
`Reference ID: 4998594
`
`
`
`
`
`
`
`Pregnancy
`8.1
`Lactation
`8.2
`Females and Males of Reproductive Potential
`8.3
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`Renal Impairment
`8.6
`Hepatic Impairment
`8.7
`11
`DESCRIPTION
`11.1
`Physical Characteristics
`11.2 External Radiation
`12
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`13
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14
`CLINICAL STUDIES
`14.1
`Progressive, Well-differentiated Advanced or Metastatic
`Somatostatin Receptor-Positive Midgut Carcinoid Tumors
`14.2
`Somatostatin Receptor-Positive Gastroenteropancreatic
`Neuroendocrine Tumors (GEP-NETs)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`17
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`
`INDICATIONS AND USAGE
`1
`LUTATHERA is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic
`neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.
`
`DOSAGE AND ADMINISTRATION
`2
`Important Safety Instructions
`2.1
`LUTATHERA is a radiopharmaceutical; handle with appropriate safety measures to minimize radiation
`exposure [see Warnings and Precautions (5.1)]. 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 (8.1, 8.3)].
`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 (5.6)].
`2.2
`Recommended Dosage
`The recommended LUTATHERA dosage is 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses.
`Administer premedications and concomitant medications as recommended [see Dosage and Administration
`(2.3)].
`Premedication and Concomitant Medications
`2.3
`Somatostatin Analogs
`• Before initiating LUTATHERA: 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 (7.1)].
`• 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 of 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 up to 18 months following treatment
`initiation.
`Antiemetic
`Administer antiemetics before the recommended amino acid solution.
`Amino Acid Solution
`Initiate an intravenous amino acid solution containing L-lysine and L-arginine (Table 1) 30 minutes before
`administering LUTATHERA. Use a three-way valve to administer amino acids using the same venous access as
`LUTATHERA or administer amino acids through a separate venous access in the patient’s other arm. Continue
`the infusion during and for at least 3 hours after the LUTATHERA infusion. Do not decrease the dose of the
`amino acid solution if the dose of LUTATHERA is reduced [see Warnings and Precautions (5.4)].
`
`
`
`
`
`Reference ID: 4998594
`
`

`

`Table 1.
`
`Amino Acid Solution
`Item
`L-Lysine HCl content
`
`
`
`Specification
`Between 18 g and
`25 g*
`L-Arginine HCl content Between 18 g and
`25 g**
`1 L to 2 L
`Volume
`< 1050 mOsmol/L
`Osmolarity
`*equivalent to 14.4 to 20 g lysine.
`**equivalent to 14.9 to 20.7 g arginine.
`
`
`Hypersensitivity Prophylaxis
`Premedicate patients who have had prior Grade 1 or 2 hypersensitivity reactions to LUTATHERA. Do not re-
`challenge patients who experience a Grade 3 or 4 hypersensitivity reactions to LUTATHERA [see Warnings
`and Precautions (5.6)].
`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
`Adverse Reaction
`Severity of Adverse Reactiona
`Dose Modification
`Thrombocytopenia [see
`Grade 2, 3 or 4
`Withhold dose until complete or partial
`resolution (Grade 0 to 1).
`Warnings and Precautions
`(5.2)]
`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) for
`next dose.
`Permanently discontinue LUTATHERA
`for Grade 2 or higher thrombocytopenia
`requiring a treatment delay of 16 weeks
`or longer.
`Permanently discontinue LUTATHERA.
`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) for next dose.
`Permanently discontinue LUTATHERA
`for Grade 3 or higher anemia or
`neutropenia requiring a treatment delay
`of 16 weeks or longer.
`Permanently discontinue LUTATHERA.
`
`Anemia and Neutropenia
`[see Warnings and
`Precautions (5.2)]
`
`Recurrent Grade 2, 3 or 4
`Grade 3 or 4
`
`Recurrent Grade 3 or 4
`
`
`
`Reference ID: 4998594
`
`

