Drug Safety-related Labeling Changes (SrLC)
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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.
LENVIMA (NDA-206947)
(LENVATINIB MESYLATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
11/20/2024 (SUPPL-32)
04/03/2024 (SUPPL-30)
11/10/2022 (SUPPL-24)
08/05/2022 (SUPPL-25)
08/10/2021 (SUPPL-19)
07/21/2021 (SUPPL-20)
12/18/2020 (SUPPL-18)
09/14/2020 (SUPPL-17)
02/20/2020 (SUPPL-12)
12/07/2018 (SUPPL-9)
08/15/2018 (SUPPL-7)
5 Warnings and Precautions
5.1 Hypertension(subsection revised, additions underlined)
Hypertension occurred in 73% of patients in SELECT (DTC) receiving LENVIMA 24 mg orally once daily and in 45% of patients in REFLECT (HCC) receiving LENVIMA 8 mg or 12 mg orally once daily. The median time to onset of new or worsening hypertension was 16 days in SELECT and 26 days in REFLECT. Grade 3 hypertension occurred in 44% of patients in SELECT and in 24% in REFLECT. Grade 4 hypertension occurred <1% in SELECT and Grade 4 hypertension was not reported in REFLECT.
patients receiving LENVIMA 18 mg orally once daily with everolimus in InStudy 205 (RCC), hypertension was reported in 42% of patients LENVIMAand the median time to onset of new or worsening hypertension was 35 days. Grade 3 hypertension occurred in 13% of patients.
Systolic
blood pressure greater than or equal to160 mmHg occurred in 29% of patients and
diastolic blood pressure grfeater than or equal to100 mmHg occurred in 21%.
Serious complications of poorly controlled hypertension have been reported.
Control blood pressure prior to initiating LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or permanently discontinue LENVIMA based on severity.
(subsection revised, additions underlined)
In SELECT (DTC), Grade 3 to 4 hypocalcemia occurred in 9% of patients receiving LENVIMA. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction.
In Study 205 (RCC), Grade 3 to 4 hypocalcemia occurred in 6% of patients treated with LENVIMA with everolimus. In REFLECT (HCC), Grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients
Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue LENVIMA depending on severity.
(subsection revised; additions underlined)
Across clinical studies of 1823 patients who received LENVIMA as a single agent, reversible posterior leukoencephalopathy syndrome (RPLS) occurred in 0.3%.
Confirm the diagnosis of RPLS with magnetic resonance imaging. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA depending on severity and persistence of neurologic symptoms.
(subsection revised, additions underlined)
Serious including fatal hemorrhagic events can occur with LENVIMA. Across SELECT (DTC), Study 205 (RCC) and REFLECT (HCC), hemorrhagic events of any grade occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria.
In SELECT, Grade 3 to 5 hemorrhage occurred in 2% of patients receiving LENVIMA, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In Study 205, Grade 3 to 5 hemorrhage occurred in 8% of patients receiving LENVIMA with everolimus, including 1 fatal cerebral hemorrhage. In REFLECT, Grade 3 to 5 hemorrhage occurred in 5% of patients receiving LENVIMA, including 7 fatal hemorrhagic events.
Serious tumor related bleeds, including fatal hemorrhagic events, occurred in patients treated with LENVIMA in clinical trials and in the post-marketing setting. In post-marketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than in other tumor types. The safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.
Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue LENVIMA based on the severity.
(subsection revised, additions underlined)
LENVIMA impairs exogenous thyroid suppression. In SELECT (DTC), 88% of all patients had a baseline thyroid stimulating hormone (TSH) level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients.
Grade 1 or 2 hypothyroidism occurred in 24% of patients receiving LENVIMA
with everolimus in Study 205 (RCC) and in 21% of patients receiving LENVIMA in REFLECT (HCC). In those patients with a normal or low TSH at baseline, an elevation of TSH was observed post baseline in 70% of patients receiving LENVIMA in REFLECT and 60% of patients receiving LENVIMA with everolimus in Study 205.
Monitor thyroid function prior to initiating LENVIMA and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.
(additions underlined)
…
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.
(Subsection revised, additions underlined)
Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC or HCC, Grade 3 or higher cardiac dysfunction (including cardiomyopathy, left or right ventricular dysfunction, congestive heart failure, ventricular hypokinesia, or in left or right ventricular ejection fraction more than 20% from baseline) occurred in 3% of LENVIMA -treated patients.
Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity.
(subsection revised, additions underlined)
Among patients receiving LENVIMA or LENVIMA with everolimus, arterial thromboembolic events of any severity occurred in 2% ofpatients in Study 205 (RCC), 2% of patients in REFLECT (HCC) and 5% of patients in SELECT (DTC). Grade 3 to 5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials.
Permanently discontinue LENVIMA following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.
(subsection revised, additions underlined)
Across clinical studiesenrolling 1327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients.
In REFLECT (HCC), hepatic encephalopathy (including hepatic encephalopathy, encephalopathy, metabolic encephalopathy, and hepatic coma) occurred in 8% of LENVIMA-treated patients and 3% of sorafenib-treated patients Grade 3 to 5 hepatic encephalopathy occurred in 5% of LENVIMA-treated patientsand 2% of sorafenib-treated patients. Grade 3 to 5 hepatic failure occurred in 3% of LENVIMA-treated patients and 3% of sorafenib-treated patients. Two percent of patients discontinued LENVIMA and 0.2% discontinued sorafenib due to hepatic encephalopathy and 1% of patients discontinued lenvatinib or sorafenib due to hepatic failure.Monitor liver function prior to initiating LENVIMA, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity.
