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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
LUTATHERA (NDA-208700)
(LUTETIUM DOTATATE LU-177)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
04/23/2024 (SUPPL-31)
5 Warnings and Precautions
5.1 Risk from Radiation Exposure
Additions and/or revisions underlined:
LUTATHERA contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. These risks of radiation associated with the use of LUTATHERA are greater in pediatric patients than in adults [see Use in Specific Populations (8.4)].
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
Adult Population
…
Pediatric Population
NETTER-P
Safety data are available from 9 pediatric patients in NETTER-P (NCT04711135), an international, multi- center, single-arm, open-label trial of patients with somatostatin receptor-positive tumors, including 4 patients with GEP-NETs. Patients received LUTATHERA 7.4 GBq (200 mCi) administered every 8 weeks concurrently with the recommended amino acid solution. Adverse reactions observed in NETTER-P were similar to those observed in adults treated with LUTATHERA.
8 Use in Specific Populations
8.4 Pediatric Use
Additions and/or revisions underlined:
Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors
The safety and effectiveness of LUTATHERA have been established in pediatric patients 12 years and older with somatostatin receptor-positive gastroenteropancreatic neuroendocrine (GEP-NET). Use of LUTATHERA for this indication is supported by evidence from an adequate and well-controlled study of LUTATHERA in adults with additional safety, pharmacokinetic, and dosimetry data in pediatric patients aged 12 years and older with somatostatin receptor-positive tumors, including 4 pediatric patients with GEP-NETs [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].
The risks of radiation exposure associated with LUTATHERA are greater in pediatric patients than in adult patients due to longer life expectancy. Continued follow-up is recommended for evaluation of long-term effects.
There was no clinically relevant difference in lutetium Lu 177 dotatate exposure in pediatric patients aged 13 to 16 years versus adult patients [see Clinical Pharmacology (12.3)].
The pharmacokinetic profile and safety of LUTATHERA in pediatric patients 12 years and older with baseline renal impairment have not been studied.
The safety and effectiveness of LUTATHERA have not been established in pediatric patients younger than 12 years old with somatostatin receptor-positive GEP-NET.
8.5 Geriatric Use
Additions and/or revisions underlined:
Of the 1325 patients treated with LUTATHERA in clinical trials, 438 patients (33%) were 65 years and older. No overall differences in safety or effectiveness were observed between older and younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
Risk From Radiation Exposure
Advise patients and/or caregivers to minimize radiation exposure to 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), Warnings and Precautions (5.1)].
Myelosuppression
Advise patients and/or caregivers to contact their healthcare provider for any signs or symptoms of myelosuppression or infection [see Warnings and Precautions (5.2)].
Secondary Myelodysplastic Syndrome and Leukemia
Advise patients and/or caregivers of the potential for secondary cancers, including myelodysplastic syndrome and acute leukemia [see Warnings and Precautions (5.3)].
Renal Toxicity
Advise patients and/or caregivers to hydrate and to urinate frequently before, on the day of, and the day after administration of LUTATHERA [see Warnings and Precautions (5.4)]. Advise patients to contact their healthcare provider for any signs or symptoms of renal toxicity [see Warnings and Precautions (5.4)].
Hepatotoxicity
Advise patients and/or caregivers of the need for periodic laboratory tests to monitor for hepatotoxicity [see Warnings and Precautions (5.5)]. Advise patients to contact their healthcare provider for any signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.5)].
Hypersensitivity
Advise patients and/or caregivers that LUTATHERA may cause hypersensitivity reactions, including angioedema, and to seek immediate medical attention for signs or symptoms of hypersensitivity [see Warnings and Precautions (5.6)].
Neuroendocrine Hormonal Crises
Advise patients and/or caregivers to contact their healthcare provider for signs or symptoms that may occur following tumor-related hormonal release [see Warnings and Precautions (5.7)].