`

`Adverse Reaction
`Renal Toxicity [see
`Warnings and Precautions
`(5.4)]
`
`Hepatotoxicity [see
`Warnings and Precautions
`(5.5)]
`
`
`Severity of Adverse Reactiona
`Defined as:
`• Creatinine clearance less than 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.
`Recurrent renal toxicity
`Defined as:
`• 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.
`
`Hypersensitivity
`Reactionsb[see Warnings and
`Precautions (5.6)]
`Other Non-Hematologic
`Adverse Reactions [see
`Adverse Reactions (6.1)]
`
`Recurrent hepatotoxicity
`Grade 3 or 4
`
`
`Grade 3 or 4
`
`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) for next dose.
`Permanently discontinue LUTATHERA
`for renal toxicity requiring a treatment
`delay of 16 weeks or longer.
`Permanently discontinue LUTATHERA.
`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) for
`next dose.
`
`Permanently discontinue LUTATHERA
`for hepatotoxicity requiring a treatment
`delay of 16 weeks or longer.
`Permanently discontinue LUTATHERA.
`Permanently discontinue LUTATHERA.
`
`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
`requiring treatment delay of 16 weeks or
`longer.
`Permanently discontinue LUTATHERA.
`Recurrent Grade 3 or 4
`aGrading of severity is defined in the most current Common Terminology Criteria for Adverse Events (CTCAE).
`bIncluding allergic reaction and anaphylaxis.
`2.5
`Preparation and Administration
`• Use aseptic technique and radiation shielding when administering the LUTATHERA solution. Use tongs
`when handling the vial to minimize radiation exposure.
`• Do not inject LUTATHERA directly into any other intravenous solution.
`• Confirm the amount of radioactivity of LUTATHERA in the radiopharmaceutical vial with an appropriate
`dose calibrator prior to and after LUTATHERA administration.
`Inspect the product visually under a shielded screen for particulate matter and discoloration prior to
`administration. Discard the vial if particulates or discoloration are present.
`• Dispose of any unused medicinal product or waste material in accordance with local and federal laws.
`
`•
`
`
`
`Reference ID: 4998594
`
`

`

`•
`
`•
`
`
`
`Administration Instructions
`The gravity method or infusion pump method may be used for administration of the recommended dosage. Use
`the infusion pump method when administering a reduced dose of LUTATHERA following a dosage
`modification for an adverse reaction; using the gravity method to administer a reduced dose of LUTATHERA
`may result in delivery of the incorrect volume of LUTATHERA, if the dose is not adjusted prior to
`administration.
`Instructions for Gravity Method
`Insert a 2.5 cm, 20 gauge needle (short needle) into the LUTATHERA vial and connect via a catheter to 500
`•
`mL 0.9% sterile sodium chloride solution (used to transport LUTATHERA during the infusion). Ensure that
`the short needle does not touch the LUTATHERA solution in the vial and do not connect this short needle
`directly to the patient. Do not allow sodium chloride solution to flow into the LUTATHERA vial prior to
`the initiation of the LUTATHERA infusion and do not inject LUTATHERA directly into the sodium
`chloride solution.
`Insert a second needle that is 9 cm, 18 gauge (long needle) into the LUTATHERA vial ensuring that this
`long needle touches and is secured to the bottom of the LUTATHERA vial during the entire infusion.
`Connect the long needle to the patient by an intravenous catheter that is pre-filled with 0.9% sterile sodium
`chloride solution and that is used exclusively for the LUTATHERA infusion into the patient.
`• Use a clamp or pump to regulate the flow of the sodium chloride solution via the short needle into the
`LUTATHERA vial at a rate of 50 mL/hour to 100 mL/hour for 5 to 10 minutes and then 200 mL/hour to
`300 mL/hour for an additional 25 to 30 minutes (the sodium chloride solution entering the vial through the
`short needle will carry the LUTATHERA from the vial to the patient via the catheter connected to the long
`needle over a total duration of 30 to 40 minutes).
`• During the infusion, ensure that the level of solution in the LUTATHERA vial remains constant.
`• Disconnect the vial from the long needle line and clamp the saline line once the level of radioactivity is
`stable for at least five minutes.
`• Follow the infusion with an intravenous flush of 25 mL of 0.9% sterile sodium chloride solution.
`Instructions for Infusion Pump Method
`Insert a 2.5 cm, 20 gauge needle (short venting needle) into the LUTATHERA vial. Ensure that the short
`•
`needle does not touch the LUTATHERA solution in the vial and do not connect this short needle directly to
`the patient or the infusion pump.
`Insert a second needle that is 9 cm, 18 gauge (long needle) into the LUTATHERA vial ensuring that this
`long needle touches and is secured to the bottom of the LUTATHERA vial during the entire infusion.
`Connect the long needle and a 0.9% sterile sodium chloride solution to a 3-way stopcock valve via
`appropriate tubing.
`• Connect the output of the 3-way stopcock valve to tubing installed on the input side of the peristaltic
`infusion pump according to manufacturer’s instruction.
`• Prime the line by opening the 3-way stopcock valve and pumping the LUTATHERA solution through the
`tubing until it reaches the exit of the valve.
`• Prime the intravenous catheter that will be connected to the patient by opening the 3-way stopcock valve to
`the 0.9% sterile sodium chloride solution and pumping the 0.9% sterile sodium chloride solution until it
`exits the end of the catheter tubing.
`• Connect the primed intravenous catheter to the patient and set the 3-way stopcock valve such that the
`LUTATHERA solution is in line with the infusion pump.
`Infuse an appropriate volume of LUTATHERA solution over a 30-40 min period to deliver the desired
`radioactivity.
`• When the desired LUTATHERA radioactivity has been delivered, stop the infusion pump and then change
`the position of the 3-way stopcock valve so that the infusion pump is in line with the 0.9% sterile sodium
`chloride solution. Restart the infusion pump and infuse an intravenous flush of 25 mL of 0.9% sterile
`sodium chloride solution through the intravenous catheter to the patient.
`
`•
`
`
`
`Reference ID: 4998594
`
`

