CLASSES
Small Molecule Antineoplastic Multikinase Inhibitors
DESCRIPTION
Oral kinase inhibitor against multiple targets, including vascular endothelial growth factor receptors
Used for advanced endometrial cancer, radioactive iodine refractory differentiated thyroid cancer, advanced renal cell carcinoma, and unresectable hepatocellular carcinoma
May cause QT prolongation; avoid other drugs that cause QT prolongation
COMMON BRAND NAMES
LENVIMA
HOW SUPPLIED
LENVIMA Oral Cap: 4mg, 10mg, 4-10mg
DOSAGE & INDICATIONS
For the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).
Oral dosage
Adults
24 mg orally once daily with or without food until disease progression or unacceptable toxicity. In a multicenter, randomized, double-blind, placebo-controlled clinical trial, treatment with lenvatinib (n = 261) significantly improved progression free survival (18.3 months vs. 3.6 months) and objective response rate (65% vs. 2%) compared with placebo (n = 131) in patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer. Overall survival was not estimable in either group, with a hazard ratio of 0.73. Of note, 83% of patients randomly assigned to placebo crossed over to receive open-label lenvatinib upon progression, which may have affected overall survival.
For the treatment of renal cell cancer (RCC).
For the treatment of RCC in patients who received 1 prior anti-angiogenic therapy, in combination with everolimus.
Oral dosage
Adults
18 mg orally once daily, in combination with everolimus 5 mg orally once daily. Continue until disease progression or unacceptable toxicity. In a multicenter, open-label, phase 2 clinical trial, patients with advanced or metastatic renal cell carcinoma (RCC) who had received prior anti-angiogenic therapy were randomized to treatment with lenvatinib plus everolimus (combination therapy, n = 51), or everolimus monotherapy (10 mg per day, n = 50). The primary outcome of investigator-assessed median progression-free survival (PFS) was significantly improved in patients receiving combination therapy compared with everolimus monotherapy (14.6 months vs. 5.5 months); this was supported by a retrospective independent review of radiographs with an observed hazard ratio of 0.43 (95% CI, 0.24 to 0.75). Additionally, the median overall survival was 25.5 months with combination therapy compared with 15.4 months in patients treated with everolimus monotherapy (HR 0.67; 95% CI, 0.42 to 1.08) and the objective response rate was 37% versus 6%, respectively; all but one response (in a patient who received combination therapy) were partial responses.
For the first-line treatment of advanced RCC, in combination with pembrolizumab.
Oral dosage
Adults
20 mg orally once daily, in combination with pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks until disease progression or for up to 24 months in patients without disease progression). After 2 years of combination therapy, lenvatinib may be continued as a single agent until disease progression or unacceptable toxicity. The primary outcome of investigator-assessed median progression-free survival time was significantly improved with lenvatinib plus pembrolizumab compared with sunitinib (23.9 months vs. 9.2 months; hazard ratio (HR) = 0.39; 95% CI, 0.32 to 0.49; p less than 0.001) in patients with previously untreated advanced RCC with a clear-cell component in a 3-arm, randomized (1:1:1), phase 3 trial (the CLEAR trial; n = 1,069). At a median follow-up time of 26.6 month, the overall survival time was significantly longer in the lenvatinib plus pembrolizumab arm compared with the sunitinib arm (median time not reached in either arm; HR = 0.66; 95% CI, 0.49 to 0.88; P = 0.005).
For the first-line treatment of unresectable hepatocellular cancer (HCC).
Oral dosage
Adults weighing 60 kg or more (actual body weight)
12 mg PO once daily until disease progression or unacceptable toxicity. In a multicenter, randomized, open-label clinical trial of patients with previously untreated unresectable hepatocellular carcinoma (HCC), treatment with lenvatinib was noninferior to sorafenib therapy for overall survival (13.6 months vs. 12.3 months). Median progression-free survival (7.3 months vs. 3.6 months) and objective response rate (ORR) were significantly improved in the lenvatinib arm. The ORR was 41% in the lenvatinib arm compared with 12% in those treated with sorafenib using modified RECIST criteria (complete response (CR), 2.1% vs. 0.8%; partial response (PR), 38.5% vs. 11.6%). Using RECIST 1.1 criteria, the ORR was 19% versus 7%, respectively (CR, 0.4% vs. 0.2%; PR, 18.4% vs. 6.3%).
Adults weighing less than 60 kg (actual body weight)
8 mg PO once daily until disease progression or unacceptable toxicity. In a multicenter, randomized, open-label clinical trial of patients with previously untreated unresectable hepatocellular carcinoma (HCC), treatment with lenvatinib was noninferior to sorafenib therapy for overall survival (13.6 months vs. 12.3 months). Median progression-free survival (7.3 months vs. 3.6 months) and objective response rate (ORR) were significantly improved in the lenvatinib arm. The ORR was 41% in the lenvatinib arm compared with 12% in those treated with sorafenib using modified RECIST criteria (complete response (CR), 2.1% vs. 0.8%; partial response (PR), 38.5% vs. 11.6%). Using RECIST 1.1 criteria, the ORR was 19% versus 7%, respectively (CR, 0.4% vs. 0.2%; PR, 18.4% vs. 6.3%).
For the treatment of endometrial cancer.
For the treatment of advanced endometrial cancer that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H) in patients who are not candidates for curative surgery or radiation, with disease progression following prior systemic therapy in any setting, in combination with pembrolizumab.
NOTE: Select patients for treatment based on MSI-H or MMR status in tumor specimens.
Oral dosage
Adults
20 mg PO once daily until disease progression, in combination with pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks until disease progression or for up to 24 months in patients without disease progression). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with pembrolizumab plus lenvatinib significantly improved the median progression-free survival (6.6 months vs. 3.8 months) and overall survival (17.4 months vs. 12 months) compared with doxorubicin or paclitaxel in patients with advanced endometrial cancer who had been previously treated with at least one prior platinum-based chemotherapy regimen in any setting and were pMMR or not MSI-H in a multicenter, randomized, open-label clinical trial (KEYNOTE-775). The objective response rate was also significantly improved in the pembrolizumab/lenvatinib arm (30% vs. 15%; complete response, 5% vs. 3%) for a median duration of 9.2 months versus 5.7 months, respectively.