03/07/2023 (SUPPL-26)
5 Warnings and Precautions
5.1 Risk from Radiation ExposureAdditions and/or revisions underlined:
LUTATHERA contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer.
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)].
Additions and/or revisions underlined:
In NETTER-1, myelosuppression occurred more frequently in patients receiving LUTATHERA with long- acting octreotide compared to patients receiving high-dose long-acting octreotide (all Grades/Grade 3 or 4): anemia (81%/0) versus (54%/1%); thrombocytopenia (53%/1%) versus (17%/0); and neutropenia (26%/3%) versus (11%/0). In NETTER-1, platelet nadir occurred at a median of 5.1 months following the first dose. Of the 59 patients who developed thrombocytopenia, 68% had platelet recovery to baseline or normal levels. The median time to platelet recovery was 2 months. Fifteen of the nineteen patients in whom platelet recovery was not documented had post-nadir platelet counts. Among these 15 patients, 5 improved to Grade 1, 9 to Grade 2, and 1 to Grade 3.
Monitor blood cell counts. Withhold dose, reduce dose, or permanently discontinue LUTATHERA based on the severity of myelosuppression [see Dosage and Administration (2.4)].
Additions and/or revisions underlined:
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 the reabsorption of lutetium Lu 177 dotatate through the proximal tubules and decrease the radiation dose to the kidneys. Advise patients to hydrate and to urinate frequently before, on the day of, and the day after administration of LUTATHERA
Monitor serum creatinine and calculated creatinine clearance. Withhold dose, reduce dose, or permanently discontinue LUTATHERA based on the severity of renal toxicity [see Dosage and Administration (2.4)].
Patients with baseline renal impairment may be at increased risk of toxicity due to increased radiation exposure [see Use in Specific Populations (8.6)].
Additions and/or revisions underlined:
In ERASMUS, 2 patients (< 1%) were reported to have hepatic tumor hemorrhage, edema, or necrosis, with one patient experiencing intrahepatic congestion and cholestasis. Patients with hepatic metastasis may be at increased risk of hepatotoxicity due to radiation exposure.
Monitor transaminases, bilirubin, serum albumin and international normalized ratio (INR) during treatment. Withhold dose, reduce dose, or permanently discontinue LUTATHERA based on the severity of hepatotoxicity [see Dosage and Administration (2.4)].
Additions and/or revisions underlined:
Based on its mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on LUTATHERA use in pregnant women. No animal studies using lutetium Lu 177 dotatate have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, radioactive emissions, including those from LUTATHERA, can cause fetal harm.
Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA [see Dosage and Administration (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 last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with LUTATHERA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
7 Drug Interactions
7.2 GlucocorticoidsSubsection title revised; Additions and/or revisions underlined:
Glucocorticoids can induce down-regulation of subtype 2 somatostatin receptors (SSTR2). Avoid repeated administration of high doses of glucocorticoids during treatment with LUTATHERA.
8 Use in Specific Populations
8.1 PregnancyAdditions and/or revisions underlined:
Risk Summary
Based on its mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on LUTATHERA use in pregnant women. No animal studies using lutetium Lu 177 dotatate have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, radioactive emissions, including those from LUTATHERA, can cause fetal harm. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Additions and/or revisions underlined:
Risk Summary
There are no data on the presence of lutetium Lu 177 dotatate in human milk, or its effects on the breastfed child or milk production. No lactation studies in animals were conducted. Because of the potential risk for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LUTATHERA and for 2.5 months after the last dose.
Additions and/or revisions underlined:
Based on mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA [see Use in Specific Populations (8.1)].
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with LUTATHERA and for 7 months after the last dose.
Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with LUTATHERA and for 4 months after the last dose [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)].
Infertility
The recommended cumulative dose of 29.6 GBq of LUTATHERA results in a radiation absorbed dose to the testes and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy [see Dosage and Administration (2.6)].