`

`Estimated Radiation Absorbed Dose for LUTATHERA in NETTER-1
`Absorbed dose per unit activity
`Calculated absorbed dose for 4 x 7.4 GBq
`(Gy/GBq)
`(29.6 GBq cumulative activity)
`(N = 20)
`(Gy)
`
`Mean
`0.037
`0.027
`0.027
`0.042
`0.032
`0.654
`0.299
`
`SD
`0.016
`0.016
`0.015
`0.019
`0.015
`0.295
`0.226
`
`Mean
`1.1
`0.8
`0.8
`1.2
`0.9
`19.4
`8.9
`
`SD
`0.5
`0.5
`0.4
`0.6
`0.4
`8.7
`6.7
`
`Radiation Dosimetry
`2.6
`The mean and standard deviation (SD) of the estimated radiation absorbed doses for adults receiving
`LUTATHERA are shown in Table 3. The maximum penetration in tissue is 2.2 mm and the mean penetration is
`0.67 mm.
`Table 3.
`
`
`
`
`Organ
`Adrenals
`Brain
`Breasts
`Gallbladder Wall
`Heart Wall
`Kidneys
`Livera
`Lower Large Intestine
`Wall
`Lungs
`Muscle
`Osteogenic Cells
`Ovariesb
`Pancreas
`Red Marrow
`Skin
`Small Intestine
`Spleen
`Stomach Wall
`Testesc
`Thymus
`Thyroid
`Total Body
`Upper Large Intestine
`0.4
`0.9
`0.015
`0.032
`Wall
`5.3
`12.8
`0.176
`0.437
`Urinary Bladder Wall
`0.4
`1.0
`0.013
`0.032
`Uterusb
`aN = 18 (two patients excluded because the liver absorbed dose was biased by the uptake of the liver metastases).
`bN = 9 (female patients only).
`cN = 11 (male patients only).
`
`0.029
`0.031
`0.029
`0.151
`0.031
`0.038
`0.035
`0.027
`0.031
`0.846
`0.032
`0.026
`0.028
`0.027
`0.052
`
`0.016
`0.015
`0.015
`0.268
`0.013
`0.016
`0.029
`0.015
`0.015
`0.804
`0.015
`0.018
`0.015
`0.016
`0.027
`
`0.9
`0.9
`0.8
`4.5
`0.9
`1.1
`1.0
`0.8
`0.9
`25.1
`0.9
`0.8
`0.8
`0.8
`1.6
`
`0.5
`0.4
`0.4
`7.9
`0.4
`0.5
`0.8
`0.4
`0.5
`23.8
`0.5
`0.5
`0.5
`0.5
`0.8
`
`DOSAGE FORMS AND STRENGTHS
`3
`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.
`
`CONTRAINDICATIONS
`
`4
`None.
`
`WARNINGS AND PRECAUTIONS
`5
`Risk From Radiation Exposure
`5.1
`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 LUTATHERA administration. Minimize
`radiation exposure to patients, medical personnel, and household contacts during and after treatment with
`
`
`
`Reference ID: 4998594
`
`