MAXIMUM DOSAGE
Adults
Differentiated Thyroid Cancer (DTC), 24 mg per day PO.
Renal Cell Carcinoma (RCC), 18 mg per day PO.
Hepatocellular Carcinoma (HCC), 12 mg per day PO.
Geriatric
Differentiated Thyroid Cancer (DTC), 24 mg per day PO.
Renal Cell Carcinoma (RCC), 18 mg per day PO.
Hepatocellular Carcinoma (HCC), 12 mg per day PO.
Adolescents
Safety and efficacy have not been established.
Children
Safety and efficacy have not been established.
Infants
Safety and efficacy have not been established.
Neonates
Safety and efficacy have not been established.
DOSING CONSIDERATIONS
Hepatic Impairment
Baseline Hepatic Impairment
Mild-to-moderate hepatic impairment (Child-Pugh Class A or B): no dosage adjustment needed for patients with DTC or RCC. There is no recommended dose for patients with HCC who have moderate hepatic impairment.
Severe hepatic impairment (Child-Pugh Class C): Reduce the starting dose for DTC to 14 mg PO once daily; reduce the starting dose for endometrial cancer and RCC to 10 mg PO once daily. There is no recommended dose for patients with HCC who have severe hepatic impairment.
Treatment-Related Hepatotoxicity
Grade 3 or 4 hepatotoxicity: Hold lenvatinib therapy. When hepatic function improves to grade 0, 1, or baseline, either resume lenvatinib therapy at a reduced dose per the above recommendations, or discontinue therapy depending on severity and persistence of hepatotoxicity. For RCC patients receiving combination therapy with everolimus, adjust or discontinue only the everolimus therapy if the toxicity is thought to be solely due to everolimus. If the toxicity is likely related to both lenvatinib and everolimus, first reduce lenvatinib and then everolimus.
Hepatic failure: Permanently discontinue lenvatinib.[58782]
Renal Impairment
Baseline Renal Impairment
CrCL greater than or equal to 30 mL/min: no dosage adjustment needed.
CrCL less than 30 mL/min: Reduce the starting dose for DTC to 14 mg PO once daily; reduce the starting dose for endometrial cancer and RCC to 10 mg PO once daily. There is no recommended dose of lenvatinib for patients with HCC and severe renal impairment.
End-stage renal disease: Recommendations not available; patients with end-stage renal disease were not studied.
Treatment-Related Nephrotoxicity
Grade 3 or 4 renal impairment, or renal failure: Hold lenvatinib therapy. When renal function improves to grade 0, 1, or baseline, either resume lenvatinib therapy at a reduced dose per the above recommendations or discontinue therapy depending on the severity and persistence of renal impairment. For RCC patients receiving combination therapy with everolimus, adjust or discontinue only the everolimus therapy if the toxicity is thought to be solely due to everolimus. If the toxicity is likely related to both lenvatinib and everolimus, first reduce lenvatinib and then everolimus.
Proteinuria (2g or greater in 24 hours): Hold lenvatinib therapy. When there is less than or equal to 2 g of proteinuria per 24 hours, resume lenvatinib therapy at a reduced dose per the recommendations above.
Nephrotic syndrome: Permanently discontinue lenvatinib therapy.[58782]
ADMINISTRATION
Hazardous Drugs Classification
NIOSH (Draft) 2020 List: Table 2
Approved by FDA after NIOSH 2016 list published. The manufacturer recommends this drug be handled as a hazardous drug.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Emetic Risk
Moderate/High
Administer routine antiemetic prophylaxis prior to treatment.
Oral Administration
Lenvatinib may be taken with or without food. Take at the same time each day.
If a dose is missed, take it as soon as possible. If it cannot be taken within 12 hours, skip that dose and take the next dose at the usual time; do not take a double dose.
Capsules should be swallowed whole.
Other Administration Route(s)
Extemporaneous Compounding-Other
The compounded lenvatinib suspension is compatible with polypropylene syringes and with feeding tubes of at least 5 French diameter (polyvinyl chloride or polyurethane tube) and at least 6 French diameter (silicone tube).
Extemporaneous compounding instructions for lenvatinib suspension:
Place up to 5 capsules in a small container with a capacity of approximately 20 mL or a 20 mL syringe. Do not break or crush the capsules. If 6 capsules are required for a dose, follow these instructions using 3 capsules at a time.
Add 3 mL of water or apple juice to the container or syringe; if preparing the suspension for feeding tube administration, use water.
Wait 10 minutes for the outer shell of the capsule to disintegrate, and then stir or shake the mixture for 3 minutes until the capsules are fully disintegrated.
Administer the entire contents of the container or syringe.
Add an additional 2 mL of water or apple juice to the container or syringe using a second syringe or dropper.
Swirl or mix and administer this mixture.
Repeat this step at least once, and until there is no visible residue on the container or syringe.
Storage after preparation: Lenvatinib suspension may be stored under refrigeration at 36 to 46 degrees F (2 to 8 degrees C) for up to 24 hours in a covered container.
