`
`
`
`
`
`
`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, Preparation and Administration (2.5)
`5/2020
`
`
`
`
`--------------------------- 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 in 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 3 hours after
`
`
`LUTATHERA infusion. Do not reduce 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)
`
`
`
`
`
`
`
`----------------------- 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 development: MDS is 28 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 albumin. (2.4, 5.5)
`
`
`
`• Neuroendocrine Hormonal Crisis: Monitor for flushing, diarrhea,
`
`
`
`
`hypotension, bronchoconstriction or other signs and symptoms. (5.6)
`
`
`
`
`• 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 (5.7, 8.1, 8.3)
`
`• Risk of Infertility: LUTATHERA may cause infertility. (5.8, 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 Advanced
`
`
`
`Accelerator Applications USA, Inc. at 1-844-863-1930 or
`
`
`
`us-pharmacovigilance@adacap.com, 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: 5/2020
`
`
`
`
`
`
` ______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`
`Important Safety Instructions
`2.1
`
`
`2.2
`Recommended Dosage
`
`
`2.3
`Premedication and Concomitant Medications
`
`
`2.4
`Dose Modifications for Adverse Reactions
`
`
`
`2.5
`Preparation and Administration
`
`
`2.6
`Radiation Dosimetry
`
`DOSAGE FORMS AND STRENGTHS
`
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`
`Risk from Radiation Exposure
`5.1
`
`
`5.2 Myelosuppression
`
`
`5.3
`Secondary Myelodysplastic Syndrome and Leukemia
`
`
`
`5.4
`Renal Toxicity
`
`
`5.5
`Hepatotoxicity
`
`
`5.6
`Neuroendocrine Hormonal Crisis
`
`
`5.7
`Embryo-Fetal Toxicity
`
`
`5.8
`Risk of Infertility
`
`ADVERSE REACTIONS
`
`
`6.1
`Clinical Trials Experience
`
`DRUG INTERACTIONS
`
`
`7.1
`Somatostatin Analogs
`
`
`7.2
`Corticosteriods
`
`
`USE IN SPECIFIC POPULATIONS
`8
`
`
`8.1
`Pregnancy
` ______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`
`
`
`
`3
`
`4
`
`5
`
`
`6
`
`7
`
`Reference ID: 4615991
`
`Page 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
`
`
`DESCRIPTION
`11
`
`
`Physical Characteristics
`11.1
`
`
`11.2 External Radiation
`
`
`CLINICAL PHARMACOLOGY
`12
`
`
`12.1 Mechanism of Action
`
`
`12.2
`Pharmacodynamics
`
`
`12.3
`Pharmacokinetics
`
`
`NONCLINICAL TOXICOLOGY
`13
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`CLINICAL STUDIES
`14
`
`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
`
`
`somatostatin
`of
`the
`indicated
`
`
`
` treatment
` receptor-positive
`LUTATHERA
` is
`for
`
`
`
` gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and
`
`
` hindgut neuroendocrine tumors in adults.
`
`
`
`
`
`
`
`
`
`
`
`
` 2
`
`
` DOSAGE AND ADMINISTRATION
` 2.1 Important Safety Instructions
`
`
`
` LUTATHERA is a radiopharmaceutical; handle with appropriate safety measures to minimize
`
`
`
`
` radiation exposure [see Warnings and Precautions (5.1)]. Use waterproof gloves and effective
`
` shielding when handling LUTATHERA. Radiopharmaceuticals,
` including
`
`
`
`
`radiation
` 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)].
`
`
` 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)].
` 2.3 Premedication and Concomitant Medications
`
`
` Somatostatin Analogs
`
`• Before initiating LUTATHERA: Discontinue long-acting somatostatin analogs (e.g., 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 [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 for 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.
`
`
`
`
`
`
`
`
`
`
`
`
`Page 2
`
`
`Reference ID: 4615991
`
`

