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lenvatinib

( len VA ti nib )
Funding:
Exceptional Access Program
  • For the treatment of patients with locally recurrent or metastatic, progressive, radioactive-iodine-refractory differentiated thyroid cancer (DTC) according to criteria
Other Name(s): Lenvima (Eisai)
Appearance: capsule in various strengths, shapes and colours
A - Drug Name

lenvatinib

COMMON TRADE NAME(S):   Lenvima (Eisai)

 
B - Mechanism of Action and Pharmacokinetics

Lenvatinib is a multiple receptor tyrosine kinase inhibitor (TKI) that selectively inhibits vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4) as well as other proangiogenic and oncogenic pathway-related receptors.



Absorption

Lenvatinib is rapidly absorbed with a tmax reached 1 to 4 hours post-dose. Food slows the rate of absorption, but does not affect the extent of absorption.

Bioavailability

data from a mass-balance  study suggests about 85%


Distribution
PPB

98-99% (mainly to albumin)

Metabolism
Main enzymes involved

Oxidation by AO, demethylation via CYP3A4, GSH conjugation.

Active metabolites

yes

Inactive metabolites

yes

Elimination

Plasma concentrations decline bi-exponentially following Cmax.

Half-life

28 hours (terminal)

 
C - Indications and Status
Health Canada Approvals:

  • For the treatment of patients with locally recurrent or metastatic, progressive, radioactive-iodine refractory differentiated thyroid cancer (DTC). 
     
  • In combination with everolimus for the treatment of locally advanced renal cell carcinoma (RCC) following prior vascular endothelial growth factor (VEGF)-targeted therapy. 


 
D - Adverse Effects

Emetogenic Potential:  

Moderate

Extravasation Potential:   Not applicable

Adverse effects included are from the phase III SELECT trial in DTC patients in which lenvatinib was compared to placebo where there was at least a 5% difference between arms.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Arrhythmia (rare) E
Arterial thromboembolism (5%) E
Bradycardia (11%) E
Cardiotoxicity (5%) E  D
Hypertension (73%) (may be severe) E
Hypotension (9%) E
QT interval prolonged (12%) (2% severe) E
Venous thromboembolism (2%) (severe) E
Dermatological Alopecia (12%) E
Hand-foot syndrome (32%) E
Other (7%) (hyperkeratosis) E
Rash (19%) E
Gastrointestinal Abdominal pain (31%) E
Anorexia, weight loss (54%) E
Constipation (29%) E
Dehydration (9%) (may be severe) E
Diarrhea (67%) (may be severe) E
Dry mouth (17%) E
Dyspepsia (13%) E
GI obstruction (rare) E
GI perforation (also fistulas; rare) E
Mucositis (41%) E
Nausea, vomiting (47%) (may be severe) E
General Edema - limbs (21%) E
Fatigue (43%) E
Wound dehiscence (rare) E
Hematological Hemorrhage (35%) (2% severe) E
Myelosuppression ± infection, bleeding (1.5%) (severe) E
Hepatobiliary ↓ albumin (49%) E
↑ Amylase / lipase (12%) (may be severe) E
Cholecystitis (rare) E
↑ LFTs (52%) (may be severe) E
Hypersensitivity Hypersensitivity (rare) E
Infection Infection (12%) E
Metabolic / Endocrine Abnormal electrolyte(s) (40%) (low Ca, K, Na, Mg, may be severe) E
Hyperglycemia (53%) E
Hypothyroidism (61%) (increased TSH; hypothyroid in 5%) E  D
↑ Triglycerides (15%) E
Musculoskeletal Fracture (rare) D  L
Musculoskeletal pain (26%) E
Rhabdomyolysis (rare) E
Neoplastic Secondary malignancy (adenocarcinoma; rare) D  L
Nervous System Dizziness (15%) E
Dysgeusia (18%) E
Headache (38%) E
Insomnia (12%) E
PRES (rare) E
Seizure (rare) E
Ophthalmic Retinal vascular disorder (retinal vein thrombosis; rare) E
Renal Creatinine increased (87%) (3% severe) E
Proteinuria (34%) (may be severe) E
Respiratory Cough, dyspnea (24%) E
Dysphonia (31%) E
Pneumonitis (rare) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for lenvatinib include creatinine increased, hypertension, diarrhea, anorexia, weight loss, hyperglycemia, ↑ lfts, ↓ albumin, nausea, vomiting, fatigue and mucositis.