STORAGE
LENVIMA:
- Store at 77 degrees F; excursions permitted to 59-86 degrees F
CONTRAINDICATIONS / PRECAUTIONS
Bleeding, thyroid cancer
Bleeding events, including fatal intracranial hemorrhages, have been reported in patients treated with lenvatinib, either as monotherapy or in combination with everolimus. Serious tumor-related bleeds, including fatalities, have also occurred. In post-marketing experience, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid cancer (ATC) than in other tumor types; the safety and effectiveness of lenvatinib therapy in patients with ATC has not been demonstrated in clinical trials. Hold lenvatinib therapy and resume treatment at a reduced dose upon recovery, or permanently discontinue lenvatinib therapy based on the severity of the bleed. Consider the risk of severe or fatal hemorrhage associated with lenvatinib therapy if there is tumor invasion/infiltration of major blood vessels (e.g., carotid artery).[58782]
Hypertension
Use caution when treating patients with preexisting hypertension with lenvatinib. Lenvatinib may increase blood pressure in both hypertensive and non-hypertensive patients. Blood pressure should be controlled before starting lenvatinib therapy, and monitored 1 week after initiation of therapy, every 2 weeks for 2 months, and then at least monthly after that. Patients who develop hypertension may require blood pressure monitoring at more frequent intervals and medical management of hypertension. Lenvatinib therapy should be permanently discontinued in patients with life-threatening hypertension; temporary suspension of therapy is recommended in patients with grade 3 or higher hypertension not controlled with medical management. The median time to onset of new or worsening hypertension was 16 to 26 days in patients with differentiated thyroid cancer (DTC) or hepatocellular carcinoma (HCC) receiving monotherapy, and 35 days in renal cell carcinoma (RCC) patients treated with the combination of lenvatinib plus everolimus.[58782]
Cardiomyopathy, heart failure
Use lenvatinib with caution in patients with a history of heart failure. Serious and sometimes fatal cardiac dysfunction (e.g., cardiomyopathy, left or right ventricular dysfunction, decreased ejection fraction, cardiac failure, ventricular hypokinesia) has been reported with lenvatinib therapy. Monitor patients for signs and symptoms of cardiac decompensation; treatment interruption, dose reduction, or permanent discontinuation may be necessary. Additionally, heart failure or cardiomyopathy may increase the risk of prolonging the QT interval when using lenvatinib.[28432] [28457] [56592] [58782]
Cardiac disease, coronary artery disease, myocardial infarction, stroke, thromboembolic disease
Use lenvatinib with caution in patients with a history of cardiac disease, coronary artery disease, myocardial infarction, stroke, or thromboembolic disease. Arterial thromboembolic events have been reported with lenvatinib therapy; if this occurs, permanently discontinue lenvatinib treatment. The safety of resuming lenvatinib after an arterial thromboembolic event has not been established. Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Additionally, myocardial infarction or stroke may increase the risk of prolonging the QT interval when using lenvatinib.[28432] [28457] [56592] [58782]
Hepatic disease, hepatotoxicity
Hepatotoxicity, including hepatic failure, has been reported with lenvatinib therapy. Use lenvatinib with caution in patients with hepatic disease; an initial dosage adjustment may be necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary in patients who develop grade 3 or higher hepatotoxicity. Obtain liver function tests before starting treatment, every 2 weeks for the first 2 months, and at least monthly thereafter during treatment.
Dehydration, hypovolemia, renal disease, renal failure, renal impairment
Use lenvatinib with caution in patients with a history of renal disease, renal impairment, or renal failure; a dose reduction may be necessary in patients with a baseline creatinine clearance (CrCl) less than 30 mL/minute. Renal impairment and renal failure have been reported in patients treated with lenvatinib. One risk factor for severe renal impairment was dehydration or hypovolemia due to diarrhea and vomiting; diarrhea is also commonly reported with lenvatinib therapy. Initiate prompt medical management in patients who develop diarrhea and monitor for dehydration. Treatment interruption, dose reduction, or discontinuation of therapy may be necessary for patients who develop severe diarrhea or renal dysfunction.[58782]
Fistula, GI perforation
GI perforation and fistula formation have been reported in patients treated with lenvatinib. Discontinue lenvatinib therapy in patients who develop GI perforation or life-threatening fistula.
Apheresis, AV block, bradycardia, celiac disease, electrolyte imbalance, females, fever, geriatric, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, long QT syndrome, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, systemic lupus erythematosus (SLE)
Prolongation of the QT interval has been reported with lenvatinib treatment. Evaluate electrolytes at baseline and monitor periodically during therapy in all patients; correct any electrolyte imbalance as necessary. Additionally, serum calcium levels should be monitored at least monthly and replaced as needed. Use with caution and monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradycardia, or who are receiving medications known to prolong the QT interval (including Class Ia and III antiarrhythmics). Treatment interruption, dose reduction, or discontinuation may be necessary. Use lenvatinib with caution in patients with conditions that may increase the risk of QT prolongation including AV block, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.[28432] [28457] [56592] [58782]
Hypothyroidism, thyroid disease
Use lenvatinib with caution in patients with a history of thyroid disease, as lenvatinib impairs exogenous thyroid suppression. Hypothyroidism has been reported with lenvatinib therapy. Monitor thyroid function before initiation of lenvatinib therapy and at least monthly during treatment; treat hypothyroidism according to standard medical practice. Hypothyroidism may increase the risk of prolonging the QT interval when using lenvatinib.[28432] [28457] [56592] [58782]
Proteinuria
Proteinuria has been reported in patients treated with lenvatinib. Patients who develop 2 grams or more of proteinuria in 24 hours may require an interruption of therapy, dose reduction, or discontinuation of therapy. Permanently discontinue lenvatinib in patients with nephrotic syndrome. Monitor patients for the development of proteinuria with urinalysis before starting treatment and periodically throughout treatment. Patients with a 2+ protein or greater urine dipstick reading should undergo further assessment (e.g., a 24-hour urine collection).
Impaired wound healing, surgery
Impaired wound healing has been reported in patients treated with lenvatinib. Therefore, temporarily hold lenvatinib therapy for at least 1 week before elective surgery; do not administer lenvatinib for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming lenvatinib after the resolution of wound healing complications has not been established.
Encephalopathy
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as Posterior Reversible Encephalopathy Syndrome (PRES), has been reported with lenvatinib use. Symptoms of RPLS include seizures, headache, visual disturbances, confusion, and altered mental status; this syndrome may be confirmed on magnetic resonance imaging. Hold lenvatinib therapy if RPLS is suspected. Upon complete resolution, resume treatment at a reduced dose or discontinue therapy, depending on the severity and persistence of neurologic symptoms.[58782]
Dental disease, dental work
Use lenvatinib with caution in patients with dental disease; osteonecrosis of the jaw (ONJ) has been reported in patients receiving lenvatinib. An oral examination should be performed prior to starting lenvatinib therapy and periodically during treatment; good oral hygiene practices should be encouraged. If possible, avoid invasive dental work while on lenvatinib treatment. Hold lenvatinib for at least 1 week prior to scheduled dental surgery or invasive dental procedures if possible; for patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may decrease the risk of ONJ. Hold lenvatinib if ONJ develops; restart treatment based on clinical judgement of adequate resolution. Exposure to risk factors such as dental disease, concurrent bisphosphonate or denosumab treatment, or invasive dental work may increase the risk of ONJ.