Additions and/or revisions underlined:
No dose adjustment is recommended for patients with baseline mild to moderate (creatinine clearance 30 to 89 mL/min by Cockcroft-Gault formula) renal impairment. However, patients with baseline mild or moderate renal impairment may be at greater risk of toxicity, including renal toxicity, due to increased radiation exposure.
Perform more frequent assessments of renal function in patients with baseline mild to moderate impairment. The pharmacokinetic profile and safety of LUTATHERA in patients with baseline severe renal impairment (creatinine clearance < 30 mL/min by Cockcroft-Gault formula) or end-stage renal disease have not been studied [see Warnings and Precautions (5.4)].
Additions and/or revisions underlined:
No dose adjustment is recommended for patients with baseline mild or moderate hepatic impairment. The pharmacokinetic profile and safety of LUTATHERA in patients with baseline severe hepatic impairment (total bilirubin > 3 times upper limit of normal, regardless of AST level) have not been studied.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or revisions underlined:
Risk From Radiation Exposure
Advise patients to minimize radiation exposure to 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), Warnings and Precautions (5.1)].
Myelosuppression
Advise patients to contact their healthcare provider for any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, or increased bleeding or bruising [see Warnings and Precautions (5.2)].
Secondary Myelodysplastic Syndrome and Leukemia
Advise patients of the potential for secondary cancers, including myelodysplastic syndrome and acute leukemia
[see Warnings and Precautions (5.3)].
Renal Toxicity
Advise patients to hydrate and to urinate frequently before, on the day of, and the day after administration of LUTATHERA [see Warnings and Precautions (5.4)]. Advise patients to contact their healthcare provider for any signs or symptoms of renal toxicity [see Warnings and Precautions (5.4)].
Hepatotoxicity
Advise patients of the need for periodic laboratory tests to monitor for hepatotoxicity [see Warnings and Precautions (5.5)]. Advise patients to contact their healthcare provider for any signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.5)].
Hypersensitivity
Advise patients that LUTATHERA may cause hypersensitivity reactions, including angioedema, and to seek immediate medical attention for signs or symptoms of hypersensitivity [see Warnings and Precautions (5.6)].
Neuroendocrine Hormonal Crises
Advise patients to contact their healthcare provider for signs or symptoms that may occur following tumor- related hormonal release, including severe flushing, diarrhea, bronchospasm, and hypotension [see Warnings and Precautions (5.7)].
Embryo-Fetal Toxicity
Advise pregnant women and males and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.1, 8.3)].
Advise females of reproductive potential to use effective contraception during treatment with LUTATHERA and for 7 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with LUTATHERA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
Lactation
Advise females not to breastfeed during treatment with LUTATHERA and for 2.5 months after the last dose
[see Use in Specific Populations (8.2)].
Infertility
Advise female and male patients that LUTATHERA may impair fertility [see Warnings and Precautions (5.9), Use in Specific Populations (8.3)].
06/13/2022 (SUPPL-23)
5 Warnings and Precautions
5.3 Secondary Myelodysplastic Syndrome and LeukemiaAdditions and/or revisions underlined:
In NETTER-1, with a median follow-up time of 76 months in the main study, myelodysplastic syndrome (MDS) was reported in 2.3% of patients receiving LUTATHERA with long-acting octreotide compared to no patients receiving high-dose long-acting octreotide.
In ERASMUS, 16 patients (2.0%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to onset was 29 months (9 to 45 months) for MDS and 55 months (32 to 125 months) for acute leukemia.
Additions and/or revisions underlined:
In ERASMUS, 2 patients (< 1%) were reported to have hepatic tumor hemorrhage, edema, or necrosis, with one patient experiencing intrahepatic congestion and cholestasis. Patients with hepatic metastasis may be at increased risk of hepatotoxicity due to radiation exposure.
Monitor transaminases, bilirubin and serum albumin during treatment. Withhold, reduce dose, or permanently discontinue LUTATHERA based on severity of hepatotoxicity [see Dosage and Administration (2.4)].
