` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208700Orig1s000
`
`
`LABELING
`
`

`

`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
`
`
`---------------------------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)
`• Premedicate with antiemetics 30 minutes 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)
`• Modify LUTATHERA dose based on adverse reactions. (2.4)
`• Prepare and administer as recommended. (2.5)
`
`
`•
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`Injection: 370 MBq/mL (10 mCi/mL) in single-dose vial. (3)
`
`------------------------------CONTRAINDICATIONS------------------------------
`None.
`
`
`-----------------------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. Withhold,
`reduce dose, or permanently discontinue based on severity. (2.4, 5.5)
`• Neuroendocrine Hormonal Crisis: Monitor for flushing, diarrhea,
`hypotension, bronchoconstriction or other signs and symptoms. (5.6)
`• Embryo-Fetal Toxicity: LUTATHERA 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. (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 for 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: 01/2018
`
` ____________________________________________________________________________________________________________________________________
`
`
`
`
`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
`Dose 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
`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
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
` ____________________________________________________________________________________________________________________________________
`
`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.
`
`6
`7
`8
`
`
`
`Reference ID: 4212675
`
`Page 1
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
` 1
`
`INDICATIONS AND USAGE
`
`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
`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 radiation shielding when handling LUTATHERA. Radiopharmaceuticals, including LUTATHERA,
`should be used by or under the control of physicians 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)].
`Recommended Dosage
`2.2
`The recommended LUTATHERA dose is 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses. Administer pre- and concomitant medications
`and administer LUTATHERA as recommended [see Dosage and Administration (2.3, 2.5)].
`
`Premedication and Concomitant Medications
`2.3
`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 30 minutes 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 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. Amino Acid Solution
`
`Item
`
`Specification
`
`Lysine HCl content
`Arginine HCl content
`Volume
`Osmolarity
`
`Between 18 g and 24 g
`Between 18 g and 24 g
`1.5 L to 2.2 L
`< 1050 mOsmol
`
`
`
`Dose Modifications for Adverse Reactions
`2.4
`Recommended dose modifications of LUTATHERA for adverse reactions are provided in Table 2.
`
`
`
`
`
`
`
`Reference ID: 4212675
`
`Page 2
`
`

`

`Adverse Reaction
`Thrombocytopenia [see Warnings and
`Precautions (5.2)]
`
`
`
`
`
`Dose Modification
`Withhold dose until complete or partial resolution
`(Grade 0 to 1).
`
`Resume LUTATHERA at 3.7 GBq (100 mCi) in
`patients with complete or partial resolution. If
`reduced dose does not result in Grade 2, 3 or 4
`thrombocytopenia, administer LUTATHERA at
`7.4 GBq (200 mCi) 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.
`Withhold dose until complete resolution.
`
`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.
`
`Resume LUTATHERA at 3.7 GBq (100 mCi) in
`patients with complete resolution. 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.
`
`Table 2. Recommended Dose Modifications of LUTATHERA for Adverse Reactions
`
`Severity of Adverse Reaction1
`Grade 2, 3 or 4
`
`
`
`Anemia and Neutropenia [see
`Warnings and Precautions (5.2)]
`
`Recurrent Grade 2, 3 or 4
`Grade 3 or 4
`
`Renal Toxicity [see Warnings and
`Precautions (5.4)]
`
`Hepatotoxicity [see Warnings and
`Precautions (5.5)]
`
`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
`
`than 30 g/L with a
`less
`• Hypoalbuminemia
`decreased prothrombin ratio less than 70%.
`
`Other Non-Hematologic Toxicity
`
`Recurrent hepatotoxicity
`Grade 3 or 4
`
`Recurrent Grade 3 or 4
`1 National Cancer Institute, Common Toxicity Criteria for Adverse Events, version 4.03
`
`
`
`
`
`
`
`Reference ID: 4212675
`
`Page 3
`
`

`

`
`
`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.
`
`
`Administration Instructions
`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).
`Do not administer LUTATHERA as an intravenous bolus.
`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.
`Dispose of any unused medicinal product or waste material in accordance with local and federal laws.
`
`•
`
`•
`
`•
`•
`•
`•
`•
`
`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.
`
`
`
`
`Reference ID: 4212675
`
`Page 4
`
`