Pregnancy
Fetal harm may occur if lenvatinib is administered during pregnancy, based on animal studies. The use of effective contraception is recommended to avoid pregnancy during treatment and for 30 days following the last dose. No human data are available regarding teratogenic risk. Women who become pregnant while receiving lenvatinib should be apprised of the potential hazard to the fetus. During the period of organogenesis, exposures of 0.14 and 0.03 times the human exposure at the recommended dose resulted in reduced fetal body weights and an increased incidence of external, visceral, and skeletal variations in rats and rabbits, respectively. Post-implantation loss occurred in more than 80% of rats at approximately 0.5 times the recommended human dose based on BSA; increased post-implantation loss, including 1 fetal death, occurred at exposures of 0.03 times the recommended human dose based on BSA in rabbits. Additionally, late abortions occurred in approximately one-third of rabbits at approximately 0.5 times the recommended human dose based on BSA.[58782]
Contraception requirements, infertility, pregnancy testing, reproductive risk
Counsel patients about the reproductive risk and contraception requirements during lenvatinib treatment. Lenvatinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for 30 days after treatment with lenvatinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of lenvatinib. Women who become pregnant while receiving lenvatinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of lenvatinib on human fertility, male and female infertility has been observed in animal studies.[58782]
Breast-feeding
Due to the potential for serious adverse reactions in nursing infants from lenvatinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether lenvatinib is present in human milk, although many drugs are excreted in human milk.[58782]
ADVERSE REACTIONS
Severe
hypertension / Early / 13.0-45.0
diarrhea / Early / 4.0-19.0
fatigue / Early / 7.0-18.0
hyperamylasemia / Delayed / 0-17.0
elevated hepatic enzymes / Delayed / 3.0-17.0
thrombocytopenia / Delayed / 2.0-16.0
hypertriglyceridemia / Delayed / 0-15.0
weight loss / Delayed / 3.0-13.0
hyponatremia / Delayed / 0-12.0
QT prolongation / Rapid / 2.0-11.0
hypophosphatemia / Delayed / 0-11.0
hypercholesterolemia / Delayed / 0-11.0
proteinuria / Delayed / 6.0-11.0
dehydration / Delayed / 2.0-10.0
renal failure (unspecified) / Delayed / 2.0-10.0
lymphopenia / Delayed / 0-10.0
hyperkalemia / Delayed / 0-9.0
hypocalcemia / Delayed / 0.8-9.0
headache / Early / 0-9.0
bleeding / Early / 2.0-8.0
anemia / Delayed / 0-8.0
vomiting / Early / 0-7.0
anorexia / Delayed / 0-7.0
neutropenia / Delayed / 0-7.0
hyperglycemia / Delayed / 0-7.0
abdominal pain / Early / 2.0-6.0
hypokalemia / Delayed / 0-6.0
nausea / Early / 1.0-5.0
stomatitis / Delayed / 0-5.0
myalgia / Early / 1.0-5.0
arthralgia / Delayed / 1.0-5.0
rash / Early / 0-5.0
hepatic encephalopathy / Delayed / 0-5.0
dyspnea / Early / 0-5.0
stroke / Early / 0-5.0
myocardial infarction / Delayed / 0-5.0
musculoskeletal pain / Early / 0-4.0
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 3.0-4.0
ascites / Delayed / 0-4.0
pleural effusion / Delayed / 0-4.0
leukopenia / Delayed / 0-3.5
hepatic failure / Delayed / 0-3.0
hypoalbuminemia / Delayed / 0-3.0
heart failure / Delayed / 3.0-3.0
cardiomyopathy / Delayed / 3.0-3.0
pulmonary embolism / Delayed / 0-3.0
hypotension / Rapid / 0-2.0
GI perforation / Delayed / 2.0-2.0
hypomagnesemia / Delayed / 0-2.0
hypermagnesemia / Delayed / 0-2.0
infection / Delayed / 0-2.0
fever / Early / 0-2.0
insomnia / Early / 0-2.0
peripheral edema / Delayed / 0.4-2.0
hypoglycemia / Early / 0-2.0
constipation / Delayed / 0-1.0
intracranial bleeding / Delayed / 0-1.0
hypercalcemia / Delayed / 0-1.0
hypothyroidism / Delayed / 0-1.0
dyspepsia / Early / 0-0.4
xerostomia / Early / 0-0.4
dizziness / Early / 0-0.4
leukoencephalopathy / Delayed / 0.3-0.3
retinopathy / Delayed / Incidence not known
hypertensive crisis / Early / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
ocular hemorrhage / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
aortic dissection / Delayed / Incidence not known
thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
hematemesis / Delayed / Incidence not known
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
coma / Early / Incidence not known
hepatotoxicity / Delayed / Incidence not known
cholecystitis / Delayed / Incidence not known
pneumonitis / Delayed / Incidence not known
cardiac arrest / Early / Incidence not known
respiratory arrest / Rapid / Incidence not known
myocarditis / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
thromboembolism / Delayed / Incidence not known
nephrotic syndrome / Delayed / Incidence not known
interstitial nephritis / Delayed / Incidence not known
azotemia / Delayed / Incidence not known
oliguria / Early / Incidence not known
wound dehiscence / Delayed / Incidence not known
osteonecrosis / Delayed / Incidence not known
Moderate
hyperbilirubinemia / Delayed / 5.0-13.0
confusion / Early / 0-4.0
adrenocortical insufficiency / Delayed / 0-2.0
angina / Early / 0-1.0
glossitis / Early / Incidence not known
oral ulceration / Delayed / Incidence not known
bone pain / Delayed / Incidence not known
erythema / Early / Incidence not known
melena / Delayed / Incidence not known
hematuria / Delayed / Incidence not known
hemoptysis / Delayed / Incidence not known
hematoma / Early / Incidence not known
encephalopathy / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
cystitis / Delayed / Incidence not known
parotitis / Delayed / Incidence not known
impaired wound healing / Delayed / Incidence not known
Mild
cough / Delayed / 24.0-37.0
gastroesophageal reflux / Delayed / 0-21.0
dysgeusia / Early / 0-18.0
epistaxis / Delayed / 0-12.0
alopecia / Delayed / 0-12.0
hyperkeratosis / Delayed / 0-7.0
cheilitis / Delayed / Incidence not known
back pain / Delayed / Incidence not known
lethargy / Early / Incidence not known
malaise / Early / Incidence not known
asthenia / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known
petechiae / Delayed / Incidence not known
purpura / Delayed / Incidence not known
ecchymosis / Delayed / Incidence not known
gingivitis / Delayed / Incidence not known
weakness / Early / Incidence not known
DRUG INTERACTIONS
Adagrasib: (Major) Concomitant use of adagrasib and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Alfuzosin: (Major) Avoid coadministration of lenvatinib with alfuzosin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Based on electrophysiology studies performed by the manufacturer, alfuzosin may also prolong the QT interval in a dose-dependent manner.