Hypertension was commonly reported and may be severe. Median time to onset was 16 days in DTC patients and 35 days in RCC patients receiving combination treatment. Blood pressure should be well controlled prior to starting treatment. Early detection and management of hypertension are important during treatment. See the dosage with toxicity section for management recommendations.

Cardiac failure was reported in in less than 1% of DTC patients, but decreases in left ventricular ejection fraction (LVEF) were seen in 5% of DTC patients and 10% of RCC patients receiving combination treatment. Patients should be monitored for signs and symptoms; dose modification may be required. Arterial thromboembolic events were reported as well, including fatal cases. Use lenvatinib with caution in patients who are at increased risk of cardiac events.

QT prolongation has been reported and may lead to severe ventricular arrhythmias, including Torsades de pointes. Lenvatinib is not recommended in patients with congenital long QT syndrome or those with risk factors for prolonged QT (see special precautions section). Electrolyte abnormalities should be corrected prior to starting treatment.

Grade 3 or 4 renal failure was reported in 3% of patients, with the primary risk factor being dehydration secondary to diarrhea or vomiting.

Proteinuria was common and may be severe. The median time to onset for RCC patients was 6 weeks for any grade and 20 weeks for grades 3 or 4. 

Lenvatinib impairs exogenous thyroid suppression and may elevate thyroid stimulating hormone (TSH) levels in both DTC and RCC patients. TSH should be monitored regularly and thyroid medication adjusted as required.

Diarrhea was reported more commonly in RCC patients on combination treatment (81%; 19% grade 3, 4).

Serious gastrointestinal peforation or fistulas have been reported, mainly in patients with prior surgery or radiotherapy.

Severe tumour-related hemorrhage, including fatal intracranial hemorrhage in patients with brain metastases has been reported.

Posterior-reversible encephalopathy syndrome (PRES) has been reported rarely and may be associated with hypertension. See the dosage with toxicity section for management recommendations.

 
E - Dosing

Refer to protocol by which the patient is being treated. Blood pressure should be well controlled and electrolyte abnormalities should be corrected prior to starting treatment.

Washout periods of 4 weeks after prior therapy such as sorafenib were used in the clinical trials. Carefully consider risk vs. benefit when tumour invasion of major blood vessels is present prior to treatment.



Adults:

DTC patients:

lenvatinib 24*mg PO daily

RCC patients:

lenvatinib 18*mg PO daily in combination with everolimus 5 mg PO daily

*available in 10 mg and 4 mg capsules

 

 


Dosage with Toxicity:

Dose level Lenvatinib DTC dose (mg daily) Lenvatinib RCC dose (mg daily)
0 24 18
-1 20 14
-2 14 10
-3 10 8
-4 Discontinue Discontinue

Lenvatinib may be delayed and/or dose reduced for toxicity as suggested below. Reduced doses should not be increased.

Refer to the everolimus drug monograph for dosage modifications for RCC patients. For toxicities related to both lenvatinib and everolimus, first dose reduce lenvatinib, then everolimus. 