Newly added subsection:
Hypersensitivity reactions, including angioedema, occurred in patients treated with LUTATHERA [see Adverse Reactions (6.2)]. Monitor patients closely for signs and symptoms of hypersensitivity reactions, including anaphylaxis, during and following LUTATHERA administration for a minimum of 2 hours in a setting where cardiopulmonary resuscitation medication and equipment are available. Discontinue the infusion upon the first observation of any signs or symptoms consistent with a severe hypersensitivity reaction, and initiate appropriate therapy.
Premedicate patients with a history of Grade 1 or 2 hypersensitivity reactions to LUTATHERA before subsequent doses [see Dosage and Administration (2.3)]. Permanently discontinue LUTATHERA in patients who experience Grade 3 or 4 hypersensitivity reactions [see Dosage and Administration (2.4)].
Additions and/or revisions underlined:
Based on its mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on LUTATHERA use in pregnant women. No animal studies using lutetium Lu 177 dotatate have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radiopharmaceuticals, including LUTATHERA, have the potential to cause fetal harm.
…
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LUTATHERA and for 7 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with LUTATHERA and for 4 months after the final dose [see Use in Specific Populations (8.1, 8.3)].
6 Adverse Reactions
Addition of the following to the bulleted line listing:
Hypersensitivity Reactions [see Warnings and Precautions (5.6)]
Extensive changes; please refer to label
Newly added subsection:
The following adverse reactions have been identified during post approval use of LUTATHERA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune System Disorders: hypersensitivity reactions, including angioedema
8 Use in Specific Populations
8.1 PregnancyAdditions and/or revisions underlined:
Risk Summary
Based on its mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on LUTATHERA use in pregnant women. No animal studies using lutetium Lu 177 dotatate have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radiopharmaceuticals, including LUTATHERA, have the potential to cause fetal harm. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Additions and/or revisions underlined:
No dose adjustment is recommended for patients with mild or moderate hepatic impairment. The safety of LUTATHERA in patients with severe hepatic impairment (total bilirubin > 3 times upper limit of normal, regardless of AST level) has not been studied.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or revisions underlined:
…
Hypersensitivity
Advise patients that LUTATHERA may cause hypersensitivity reactions, including angioedema, and seek immediate medical attention for signs or symptoms of hypersensitivity [see Warnings and Precautions (5.6)].
Neuroendocrine Hormonal Crises
Advise patients to contact their healthcare provider for signs or symptoms that may occur following tumor- related hormonal release, including severe flushing, diarrhea, bronchospasm, and hypotension [see Warnings and Precautions (5.7)].
05/28/2020 (SUPPL-10)
5 Warnings and Precautions
Additions and/or revisions underlined:
5.1 Risk from Radiation Exposure
… 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 Myelosuppresion
… Monitor blood cell counts. Withhold, reduce dose, or permanently discontinue based on severity of myelosuppression [see Dosage and Administration (2.4)].
5.4 Renal Toxicity
… 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)].
5.5 Hepatotoxicity
… 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)].
5.7 Embryo-Fetal Toxicity
… Advise pregnant women of the potential risk to a fetus.
6 Adverse Reactions
‘Clinically significant’ replaces ‘serious’ above bulleted line listing.
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
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 …
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 greater than or equal to 5% All Grades or greater than or equal to 2% Grades 3- 4) 1
Table 5. Laboratory Abnormalities Occurring at Higher Incidence in Patients Receiving LUTATHERA and Long-Acting Octreotide Compared to Long- Acting Octreotide (Between Arm Difference of greater than or equal to 5% All Grades or greater than or equal to 2% Grades 3-4) *1
7 Drug Interactions
Newly added subsection:
7.2 Corticosteroids
Corticosteroids can induce down-regulation of subtype 2 somatostatin receptors (SST2). Avoid repeated administration of high-doses of glucocorticosteroids during treatment with LUTATHERA.