Amiodarone: (Major) Avoid coadministration of lenvatinib with amiodarone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Amiodarone, a Class III antiarrhythmic agent, is also associated with a well-established risk of QT prolongation; although the frequency of torsade de pointes (TdP) is less with amiodarone than with other Class III agents, amiodarone is still also associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
Amisulpride: (Major) Avoid coadministration of lenvatinib with amisulpride due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Amisulpride causes dose- and concentration- dependent QT prolongation.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of lenvatinib with clarithromycin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Clarithromycin is also associated with an established risk for QT prolongation and torsade de pointes (TdP).
Anagrelide: (Major) Do not use anagrelide with lenvatinib due to the risk of QT prolongation. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Prolongation of the QT interval has been reported with lenvatinib therapy.
Apomorphine: (Major) Avoid coadministration of lenvatinib with apomorphine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aripiprazole: (Major) Concomitant use of lenvatinib and aripiprazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Arsenic Trioxide: (Major) Avoid coadministration of lenvatinib with arsenic trioxide due to the risk of QT prolongation. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Prolongation of the QT interval has also been reported with lenvatinib therapy.
Artemether; Lumefantrine: (Major) Avoid coadministration of lenvatinib with artemether due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Artemether; lumefantrine is also associated with prolongation of the QT interval and should be avoided in combination with other QT prolonging drugs. (Major) Avoid coadministration of lenvatinib with lumefantrine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Artemether; lumefantrine is also associated with prolongation of the QT interval and should be avoided in combination with other QT prolonging drugs.
Asenapine: (Major) Avoid coadministration of lenvatinib with asenapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Asenapine has also been associated with QT prolongation.
Atomoxetine: (Major) Concomitant use of lenvatinib and atomoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Azithromycin: (Major) Avoid coadministration of azithromycin with lenvatinib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Prolongation of the QT interval has been reported with lenvatinib therapy.
Bedaquiline: (Major) Avoid coadministration of lenvatinib with bedaquiline due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Bedaquiline has also been reported to prolong the QT interval. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Buprenorphine: (Major) Avoid coadministration of lenvatinib with buprenorphine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Buprenorphine; Naloxone: (Major) Avoid coadministration of lenvatinib with buprenorphine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Cabotegravir; Rilpivirine: (Major) Avoid coadministration of lenvatinib with rilpivirine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Ceritinib: (Major) Avoid coadministration of lenvatinib with ceritinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Ceritinib causes concentration-dependent QT prolongation.
Chloroquine: (Major) Avoid coadministration of chloroquine with lenvatinib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Prolongation of the QT interval has been reported with lenvatinib therapy.
Chlorpromazine: (Major) Avoid coadministration of lenvatinib with chlorpromazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Chlorpromazine, a phenothiazine, is also associated with an established risk of QT prolongation and torsade de pointes (TdP).
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciprofloxacin: (Major) Concomitant use of lenvatinib and ciprofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) Because of the potential for torsades de pointes (TdP), use of cisapride with lenvatinib is contraindicated. QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Prolongation of the QT interval has also been reported with lenvatinib therapy.
Citalopram: (Major) Concomitant use of lenvatinib and citalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clarithromycin: (Major) Avoid coadministration of lenvatinib with clarithromycin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Clarithromycin is also associated with an established risk for QT prolongation and torsade de pointes (TdP).
Clofazimine: (Major) Concomitant use of clofazimine and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clozapine: (Major) Avoid coadministration of lenvatinib with clozapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Treatment with clozapine has also been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of promethazine and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Codeine; Promethazine: (Major) Concomitant use of promethazine and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Crizotinib: (Major) Avoid coadministration of lenvatinib with crizotinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Crizotinib has been associated with concentration-dependent QT prolongation.
Dasatinib: (Major) Avoid coadministration of lenvatinib with dasatinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. In vitro studies have shown that dasatinib also has the potential to prolong the QT interval.
Degarelix: (Major) Avoid coadministration of lenvatinib with degarelix due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval.
Deutetrabenazine: (Major) Avoid coadministration of lenvatinib with deutetrabenazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dextromethorphan; Quinidine: (Major) Avoid coadministration of lenvatinib with quinidine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Quinidine administration is also associated with QT prolongation as well as torsade de pointes (TdP).
Disopyramide: (Major) Avoid coadministration of lenvatinib with disopyramide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Disopyramide administration is also associated with QT prolongation and torsade de pointes (TdP).
Dofetilide: (Major) Coadministration of dofetilide and lenvatinib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Prolongation of the QT interval has been reported with lenvatinib therapy.
Dolasetron: (Major) Avoid coadministration of lenvatinib with dolasetron due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Major) Avoid coadministration of lenvatinib with rilpivirine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Donepezil: (Major) Avoid coadministration of lenvatinib with donepezil due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Case reports indicate that QT prolongation and torsade de pointes (TdP) can also occur during donepezil therapy.
Donepezil; Memantine: (Major) Avoid coadministration of lenvatinib with donepezil due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Case reports indicate that QT prolongation and torsade de pointes (TdP) can also occur during donepezil therapy.
Dronedarone: (Contraindicated) Because of the potential for torsades de pointes (TdP), use of dronedarone with lenvatinib is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Prolongation of the QT interval has also been reported with lenvatinib therapy.