 

 

Toxicity Severity Action
Hypertension ≥ 140/90 Treat with anti-hypertensives
  Grade 3 that persists despite optimal antihypertensive therapy Hold until recovery to ≤ grade 2, resume at one dose level reduction*
  Grade 4, life-threatening Discontinue
Cardiotoxicity or hemorrhage Grade 3 Hold until recovery to ≤ grade 1 or baseline, resume at one dose level reduction* or discontinue depending on severity and persistence.
  Grade 4 Discontinue
Arterial thromboembolism   Discontinue
Nephrotoxicity or hepatotoxicity Grade 3 Hold until recovery to ≤ grade 1 or baseline, resume at one dose level reduction* or discontinue depending on severity and persistence.
  Hepatic failure Discontinue
Proteinuria ≥ 2 g proteinuria / 24 h (≥ 2+ on urine dipstick) Hold until proteinuria < 2 g / 24 h, resume at one dose level reduction*
  Nephrotic syndrome Discontinue
GI perforation or fistula   Discontinue
Nausea, vomiting, diarrhea** Grade 3 Hold until recovery to ≤ grade 1 or baseline. Resume at one dose level reduction*
  Grade 4 despite medical management Discontinue
QT prolongation Grade 3 or 4 Hold until recovery to ≤ grade 1 or baseline, resume at one dose level reduction*
PRES   Hold until fully resolved. Resume at a reduced dose or discontinue depending on the severity and persistence of neurologic symptoms.
Other treatment-related toxicity Persistent and intolerable grade 2 or grade 3 Medically manage nausea/vomiting/diarrhea. Hold until recovery to ≤ grade 1 or baseline, resume at one dose level reduction*
  Grade 4 Discontinue
Major surgery   Hold temporarily. Resume after adequate wound healing.

*For each occurrence of toxicity, reduce dose in succession based on the previous dose level (see dose levels table). 

**Initiate prompt medical management



Dosage with Hepatic Impairment:

Lenvatinib exposure increases in severe hepatic impairment. 

Childs classification of hepatic impairment

Starting dose DTC patients

(mg daily) 

Starting dose RCC patients

(mg daily)

A

24

18

B

24

18

C

14

10


Dosage with Renal Impairment:

Lenvatinib exposure increases with severe renal impairment. 

Creatinine clearance (ml/min)

Starting dose DTC patients

(mg daily)

Starting dose RCC patients

(mg daily)

50-80

24

18

30-49

24

18

< 30

14

10

End stage renal failure

No data: not recommended for use

No data; not recommended for use


Dosage in the elderly:

Patients aged 75 and older had more toxicity, including fatal adverse events compared to younger patients. Hypertension, cough/dyspnea, fatigue, edema, proteinuria, anorexia, nausea/vomiting and dehydration were more common. No dosage adjustment is recommended. Use with caution and monitor patients closely.

 

Body weight

In the DTC study, patients with body weight less than 60 kg had a higher incidence of hand-foot syndrome, proteinuria, severe electrolyte abnormalities and a trend towards severe anorexia.



Dosage based on gender:

In the DTC study, females had a higher incidence of hypertension, including severe hypertension, proteinuria and hand-foot syndrome, while males had a higher incidence of cardiotoxicity, GI perforation and fistulas. In the RCC study, females had a higher incidence of hepatotoxicity, while males had a higher incidence of hemorrhage, nephrotoxicity, proteinuria and hand-foot syndrome. 



Dosage based on ethnicity:

In the DTC study, Asian patients had a higher incidence of peripheral edema, hypertension, fatigue, hand-foot syndrome, proteinuria, thrombocytopenia and elevated TSH levels compared to Caucasian patients.



Children:

Safety and efficacy have not been established in pediatric patients. Animal studies suggest the potential for impaired bone growth in children.

 



 
F - Administration Guidelines
  • Levnatinib should be taken at the same time daily, with or without food
  • Capsules should be swallowed whole with water
  • If a dose is missed and it cannot be taken within 12 hours, then that dose should be skipped and the next dose should be taken at the usual time
  • Lenvatinib should be stored between 15-30oC
 
G - Special Precautions
Contraindications:

  • Patients who have a hypersensitivity to this drug or any of its components
  • The degree of tumour invasion of major blood vessels should be considered prior to treatment given the potential risk of hemorrhage associated with tumour shrinkage.