`

`
`
`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 (2.1), Clinical Pharmacology (12.3)].
`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 weeks following the first dose. Of the
`59 patients who developed thrombocytopenia, 68% had platelet recovery to baseline or normal levels. The
`median time to platelet recovery was 2 months. Fifteen of the 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, reduce dose, or permanently discontinue based on severity of
`myelosuppression [see Dosage and Administration (2.4)].
`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.
`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 (2.3)] to decrease reabsorption of lutetium Lu 177 dotatate through the proximal tubules and
`decrease the radiation dose to the kidneys. Do not decrease the dose of the amino acid solution if the dose of
`LUTATHERA is reduced. Advise patients to urinate frequently during and after administration of
`LUTATHERA.
`Monitor serum creatinine and calculated creatinine clearance. Withhold, reduce dose, or permanently
`discontinue LUTATHERA based on severity of renal toxicity [see Dosage and Administration (2.4)].
`Patients with baseline renal impairment may be at greater risk of toxicity; perform more frequent assessments of
`renal function in patients with mild or moderate impairment. LUTATHERA has not been studied in patients
`with severe renal impairment (creatinine clearance < 30 mL/min).
`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 and serum albumin during treatment. Withhold, reduce dose, or permanently
`discontinue LUTATHERA based on severity of hepatotoxicity [see Dosage and Administration (2.4)].
`5.6 Hypersensitivity Reactions
`Hypersensitivity reactions, including angioedema, occurred in patients treated with LUTATHERA [see Adverse
`Reactions (6.2)]. 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
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`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 (2.3)]. Permanently discontinue LUTATHERA in patients
`who experience Grade 3 or 4 hypersensitivity reactions [see Dosage and Administration (2.4)].
`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.
`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 (12.1)]. 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, all radiopharmaceuticals, including LUTATHERA, have the potential
`to cause fetal harm.
`Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA [see Dosage and
`Administration (2.1)].
`Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective
`contraception during treatment with LUTATHERA and for 7 months after the final dose. Advise males with
`female partners of reproductive potential to use effective contraception during treatment with LUTATHERA
`and for 4 months after the final dose [see Use in Specific Populations (8.1, 8.3)].
`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 testis and ovaries within the range where temporary or
`permanent infertility can be expected following external beam radiotherapy [see Dosage and Administration
`(2.6), Use in Specific Populations (8.3)].
`
`ADVERSE REACTIONS
`6
`The following clinically significant adverse reactions are described elsewhere in the labeling.
`• Myelosuppression [see Warnings and Precautions (5.2)]
`• Secondary Myelodysplastic Syndrome and Leukemia [see Warnings and Precautions (5.3)]
`• Renal Toxicity [see Warnings and Precautions (5.4)]
`• Hepatotoxicity [see Warnings and Precautions (5.5)]
`• Hypersensitivity Reactions [see Warnings and Precautions (5.6)]
`• Neuroendocrine Hormonal Crisis [see Warnings and Precautions (5.7)]
`6.1
`Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
`reflect the rates observed in practice.
`The data in Warnings and Precautions reflect exposure to LUTATHERA in 111 patients with advanced,
`progressive midgut neuroendocrine tumors (NETTER-1). Safety data in Warnings and Precautions were also
`obtained in an additional 22 patients in a non-randomized pharmacokinetic sub-study of NETTER-1 and in a
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`subset of patients (811 of 1214) with advanced somatostatin receptor-positive tumors enrolled in ERASMUS
`[see Warnings and Precautions (5)].
`NETTER-1