Droperidol: (Major) Avoid coadministration of lenvatinib with droperidol due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
Efavirenz: (Major) Avoid coadministration of lenvatinib with efavirenz due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QTc interval has also been observed with the use of efavirenz.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of lenvatinib with efavirenz due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QTc interval has also been observed with the use of efavirenz.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of lenvatinib with efavirenz due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QTc interval has also been observed with the use of efavirenz.
Eliglustat: (Major) Avoid coadministration of lenvatinib with eliglustat due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of lenvatinib with rilpivirine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of lenvatinib with rilpivirine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Encorafenib: (Major) Avoid coadministration of encorafenib and lenvatinib due to QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation was reported during clinical trials of lenvatinib.
Entrectinib: (Major) Avoid coadministration of entrectinib with lenvatinib due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Prolongation of the QT interval has also been reported with lenvatinib therapy.
Eribulin: (Major) Avoid coadministration of lenvatinib with eribulin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Eribulin has also been associated with QT prolongation.
Erythromycin: (Major) Concomitant use of lenvatinib and erythromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Escitalopram: (Major) Concomitant use of lenvatinib and escitalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fingolimod: (Major) Avoid coadministration of lenvatinib with fingolimod due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Although fingolimod has not been studied in patients treated with drugs that prolong the QT interval, drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Avoid coadministration of lenvatinib with flecainide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Fluconazole: (Major) Concomitant use of lenvatinib and fluconazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluoxetine: (Major) Concomitant use of lenvatinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluphenazine: (Minor) Use caution if coadministration of fluphenazine with lenvatinib is necessary. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as lenvatinib.
Fluvoxamine: (Major) Avoid coadministration of lenvatinib with fluvoxamine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation and torsade de pointes (TdP) have also been reported during fluvoxamine in postmarketing experience.
Foscarnet: (Major) Avoid coadministration of lenvatinib with foscarnet due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
Fostemsavir: (Major) Avoid coadministration of lenvatinib with fostemsavir due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gemifloxacin: (Major) Avoid coadministration of lenvatinib with gemifloxacin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) Avoid coadministration of lenvatinib with gemtuzumab due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
Gilteritinib: (Major) Avoid coadministration of lenvatinib with gilteritinib due to the potential for additive QT prolongation. Both drugs have been associated with QT prolongation.
Glasdegib: (Major) Avoid coadministration of lenvatinib with glasdegib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
Goserelin: (Major) Avoid coadministration of lenvatinib with goserelin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
Granisetron: (Major) Avoid coadministration of lenvatinib with granisetron due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Granisetron has also been associated with QT prolongation.
Halogenated Anesthetics: (Major) Avoid coadministration of lenvatinib with halogenated anesthetics due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Halogenated anesthetics can also prolong the QT interval.
Haloperidol: (Major) Avoid coadministration of lenvatinib with haloperidol due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation and torsade de pointes (TdP) have also been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
Histrelin: (Major) Avoid coadministration of lenvatinib with histrelin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
Hydroxychloroquine: (Major) Concomitant use of lenvatinib and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of lenvatinib and hydroxyzine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ibutilide: (Major) Avoid coadministration of lenvatinib with ibutilide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Ibutilide administration can also cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Iloperidone: (Major) Avoid coadministration of lenvatinib with iloperidone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Iloperidone has also been associated with QT prolongation.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of lenvatinib with inotuzumab due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Inotuzumab has also been associated with QT interval prolongation.
Itraconazole: (Major) Avoid coadministration of lenvatinib with itraconazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Itraconazole has also been associated with prolongation of the QT interval.
Ivosidenib: (Major) Avoid coadministration of lenvatinib with ivosidenib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QTc interval and ventricular arrhythmias have also been reported in patients treated with ivosidenib.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and lenvatinib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of lenvatinib with clarithromycin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Clarithromycin is also associated with an established risk for QT prolongation and torsade de pointes (TdP).
Lapatinib: (Major) Avoid coadministration of lenvatinib with lapatinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
Lefamulin: (Major) Avoid coadministration of lefamulin with lenvatinib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Prolongation of the QT interval has been reported with lenvatinib therapy.
Leuprolide: (Major) Avoid coadministration of lenvatinib with leuprolide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Avoid coadministration of lenvatinib with leuprolide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
Levofloxacin: (Major) Concomitant use of levofloxacin and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and lenvatinib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Lithium: (Major) Concomitant use of lithium and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Lofexidine: (Major) Avoid coadministration of lenvatinib with lofexidine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Lofexidine also prolongs the QT interval.
Loperamide: (Major) Avoid coadministration of lenvatinib with loperamide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Loperamide; Simethicone: (Major) Avoid coadministration of lenvatinib with loperamide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with lenvatinib due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Prolongation of the QT interval has also been reported with lenvatinib therapy.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as lenvatinib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. QT prolongation was also reported during clinical trials of lenvatinib.
Maprotiline: (Major) Avoid coadministration of lenvatinib with maprotiline due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
Mefloquine: (Major) Avoid coadministration of lenvatinib with mefloquine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
Meperidine; Promethazine: (Major) Concomitant use of promethazine and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Methadone: (Major) Avoid coadministration of lenvatinib with methadone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Methadone is also considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
Metronidazole: (Major) Concomitant use of metronidazole and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midostaurin: (Major) Avoid coadministration of lenvatinib with midostaurin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QT interval was also reported in patients who received midostaurin in clinical trials.
Mifepristone: (Major) Concomitant use of mifepristone and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mirtazapine: (Major) Concomitant use of lenvatinib and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mobocertinib: (Major) Concomitant use of mobocertinib and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Moxifloxacin: (Major) Avoid coadministration of lenvatinib with moxifloxacin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Quinolones have also been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
Nilotinib: (Major) Avoid coadministration of lenvatinib with nilotinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Octreotide: (Major) Avoid coadministration of lenvatinib with octreotide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
Ofloxacin: (Major) Concomitant use of ofloxacin and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Avoid coadministration of lenvatinib with olanzapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Major) Avoid coadministration of lenvatinib with olanzapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Major) Concomitant use of lenvatinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine; Samidorphan: (Major) Avoid coadministration of lenvatinib with olanzapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ondansetron: (Major) Concomitant use of ondansetron and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Osilodrostat: (Major) Avoid coadministration of lenvatinib with osilodrostat due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of lenvatinib with osimertinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
Oxaliplatin: (Major) Avoid coadministration of lenvatinib with oxaliplatin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking lenvatinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Prolongation of the QT interval has been reported with lenvatinib therapy.