Other Warnings/Precautions:

  • Lenvatinib is not recommended in patients with congenital long QT syndrome or those who are taking medications known to prolong the QT interval
  • Use with caution in patients at risk of prolonged QT, including females, aged ≥ 65 years, family history of sudden cardiac death at < 50 years of age, pre-existing cardiac disease, history of arrhythmias, electrolyte disturbances or conditions leading to electrolyte disturbances, bradycardia, acute neurological events, diabetes mellitus and autonomic neuropathy.
  • Lenvatinib has not been studied in patients with end stage renal disease or severe hepatic impairment
  • Use lenvatinib with caution in patients who are at risk for, or have a history of cardiac events. The drug has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.
  • Patients with prior surgery or radiotherapy are at increased risk of GI perforation or fistulas


Other Drug Properties:

  • Carcinogenicity: Unknown

    Carcinogenicity studies have not been conducted.

Pregnancy and Lactation:
  • Embryotoxicity: Yes
  • Fetotoxicity: Yes
  • Teratogenicity: Yes

    Lenvatinib is not recommended for use in pregnancy as it's likely to cause fetal harm. Highly effective contraception (including barrier method) should be used by both sexes during treatment, and for at least 1 month after the last dose.

  • Excretion into breast milk: Yes

    Breastfeeding is not recommended.

  • Fertility effects: Likely

    Animal studies suggest decreased male and female fertility.

 
H - Interactions

Lenvatinib is extensively metabolized by CYP3A4. The drug may be an inducer of CYP3A4 and PgP in the GI tract that could lead to decreased exposure to oral CYP3A4/PgP substrates. Lenvatinib inhibited UGT1A1 and UGT1A4 as well as OAT1, OAT3, OCT1, OCT2, OATP1B1 and BSEP. It is not considered a strong inducer or inhibitor P450 or UGT enzymes. 

Lenvatinib may be co-administered with CYP3A4 inhibitors and inducers, PGP inducers and inhibitors, BRCP inhibitors and drugs that effect gastric pH without dosage adjustment.

AGENT EFFECT MECHANISM MANAGEMENT
Use of lenvatinib immediately following sorafenib or other anticancer drugs Potential for additive toxicities Additive Use a minimal washout period of 4 weeks between anticancer drugs
Drugs decrease heart rate and/or prolong PR interval (e.g. antiarrhythmics, beta blockers, non-dihydropyridine Ca channel blockers, digoxin, some HIV protease inhibitors, sphingosine-1 phospate receptor modulators) Decreased heart rate, prolonged PR interval Additive Avoid if possible; monitor closely if used together
Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) Prolonged QT, Torsades de pointes Additive Avoid if possible; monitor closely if used together
CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) Reduced efficacy of substrate Lenvatinib may induce CYP3A4 Use with caution with substrates that have a narrow therapeutic index
P-glycoprotein substrates (i.e. verapamil, digoxin, morphine, ondansetron) Reduced efficacy of substrate Lenvatinib may induce PgP Use with caution with substrates that have a narrow therapeutic index
Drugs that disrupt electrolyte levels (i.e. loop/thiazide diuretics, laxatives, amphotericin B, high dose corticosteroids) Increased risk of arrhythmias Additive Avoid if possible; monitor closely if used together
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

 

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

Blood pressure

Baseline, after 1 week, then every 2 weeks for the first 2 months, monthly thereafter

CBC

Baseline and at each visit

ECG and electrolytes

Baseline and at each visit

Urine protein

Baseline and at each visit

TSH levels

Baseline and monthly during treatment

Liver function tests

Baseline, every 2 weeks for the first 2 months, then monthly during treatment

Clinical toxicity assessment for GI effects, infection, bleeding, hypertension, cardiac and neurologic effects

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
J - Supplementary Public Funding

Exceptional Access Program (EAP Website)

  • For the treatment of patients with locally recurrent or metastatic, progressive, radioactive-iodine-refractory differentiated thyroid cancer (DTC) according to criteria

 
K - References

Lenvatinib product monograph, Eisai Limited. Sept 11, 2017

Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015 Feb 12;372(7):621-30.
 


October 2017 added indication for RCC; updated adverse effects description, dosage and dosage with toxicity sections

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

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