`

`Table 3. 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
`SD
`Mean
`Organ
`1.1
`0.016
`0.037
`Adrenals
`0.8
`0.016
`0.027
`Brain
`0.8
`0.015
`0.027
`Breasts
`1.2
`0.019
`0.042
`Gallbladder Wall
`0.9
`0.015
`0.032
`Heart Wall
`19.4
`0.295
`0.654
`Kidneys
`8.9
`0.226
`0.299
`Liver*
`0.9
`0.016
`0.029
`Lower Large Intestine Wall
`0.9
`0.015
`0.031
`Lungs
`0.8
`0.015
`0.029
`Muscle
`4.5
`0.268
`0.151
`Osteogenic Cells
`0.9
`0.013
`0.031
`Ovaries**
`1.1
`0.016
`0.038
`Pancreas
`1.0
`0.029
`0.035
`Red Marrow
`0.8
`0.015
`0.027
`Skin
`0.9
`0.015
`0.031
`Small Intestine
`25.1
`0.804
`0.846
`Spleen
`0.9
`0.015
`0.032
`Stomach Wall
`0.8
`0.018
`0.026
`Testes***
`0.8
`0.015
`0.028
`Thymus
`0.8
`0.016
`0.027
`Thyroid
`1.6
`0.027
`0.052
`Total Body
`0.9
`0.015
`0.032
`Upper Large Intestine Wall
`12.8
`0.176
`0.437
`Urinary Bladder Wall
`1.0
`0.013
`0.032
`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)
`
`
`
`SD
`0.5
`0.5
`0.4
`0.6
`0.4
`8.7
`6.7
`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
`0.4
`5.3
`0.4
`
` 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
`
`WARNINGS AND PRECAUTIONS
`
` 4
`
`
`None.
`
` 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 LUTATHERA consistent with institutional good radiation safety practices and
`patient management procedures [see Dosage and Administration (2.1)].
`
`Myelosuppression
`5.2
`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 adverse reaction [see Dosage and Administration
`(2.4)].
`
`
`
`
`Reference ID: 4212675
`
`Page 5
`
`

`

`
`
`Secondary Myelodysplastic Syndrome and Leukemia
`5.3
`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, 15 patients (1.8%)
`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.
`
`Renal Toxicity
`5.4
`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 reaction [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).
`
`Hepatotoxicity
`5.5
`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 reaction [see Dosage and Administration (2.2)].
`
`Neuroendocrine Hormonal Crisis
`5.6
`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
`5.7
`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 females and males of reproductive potential 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)].
`
`Risk of Infertility
`5.8
`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) and Use in Specific Populations (8.3)].
`
` 6
`
`ADVERSE REACTIONS
`
`The following serious 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)]
`•
`
`
`Clinical Trials Experience
`6.1
`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)].
`
`
`
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`

`
`
`
`NETTER-1
`The safety data described below are from NETTER-1, which randomized (1:1) 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).
`
`
`Table 4. Adverse Reactions Occurring in ≥ 5% (All Grades) of Patients Receiving LUTATHERA with Octreotide in NETTER-11
`
`LUTATHERA and Long-Acting
`Octreotide (30 mg) (N = 111)
`All Grades %
`Grades 3-4 %
`
`Long-Acting Octreotide (60 mg)
`(N = 112)
`All Grades %
`Grades 3-4 %
`
`
`
`
`
`
`
`
`
`
`Adverse Reaction1
`Cardiac disorders
`Atrial fibrillation
`Gastrointestinal disorders
`Nausea
`Vomiting
`Abdominal pain
`Diarrhea
`Constipation
`General disorders
`Fatigue
`Peripheral edema
`Pyrexia
`Metabolism and nutrition disorders
`Decreased appetite
`Musculoskeletal and connective tissue disorders
`Back pain
`Pain in extremity
`Myalgia
`Neck Pain
`Nervous system disorders
`Headache
`Dizziness
`Dysgeusia
`Psychiatric disorders
`Anxiety
`Renal and urinary disorders
`Renal failure*
`Radiation-related urinary tract toxicity**
`Respiratory, thoracic and mediastinal disorders
`Cough
`Skin and subcutaneous tissue disorders
`Alopecia
`Vascular disorders
`0
`9
`1
`14
`Flushing
`2
`7
`2
`12
`Hypertension
`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)]
`*Includes the terms: Glomerular filtration rate decreased, acute kidney injury, acute prerenal failure, azotemia, renal disorder, renal failure, renal impairment
`**Includes the terms: Dysuria, micturition urgency, nocturia, pollakiuria, renal colic, renal pain, urinary tract pain and urinary incontinence
`
`5
`
`65
`53
`26
`26
`10
`
`38
`16
`8
`
`21
`
`13
`11
`5
`5
`
`17
`17
`8
`
`12
`
`12
`8
`
`11
`
`12
`
`1
`
`5
`7
`3
`3
`0
`
`1
`0
`0
`
`0
`
`2
`0
`0
`0
`
`0
`0
`0
`
`1
`
`3
`0
`
`1
`
`0
`
`0
`
`12
`9
`19
`18
`5
`
`26
`9
`3
`
`11
`
`10
`5
`0
`0
`
`5
`8
`2
`
`5
`
`3
`3
`
`6
`
`2
`
`0
`
`2
`0
`3
`1
`0
`
`2
`1
`0
`
`3
`
`0
`0
`0
`0
`
`0
`0
`0
`
`0
`
`1
`0
`
`0
`
`0
`
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`