`The safety data of LUTATHERA with octreotide was evaluated in NETTER-1 [see Clinical Studies (14.1)].
`Patients with progressive, somatostatin receptor-positive midgut carcinoid tumors received LUTATHERA 7.4
`GBq (200 mCi) administered every 8 to 16 weeks concurrently with the recommended amino acid solution and
`with long-acting octreotide (30 mg administered by intramuscular injection within 24 hours of each
`LUTATHERA dose) (N = 111), or high-dose octreotide (defined as long-acting octreotide 60 mg by
`intramuscular injection every 4 weeks) (N = 112) [see Clinical Studies (14.1)]. Among patients receiving
`LUTATHERA with octreotide, 79% received a cumulative dose > 22.2 GBq (> 600 mCi) and 76% of patients
`received all four planned doses. Six percent (6%) of patients required a dose reduction and 13% of patients
`discontinued LUTATHERA. Five patients discontinued LUTATHERA for renal-related events and 4
`discontinued for hematological toxicities.
`Table 4 and Table 5 summarize the incidence of adverse reactions and laboratory abnormalities, respectively.
`The most common Grade 3-4 adverse reactions occurring with a greater frequency among patients receiving
`LUTATHERA with octreotide compared to patients receiving high-dose octreotide include: lymphopenia
`(44%), increased GGT (20%), vomiting (7%), nausea and elevated AST (5% each), and increased ALT,
`hyperglycemia and hypokalemia (4% each).
`Table 4.
`Adverse Reactions Occurring at Higher Incidence in Patients Receiving LUTATHERA
`with Long-Acting Octreotide Compared to High-dose Long-Acting Octreotide (Between
`Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4)1
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`Adverse Reaction1
`
`
`LUTATHERA with Long-
`Acting Octreotide (30 mg)
`(N = 111)
`All Grades
`Grades 3-4
`%
`%
`
`Long-Acting Octreotide (60 mg)
`(N = 112)
`
`All Grades
`%
`
`Grades 3-4
`%
`
`Gastrointestinal disorders
`Nausea
`Vomiting
`Abdominal pain
`Diarrhea
`Constipation
`General disorders
`Fatigue
`Peripheral edema
`Pyrexia
`Metabolism and nutrition disorders
`Decreased appetite
`Nervous system disorders
`Headache
`Dizziness
`Dysgeusia
`Vascular disorders
`14
`Flushing
`12
`Hypertension
`Musculoskeletal and connective tissue disorders
`Back pain
`13
`Pain in extremity
`11
`Myalgia
`5
`Neck Pain
`5
`Renal and urinary disorders
`
`Renal failurea
`13
`Radiation-related urinary tract adverse
`8
`reactionsb
`Psychiatric disorders
`Anxiety
`Skin and subcutaneous tissue disorders
`12
`Alopecia
`Respiratory, thoracic and mediastinal disorders
`Cough
`11
`Cardiac disorders
`0
`0
`1
`5
`Atrial fibrillation
`1National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Only displays adverse reactions occurring at a
`higher incidence in LUTATHERA-treated patients [between arm difference of ≥ 5% (all Grades) or ≥ 2% (Grades 3-4)].
`aIncludes the terms: Glomerular filtration rate decreased, acute kidney injury, acute prerenal failure, azotemia, renal disorder, renal failure, renal
`impairment.
`bIncludes the terms: Dysuria, micturition urgency, nocturia, pollakiuria, renal colic, renal pain, urinary tract pain and urinary incontinence.
`Table 5.
`Laboratory Abnormalities Occurring at Higher Incidence in Patients Receiving
`LUTATHERA with Long-Acting Octreotide Compared to High-Dose Long-Acting
`Octreotide (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4)1,2
`
`65
`53
`26
`26
`10
`
`38
`16
`8
`
`21
`
`17
`17
`8
`
`12
`
`5
`7
`3
`3
`0
`
`1
`0
`0
`
`0
`
`0
`0
`0
`
`1
`2
`
`2
`0
`0
`0
`
`3
`0
`
`1
`
`0
`
`1
`
`12
`10
`19
`18
`5
`
`26
`9
`3
`
`11
`
`5
`8
`2
`
`9
`7
`
`10
`5
`0
`0
`
`4
`3
`
`5
`
`2
`
`6
`
`2
`0
`3
`1
`0
`
`2
`1
`0
`
`3
`
`0
`0
`0
`
`0
`2
`
`0
`0
`0
`0
`
`1
`0
`
`0
`
`0
`
`0
`
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`Laboratory Abnormality2
`
`
`LUTATHERA with Long-Acting
`Octreotide (30 mg)
`(N = 111)
`All Grades
`Grades 3-4
`%
`%
`
`Long-Acting Octreotide
`(60 mg)
`(N = 112)
`All Grades
`Grades 3-4
`%
`%
`
`Hematology
`Lymphopenia
`Anemia
`Leukopenia
`Thrombocytopenia
`Neutropenia
`Renal/Metabolic
`Creatinine increased
`Hyperglycemia
`Hyperuricemia
`Hypocalcemia
`Hypokalemia
`Hyperkalemia
`Hypernatremia
`Hypoglycemia
`Hepatic
`66
`GGT increased
`65
`Alkaline phosphatase increased
`50
`AST increased
`43
`ALT increased
`30
`Blood bilirubin increas