Pacritinib: (Major) Concomitant use of pacritinib and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Paliperidone: (Major) Avoid coadministration of lenvatinib with paliperidone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of paliperidone overdose.
Panobinostat: (Major) Avoid coadministration of lenvatinib with panobinostat due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation has also been reported with panobinostat.
Pasireotide: (Major) Avoid coadministration of lenvatinib with pasireotide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QT interval has occurred with pasireotide at therapeutic and supra-therapeutic doses.
Pazopanib: (Major) Avoid coadministration of lenvatinib with pazopanib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Pazopanib has also been reported to prolong the QT interval.
Pentamidine: (Major) Avoid coadministration of lenvatinib with pentamidine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Systemic pentamidine has also been associated with QT prolongation.
Perphenazine: (Minor) Use caution if coadministration of perphenazine with lenvatinib is necessary. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as lenvatinib.
Perphenazine; Amitriptyline: (Minor) Use caution if coadministration of perphenazine with lenvatinib is necessary. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as lenvatinib.
Pimavanserin: (Major) Avoid coadministration of lenvatinib with pimavanserin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Pimavanserin may also cause QT prolongation.
Pimozide: (Contraindicated) Because of the potential for torsades de pointes (TdP), use of pimozide with lenvatinib is contraindicated. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Prolongation of the QT interval has been reported with lenvatinib therapy.
Pitolisant: (Major) Avoid coadministration of pitolisant with lenvatinib as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Prolongation of the QT interval has also been reported with lenvatinib therapy.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking lenvatinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Prolongation of the QT interval has been reported with lenvatinib therapy.
Posaconazole: (Major) Avoid coadministration of lenvatinib with posaconazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes.
Primaquine: (Major) Avoid coadministration of lenvatinib with primaquine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Primaquine also prolongs the QT interval.
Procainamide: (Major) Avoid coadministration of lenvatinib with procainamide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Prochlorperazine: (Minor) Use caution if coadministration of prochlorperazine with lenvatinib is necessary. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as lenvatinib.
Promethazine: (Major) Concomitant use of promethazine and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Dextromethorphan: (Major) Concomitant use of promethazine and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Phenylephrine: (Major) Concomitant use of promethazine and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propafenone: (Major) Concomitant use of propafenone and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quetiapine: (Major) Concomitant use of quetiapine and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quinidine: (Major) Avoid coadministration of lenvatinib with quinidine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Quinidine administration is also associated with QT prolongation as well as torsade de pointes (TdP).
Quinine: (Major) Avoid coadministration of lenvatinib with quinine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Quinine has also been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Ranolazine: (Major) Avoid coadministration of lenvatinib with ranolazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Relugolix: (Major) Avoid coadministration of lenvatinib with relugolix due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of lenvatinib with relugolix due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Ribociclib: (Major) Avoid coadministration of ribociclib with lenvatinib due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; QT prolongation was also reported during clinical trials of lenvatinib. Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with lenvatinib due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; QT prolongation was also reported during clinical trials of lenvatinib. Concomitant use may increase the risk for QT prolongation.
Rilpivirine: (Major) Avoid coadministration of lenvatinib with rilpivirine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Risperidone: (Major) Avoid coadministration of lenvatinib with risperidone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Risperidone has also been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP), primarily in the overdose setting.
Romidepsin: (Major) Avoid coadministration of lenvatinib with romidepsin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Romidepsin has also been reported to prolong the QT interval.
Saquinavir: (Major) Avoid coadministration of lenvatinib with saquinavir due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP).
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Selpercatinib: (Major) Avoid coadministration of lenvatinib with selpercatinib due to the risk of QT prolongation. Monitor ECGs more frequently for QT prolongation if coadministration is necessary. Prolongation of the QT interval has been reported with lenvatinib therapy. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
Sertraline: (Major) Concomitant use of sertraline and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Siponimod: (Major) Avoid coadministration of siponimod and lenvatinib due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Prolongation of the QT interval has been reported with lenvatinib therapy.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Solifenacin: (Major) Avoid coadministration of lenvatinib with solifenacin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Solifenacin has also been associated with dose-dependent prolongation of the QT interval; torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
Sorafenib: (Major) Avoid coadministration of lenvatinib with sorafenib due to the risk of additive QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Sorafenib is also associated with QTc prolongation.
Sotalol: (Major) Concomitant use of sotalol and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sunitinib: (Major) Avoid coadministration of lenvatinib with sunitinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Sunitinib can also prolong the QT interval.
Tacrolimus: (Major) Avoid coadministration of lenvatinib with tacrolimus due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tacrolimus also causes QT prolongation.
Tamoxifen: (Major) Concomitant use of tamoxifen and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Telavancin: (Major) Avoid coadministration of lenvatinib with telavancin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Telavancin also has been associated with QT prolongation.
Tetrabenazine: (Major) Avoid coadministration of lenvatinib with tetrabenazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tetrabenazine also causes a small increase in the corrected QT interval (QTc).
Thioridazine: (Contraindicated) Because of the potential for torsades de pointes (TdP), use of thioridazine with lenvatinib is contraindicated. Thioridazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP) and is contraindicated for use with other drugs that are known to prolong the QT interval. Prolongation of the QT interval has also been reported with lenvatinib therapy.
Tolterodine: (Major) Avoid coadministration of lenvatinib with tolterodine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Toremifene: (Major) Avoid coadministration of lenvatinib with toremifene due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
Trazodone: (Major) Concomitant use of trazodone and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Triclabendazole: (Major) Concomitant use of triclabendazole and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Trifluoperazine: (Minor) Use caution if coadministration of trifluoperazine with lenvatinib is necessary. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as lenvatinib.
Triptorelin: (Major) Avoid coadministration of lenvatinib with triptorelin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
Vandetanib: (Major) Avoid coadministration of lenvatinib with vandetanib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib.