(subsection revised, additions underlined)
Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment occurred in 14% of patients receiving LENVIMA in SELECT (DTC) and in 7% of patients receiving LENVIMA in REFLECT (HCC). Grade 3 to 5 renal failure or impairment occurred in 3% (DTC) and 2% (HCC) of patients, including 1 fatality in each study.
In Study 205 (RCC), renal impairment or renal failure occurred in 18% of patients receiving LENVIMA with everolimus, including Grade 3 in 10% of patients.
Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA for renal failure or impairment based on severity.
(subsection revised, additions underlined)
Proteinuria occurred in 34% of LENVIMA-treated patients in SELECT (DTC) and in 26% of LENVIMA-treated patients in REFLECT (HCC). Grade 3 proteinuria occurred in 11% and 6% in SELECT and REFLECT, respectively. In Study 205 (RCC), proteinuria occurred in 31% of patients receiving LENVIMA with everolimus and 14% of patients receiving everolimus. Grade 3 proteinuria occurred in 8% of patients receiving LENVIMA with everolimus compared to 2% of patients receiving everolimus.
Monitor for proteinuria prior to initiating LENVIMA and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA on severity.
(subsection revised, additions underlined)
Of the 737 patients treated with LENVIMA in SELECT (DTC) and REFLECT (HCC), diarrhea occurred in 49% of patients, including Grade 3 in 6%.
In Study 205 (RCC), diarrhea occurred in 81% of patients receiving LENVIMA with everolimus, including Grade 3 in 19%. Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction.
Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA.
(subsection revised, additions underlined)
Of 799 patients treated with LENVIMA or LENVIMA with everolimus in SELECT (DTC), Study 205 (RCC) and REFLECT (HCC), fistula or gastrointestinal perforation occurred in 2%.
Permanently discontinue LENVIMA in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula.
(subsection revised, additions underlined)
In SELECT (DTC), QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%.In Study 205 (RCC), QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA with everolimus and QTc interval >500 ms occurred in 6%. In REFLECT (HCC), QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.
Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose of LENVIMA upon recovery based on severity.
6 Adverse Reactions
6.1 Clinical Trials Experience(extensive revisions and additions, please refer to label)
7 Drug Interactions
7.1 Drugs That Prolong the QT Interval(additions underlined)
LENVIMA has been reported to prolong the QT/QTc interval. Avoid coadministration of LENVIMA with medicinal products with a known potential to prolong the QT/QTc interval.
8 Use in Specific Populations
8.1 Pregnancy(additions underlined)
…
Data
Animal Data
In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses greater than or equal to 0.3 mg/kg [approximately 0.14 times the recommended clinical dose of 24 mg based on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies.
Greater than 80% postimplantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).
…
(additions underlined)
Risk Summary
It is not known whether LENVIMA is present in human milk; however, lenvatinib and its metabolites are excreted in rat milk at concentrations higher than those in maternal plasma (see Data). Because of the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment with LENVIMA and for at least 1 week after the last dose.
…
(additions underlined)
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating LENVIMA.
Contraception
Based on its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman.
Females
Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.
Infertility
LENVIMA may impair fertility in males and females of reproductive potential.
(additions underlined)
…
Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth retardation (decreased body weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) and secondary delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the human exposure based on AUC at the recommended clinical dose of 24 mg). Decreased length of the femur and tibia persisted following 4 weeks of recovery.
…
(additions underlined)
Of the 261 patients with differentiated thyroid cancer (DTC) who received LENVIMA in SELECT, 45% were greater than or equal to 65 years of age and 11% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
Of the 62 patients with renal cell carcinoma (RCC) who received LENVIMA with everolimus in Study 205, 36% were greater than or equal to 65 years of age. Conclusions are limited due to the small sample size, but there appeared to be no overall differences in safety or effectiveness between these subjects and younger subjects.
Of the 476 patients with hepatocellular carcinoma (HCC) who received LENVIMA in REFLECT, 44% were greater than or equal to 65 years of age and 12% were greater than or equal to75 years of age. No overall differences in safety or effectiveness were observed between patients greater than or equal to 65 and younger subjects. Patients greater than or equal to 75 years of age showed reduced tolerability to LENVIMA.
(additions underlined)
No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. Lenvatinib concentrations may increase in patients with DTC or RCC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with RCC or DTC and severe renal impairment.There is no recommended doseLENVIMA for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end stage renal disease.
(additions underlined)
No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate or severe hepatic impairment.
No dose adjustment is recommended for patients with DTC or RCC and mild or moderate hepatic impairment (Child-Pugh A or B). Lenvatinib concentrations may increase in patients with DTC or RCC and severe hepatic impairment (Child-Pugh C). Reduce the dose for patients with DTC or RCC and severe hepatic impairment.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(additions underlined)
…
Proteinuria and Renal Failure/Impairment
Advise patients that they will need to undergo regular laboratory tests to monitor kidney function and protein in the urine.
…
Hypocalcemia
Advise patients of the risks of hypocalcemia, that they will need to undergo laboratory tests to monitor calcium levels, and the potential requirement for calcium supplementation.
Reversible Posterior Leukoencephalopathy Syndrome
Advise patients of the signs and symptoms of RPLS and to contact their healthcare provider for new onset or worsening neurological function.
...
Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.
Lactation
Advise women to discontinue breastfeeding during treatment with LENVIMA and for at least 1 week after the last dose.