`

`
`
`
` 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 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)].
`
`
`
`
`
`Table 1.
`
`
`
` Item
` L-Lysine HCl content
`
`
`
`Amino Acid Solution
`
`
` Specification
`
`Between 18 g and
`
`
` 25 g*
` L-Arginine HCl content Between 18 g and
`
` 25 g**
` Volume
`
` 1 L to 2 L
`
` < 1050 mOsmol/L
`
`
` Osmolarity
`
`
` *equivalent to 14.4 to 20 g lysine
` **equivalent to 14.9 to 20.7 g arginine
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.4 Dosage Modifications for Adverse Reactions
`
`
`
` Recommended dose modifications of LUTATHERA for adverse reactions are provided in Table
`2.
`
`
` Recommended Dosage Modifications of LUTATHERA for Adverse Reactions
`
` Table 2.
`
`
`
`
`
` Severity of Adverse Reaction*
`
` Adverse Reaction
`
`
` Dose Modification
`
` Grade 2, 3 or 4
`
`
`
`
` Thrombocytopenia [see
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Anemia and Neutropenia
` [see Warnings and
`
`
` Precautions (5.2)]
`
`
`
`
`
`
` Recurrent Grade 2, 3 or 4
`
`
` Grade 3 or 4
`
`
`
`
`
`
`
`Page 3
`
`
`Reference ID: 4615991
`
`

`

`
`
`
`
` Severity of Adverse Reaction*
`
`
`
`
`
`
`
`
`
` Recurrent Grade 3 or 4
` 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
`
`
`
`
`
` • Hypoalbuminemia less than 30 g/L with
`
`
`
`
`
`
`
`
`
`
`
` a decreased prothrombin ratio less than
`
` 70%.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Dose Modification
`
` 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.
`
` Withhold dose until complete resolution
`
`
`
`
`
` or return to baseline.
`
`
`
`
`
`Resume LUTATHERA at 3.7 GBq (100
`
`
`
`mCi) in patients with complete
`
`
`
`
`
`resolution. 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.
`
`
` 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 toxicity requiring
`
`
`
`
` treatment delay of 16 weeks or longer.
`
`
`
`
`
`
` Permanently discontinue LUTATHERA.
`
`
`
`
` Recurrent Grade 3 or 4
` * Grading of severity is defined in the most current Common Terminology Criteria for Adverse Events (CTCAE)
`
`
`
`
`
`
`
`
`
`
`
`
` Adverse Reaction
`
`
`
` Renal Toxicity [see
` Warnings and Precautions
`
`
`
` (5.4)]
`
`
`
`
` Hepatotoxicity [see
` Warnings and Precautions
`
`
`
` (5.5)]
`
`
`
`
` Other Non-Hematologic
`
` Toxicity [see Adverse
`
` Reactions (6.1)]
`
`
`
`
` Recurrent hepatotoxicity
` Grade 3 or 4
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4615991
`
`Page 4
`
`
`

`

`
`
`
`
`
`
`
`
`
`•
`
`
`
`
`
` 2.5 Preparation and Administration
`
`
`
` • Use aseptic technique and radiation shielding when administering the LUTATHERA solution.
`
`
`
` Use tongs when handling 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 for particulate matter and discoloration prior to administration
`
`
`
` under a shielded screen. Discard vial if particulates or discoloration are present.
` • Dispose of any unused medicinal product or waste material in accordance with local and federal
`
`
`laws.
`
`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 prefilled
`
`
`
`
`
`
`with 0.9% sterile sodium chloride 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.
`
`
`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.
`
`
`
`
`
`
`
`•
`
`
`
`Page 5
`
`
`Reference ID: 4615991
`
`

`

`
`
`
`•
`
` 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.
`
`
`• Purge 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.
`
`• Purge the intravenous catheter which 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 purged 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 one-half the volume listed on the LUTATHERA vial over a 30 min period
`
`
`
`(approximately 25 mL/h).
`
`
`• When the correct volume of LUTATHERA 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.
`
`2.6 Radiation Dosimetry
`
`
`
`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.
`
`
`
`
`
`•
`
`
`
`Page 6
`
`
`Reference ID: 4615991
`
`

