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
`
`
`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
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 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
`
`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
`
`
`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.
`
`
`
`6
`
`7
`
`8
`
`
`
`Reference ID: 4212675
`
`
`Page 1
`
`

`

`
`
`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
`
`
`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)].
`
`
`
`
`
`
`2.2
`Recommended Dosage
`
`
`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)]
`
`
`
`
`
`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)]
`
`
`
` Renal Toxicity [see Warnings and
`
`
`
` Precautions (5.4)]
`
`
`
`
` Hepatotoxicity [see Warnings and
` Precautions (5.5)]
`
`
`
`
`
`
` Other Non-Hematologic Toxicity
`
`
`
`
`
` Recurrent Grade 2, 3 or 4
`
`
` Grade 3 or 4
`
`
`
`
`
` 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%.
`
`
`
`
`
`
`
`
` Recurrent hepatotoxicity
`
`
` Grade 3 or 4
`
`
`
`
`
`
`
`
`
` Dose Modification
`
`
` Withhold dose until complete or partial resolution
`
` (Grade 0 to 1).
`
`
`Resume LUTATHERA at 3.7 GBq (100 mCi) in
`
`patients with complete or partial resolution. If
`
`
`reduced dose does not result in Grade 2, 3 or 4
`
`
`
`
`thrombocytopenia, administer LUTATHERA at
`
`
`7.4 GBq (200 mCi) 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.
`
` 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
`
`
`

`

`
`
` Organ
`
` SD
`
` Mean
`
`
` Mean
` Adrenals
`
`
` 1.1
`
` 0.016
`
` 0.037
`
` Brain
`
` 0.8
`
` 0.016
`
` 0.027
` Breasts
`
`
` 0.8
`
` 0.015
`
` 0.027
`
` Gallbladder Wall
`
` 1.2
`
` 0.019
`
` 0.042
`
` Heart Wall
`
` 0.9
`
` 0.015
`
` 0.032
` Kidneys
`
`
` 19.4
`
` 0.295
`
` 0.654
`
` Liver*
`
` 8.9
`
` 0.226
`
` 0.299
`
` Lower Large Intestine Wall
`
`
` 0.9
`
` 0.016
`
` 0.029
`
` Lungs
`
` 0.9
`
` 0.015
`
` 0.031
` Muscle
`
` 0.8
`
` 0.015
`
` 0.029
`
`
` 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
`
`
` 0.013
`
` 0.032
`
` Uterus
` 1.0
`
` *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)
`
`
`
`
`
`
`
`
`
`
`
`Table 3. Estimated Radiation Absorbed Dose for LUTATHERA in NETTER-1
`
`
`
`
`
`
`
`
` Calculated absorbed dose for 4 x 7.4 GBq
`
`
` Absorbed dose per unit activity
` (Gy/GBq)
`
`
` (29.6 GBq cumulative activity)
`
` (N=20)
`
` (Gy)
`
`
`
`
`
`
` 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
`
`
`CONTRAINDICATIONS
`
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`
`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.
`
`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)].
`
`
`
`
`
`
`
`
`ADVERSE REACTIONS
`6
`
`
`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)].
`
`
`
`
`
`Reference ID: 4212675
`
`Page 6
`
`
`

`

`
`
`
`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)
`
`
`
` Grades 3-4 %
`
` All Grades %
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`Reference ID: 4212675
`
`Page 7
`
`
`
`
`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
`
` Flushing
`
` 0
`
` 9
`
` 1
`
` 14
` Hypertension
`
` 2
`
` 7
`
` 2
`
` 12
`
`
`
` 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
`
`
`
`
`
`
` Long-Acting Octreotide (60 mg)
` (N = 112)
`
`
` Grades 3-4 %
`
` All Grades %
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`

`

`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 %
`
`
`
`
`
`
` 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
`
`
`
` 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-treat