`Table 5. Laboratory Abnormalities Occurring in ≥ 5% (All Grades) of Patients Receiving LUTATHERA with Octreotide in NETTER-1*1
`
`
`Laboratory Abnormality1
`
`LUTATHERA and Long-Acting
`Octreotide (30 mg) (N = 111)
`
`Long-Acting Octreotide (60 mg)
`(N = 112)
`
`All grades %
`
`Grade 3-4 %
`
`All grades %
`
`Grade 3-4 %
`
`
`
`Hematology
`Lymphopenia
`Anemia
`Leukopenia
`Thrombocytopenia
`Neutropenia
`Renal/Metabolic
`Creatinine increased
`Hyperglycemia
`Hyperuricemia
`Hypocalcemia
`Hypokalemia
`Hyperkalemia
`Hypernatremia
`Hypoglycemia
`Hepatic
`GGT increased
`Alkaline phosphatase increased
`AST increased
`ALT increased
`Blood bilirubin increased
`*Values are worst grade observed after randomization
`1National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4 03 Only displays laboratory abnormalities occurring at a
`higher incidence in LUTATHERA-treated patients [between arm difference of ≥5% (all grades) or ≥2%(grades 3-4)]
`
`90
`81
`55
`53
`26
`
`85
`82
`34
`32
`26
`19
`17
`15
`
`66
`65
`50
`43
`30
`
`44
`0
`2
`1
`3
`
`1
`4
`6
`0
`4
`0
`0
`0
`
`20
`5
`5
`4
`2
`
`39
`54
`20
`17
`11
`
`73
`67
`29
`14
`21
`11
`7
`8
`
`67
`54
`35
`34
`28
`
`4
`1
`0
`0
`0
`
`0
`2
`6
`0
`2
`0
`0
`0
`
`16
`9
`0
`0
`0
`
`
`
`ERASMUS
`Safety data are available from 1214 patients in ERASMUS, an international, single-institution, single-arm, open-label trial of patients with
`somatostatin receptor-positive tumors (neuroendocrine and other primaries). Patients received LUTATHERA 7.4 GBq (200 mCi) administered
`every 6 to 13 weeks with or without octreotide. Retrospective medical record review was conducted on a subset of 811 patients to document serious
`adverse reactions. Eighty-one (81%) percent of patients in the subset received a cumulative dose ≥ 22.2 GBq (≥ 600 mCi). With a median follow-
`up time of more than 4 years, the following rates of serious adverse reactions were reported: myelodysplastic syndrome (2%), acute leukemia (1%),
`renal failure (2%), hypotension (1%), cardiac failure (2%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%).
`
` 7
`
`DRUG INTERACTIONS
`
`Somatostatin Analogs
`7.1
`Somatostatin and its analogs competitively bind to somatostatin receptors and may interfere with the efficacy of LUTATHERA. Discontinue long-
`acting somatostatin analogs at least 4 weeks and short-acting octreotide at least 24 hours prior to each LUTATHERA dose. Administer short- and
`long-acting octreotide during LUTATHERA treatment as recommended [see Dosage and Administration (2.3)].
`
` 8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Risk Summary
`Based on its mechanism of action, LUTATHERA can cause fetal harm [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.
`Advise pregnant women of the 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.
`
`
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`Reference ID: 4212675
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`
`
`Lactation
`8.2
`Risk Summary
`There are no data on the presence of lutetium Lu 177 dotatate in human milk, or its effects on the breastfed infant or milk production. No lactation
`studies in animals were conducted. Because of the potential risk for serious adverse reactions in breastfed infants, advise women not to breastfeed
`during treatment with LUTATHERA and for 2.5 months after the final dose.
`
`Females and Males of Reproductive Potential
`8.3
`Pregnancy Testing
`Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA [see Use in Specific Populations (8.1)].
`
`Contraception
`Females
`LUTATHERA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive
`potential to use effective contraception during treatment and for 7 months following the final dose of LUTATHERA.
`
`
`Males
`Based on its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during and for 4 months
`following the final dose of LUTATHERA [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)].
`
`Infertility
`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)].
`
`Pediatric Use
`8.4
`The safety and effectiveness of LUTATHERA have not been established in pediatric patients.
`
`Geriatric Use
`8.5
`Of the 1325 patients treated with LUTATHERA in clinical trials, 438 patients (33%) were 65 years and older. The response rate and number