`

`
`
` Estimated Radiation Absorbed Dose for LUTATHERA in NETTER-1
`
` Calculated absorbed dose for 4 x 7.4 GBq
`
`
`
`
`
`
`
` Absorbed dose per unit activity
`
` (29.6 GBq cumulative activity)
`
`
`
` (Gy/GBq)
`
`
` (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
`
`
`
` Table 3.
`
`
`
`
`
`
`
`
` Organ
`
`
` Adrenals
`
` Brain
` Breasts
`
`
`
` Gallbladder Wall
`
`
` Heart Wall
` Kidneys
`
`
` Liver*
`
` Lower Large Intestine
`
` Wall
` Lungs
`
` Muscle
`
`
`
` Osteogenic Cells
`
` Ovaries**
` Pancreas
`
`
` Red Marrow
`
` Skin
`
` Small Intestine
`
` Spleen
`
`
` Stomach Wall
` Testes***
`
`
` Thymus
`
` Thyroid
`
` Total Body
`
` Upper Large Intestine
`
` 0.9
`
` 0.4
`
`
` 0.015
`
` 0.032
`
` Wall
`
` 5.3
`
` 12.8
`
` 0.176
`
` 0.437
`
` Urinary Bladder Wall
`
` 0.4
`
`
` 0.013
`
` 0.032
`
` 1.0
` Uterus
`
`
` *N=18 (two patients excluded because the liver absorbed dose was biased by the uptake of the liver metastases)
`
`
`
` **N=9 (female patients only)
`
`
`
`
`
` ***N=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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3
` DOSAGE FORMS AND STRENGTHS
`
`
`
`
` 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.
`
` 5 WARNINGS AND PRECAUTIONS
`
` 5.1 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.
`
`
`
`
`
`
`
`Page 7
`
`
`Reference ID: 4615991
`
`

`

`
`
`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 (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 24 months, myelodysplastic syndrome (MDS) was
`
`
`reported in 2.7% 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 the development of MDS was
`
`
`
`
`28 months (9 to 41 months) for MDS and 55 months (32 to 155 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).
`
`
`
`
`
`
`
`Page 8
`
`
`Reference ID: 4615991
`
`

`

`
`
`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 hepatic impairment [see Dosage and
`
`
`
`
`
`Administration (2.4)].
`5.6 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.
`
`
`5.7 Embryo-Fetal Toxicity
`
`
`Based on its mechanism of action, LUTATHERA can cause fetal harm [see Clinical Pharmacology
`
`
`
`
`
`(12.1)]. There are no available data on the use of LUTATHERA 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 and for 4 months after the final dose [see Use in Specific Populations (8.1, 8.3)].
`
`
`
`
`
`
`5.8 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)]
`
`
`• Neuroendocrine Hormonal Crisis [see Warnings and Precautions (5.6)]
`
`
`
`
`
`
`
`Page 9
`
`
`Reference ID: 4615991
`
`

`

`
`
`
` 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
`
`
`
`
` substudy of NETTER-1 and in a 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
`
`
`
`to receive 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. The median duration of follow-up was 24 months for
`
`
`
`
`
`
`patients receiving LUTATHERA with octreotide and 20 months for patients receiving high-dose
`
`
`
`
`
`
`octreotide.
`
`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).
`
`
`
`
`
`
`
`Page 10
`
`
`Reference ID: 4615991
`
`

`

`
`
` Table 4.
`
`
`
`
` Adverse Reactions Occurring at Higher Incidence in Patients Receiving
`
` LUTATHERA and Long-Acting Octreotide Compared to Long-Acting
`
`
` Octreotide (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3­
`
`
`
`
`
`
`
`
` 4) 1
`
`
`
`
`
`
`
`
`
`Adverse Reaction1
`
`
`
` LUTATHERA and Long-
` Acting Octreotide (30 mg)
`
`
` (N = 111)
`
`
`
`
`
` Grades 3-4
`
` All Grades
`
`
` %
` %
`
`
`
`
`
` Long-Acting Octreotide (60 mg)
`
`
`
`
` (N = 112)
`
` Grades 3-4
`
`
` All Grades
`
`
` %
` %
`
`
`
`
`
`
`
`
` 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