Vardenafil: (Major) Concomitant use of vardenafil and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vemurafenib: (Major) Avoid coadministration of lenvatinib with vemurafenib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Vemurafenib has also been associated with QT prolongation.
Venlafaxine: (Major) Concomitant use of venlafaxine and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Voclosporin: (Major) Avoid concomitant use of lenvatinib and voclosporin due to the risk of additive QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of lenvatinib with clarithromycin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Clarithromycin is also associated with an established risk for QT prolongation and torsade de pointes (TdP).
Voriconazole: (Major) Avoid coadministration of lenvatinib with voriconazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Voriconazole has also been associated with QT prolongation and rare cases of torsade de pointes.
Vorinostat: (Major) Avoid coadministration of lenvatinib with vorinostat due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Vorinostat therapy is also associated with a risk of QT prolongation.
Ziprasidone: (Major) Avoid coadministration of lenvatinib with ziprasidone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.
PREGNANCY AND LACTATION
Pregnancy
Fetal harm may occur if lenvatinib is administered during pregnancy, based on animal studies. The use of effective contraception is recommended to avoid pregnancy during treatment and for 30 days following the last dose. No human data are available regarding teratogenic risk. Women who become pregnant while receiving lenvatinib should be apprised of the potential hazard to the fetus. During the period of organogenesis, exposures of 0.14 and 0.03 times the human exposure at the recommended dose resulted in reduced fetal body weights and an increased incidence of external, visceral, and skeletal variations in rats and rabbits, respectively. Post-implantation loss occurred in more than 80% of rats at approximately 0.5 times the recommended human dose based on BSA; increased post-implantation loss, including 1 fetal death, occurred at exposures of 0.03 times the recommended human dose based on BSA in rabbits. Additionally, late abortions occurred in approximately one-third of rabbits at approximately 0.5 times the recommended human dose based on BSA.[58782]
Counsel patients about the reproductive risk and contraception requirements during lenvatinib treatment. Lenvatinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for 30 days after treatment with lenvatinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of lenvatinib. Women who become pregnant while receiving lenvatinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of lenvatinib on human fertility, male and female infertility has been observed in animal studies.[58782]
MECHANISM OF ACTION
Lenvatinib is a kinase inhibitor, inhibiting the kinase activities of vascular endothelial growth factor receptor 1 (VEGFR1; FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression including fibroblast growth factor receptors 1 (FGFR1), FGFR2, FGFR3, and FGFR4, platelet-derived growth factor receptor alpha (PDGFR-alpha), KIT, and RET. It also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2 alpha (FRS2 alpha) phosphorylation. The combination of lenvatinib and everolimus showed increased anti-angiogenic and anti-tumor activity (decreased endothelial cell proliferation, tube formation, and VEGF signaling, as well as tumor volume) in mouse xenograft models of human renal cell carcinoma, greater than each drug alone.[58782]
PHARMACOKINETICS
Lenvatinib is administered orally. Lenvatinib is 97% to 99% bound in vitro to human plasma proteins independent of drug concentration; in vitro, the blood-to-plasma concentration ratio was 0.59 to 0.61 (0.1 to 10 micrograms/mL). The model-predicted geometric mean steady-state volume of distribution was 97 L (coefficient of variation (CV), 30.2%) and the terminal elimination half-life was approximately 28 hours. The main metabolic pathways are enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic. Radiolabeled lenvatinib was administered to 6 patients with solid tumors; after 10 days, approximately 64% and 25% of the dose were eliminated in the feces and urine, respectively.
A dose-response relationship has been observed for overall response rate over the range of 18 mg to 24 mg in patients with radioactive iodine-refractory differentiated thyroid cancer in a randomized clinical trial (n = 152). No dose-response relationships were observed for adverse reactions over the same dose range.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)
CYP3A is one of the main metabolic pathways for lenvatinib; in vitro, lenvatinib is also a P-gp and BCRP substrate. When administered with ketoconazole (a CYP3A, P-gp, and BCRP inhibitor) in a dedicated clinical trial, the AUC and Cmax of lenvatinib increased by 15% and 19%, respectively. Administration with rifampin as a single dose increased the AUC (31%) and Cmax (33%) of lenvatinib, but reduced the AUC by 18% when administered daily for 21 days (no change to the Cmax). The concomitant use of lenvatinib with midazolam, a sensitive CYP3A4 substrate, had no effect on the pharmacokinetic parameters of midazolam. Lenvatinib inhibits CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A in vitro; lenvatinib also induces CYP3A. Lenvatinib inhibits UGT1A1, UGT1A4, and UGT1A9 in vitro, but likely only inhibits UGT1A1 in vivo in the gastrointestinal tract based on the expression of the enzyme in tissues.[58782]
Oral Route
The geometric mean steady-state Cmax and AUC values were 323 nanogram (ng)/mL (coefficient of variation (CV), 33.3%) and 3,483 ng x hour/mL (CV, 34.7%), respectively, in 251 patients with differentiated thyroid cancer who received lenvatinib 24 mg/day. The Cmax values were 267 ng/mL (CV, 36.7%) and 275 ng/mL (CV, 32.6%) in patients with renal cell carcinoma who received lenvatinib 18 mg/day (n = 350) and 20 mg/day (n = 346), respectively; the AUC values were 3,148 ng x hour/mL (CV, 42.5%) and 3,135 ng x hour/mL (CV, 41.3%), respectively. The Cmax values were 154 ng/mL (CV, 25.4%) and 172 ng/mL (CV, 23.1%) in patients with hepatocellular carcinoma who received lenvatinib 8 mg/day (n = 150) and 12 mg/day (n = 318), respectively; the AUC values were 1,835 ng x hour/mL (CV, 34%) and 2,013 ng x hour/mL (CV, 29.3%), respectively. Cmax and AUC values increased proportionally over the dose range of 3.2 to 32 mg, with a median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg). Peak plasma concentrations of lenvatinib (Tmax) are observed 1 to 4 hours after oral administration.
Effect of food: Administration with a high-fat meal (approximately 900 calories; fat, 55%; protein, 15%; carbohydrates, 30%) does not affect the extent of absorption but decreases the rate of absorption and delays the median Tmax from 2 to 4 hours.