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lenvatinib
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.
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% |
| PPB |
98-99% (mainly to albumin) |
| Active metabolites |
yes |
| Inactive metabolites |
yes |
Plasma concentrations decline bi-exponentially following Cmax.
| Half-life |
28 hours (terminal) |
| Feces |
64% |
| Urine |
25% |
-
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 advanced renal cell carcinoma (RCC) following prior vascular endothelial growth factor (VEGF)-targeted therapy.
-
For the first-line treatment of adult patients with unresectable hepatocellular carcinoma (HCC).*
*Efficacy and safety data for Child-Pugh Class B and Class C are not available.
Emetogenic Potential:
Extravasation Potential: Not applicable
The following table lists adverse effects that occurred in ≥5% of patients in the phase III SELECT trial in DTC patients comparing lenvatinib vs placebo, where there was at least a 5% difference between arms. Severe adverse events from other studies or post-marketing are also included.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (rare) | E | |||
| Arterial thromboembolism (5%) (may be severe) | E | ||||
| Bradycardia (11%) | E | ||||
| Cardiotoxicity (5%) | E D | ||||
| Hypertension (73%) (44% severe) | E | ||||
| Hypotension (9%) | E | ||||
| Other - Artery dissection or aneurysm (rare) | L | ||||
| QT interval prolonged (12%) (2% severe) | E | ||||
| Venous thromboembolism (3%) (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%) (9% severe) | E | ||||
| Dry mouth (17%) | E | ||||
| Dyspepsia (13%) | E | ||||
| GI obstruction (rare) | E | ||||
| GI perforation (2% fistulas; may be severe) | E | ||||
| Mucositis (41%) (5% severe) | 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 (14%) | E D | ||||
| Hepatobiliary | ↓ albumin (49%) | E | |||
| ↑ Amylase / lipase (12%) (may be severe) | E | ||||
| Cholecystitis (rare) | E | ||||
| Hepatotoxicity (8%) (including hepatic encephalopathy) | E | ||||
| ↑ LFTs (52%) (4% severe) | E | ||||
| Pancreatitis (rare) | E | ||||
| Hypersensitivity | Hypersensitivity (rare) | E | |||
| Infection | Infection (12%) | E | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (40%) (low Ca, K, Na, Mg; 9% severe) | E | |||
| Hyperglycemia (53%) (<1% severe) | E | ||||
| Hypoglycemia (19%) (mild to moderate) | E | ||||
| Hypothyroidism (21%) | E D | ||||
| Other - ↑ TSH (61%) | 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 | ||||
| Posterior reversible encephalopathy syndrome (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 | ||||
* "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.
** 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 16-35 days. Serious complications, including aortic dissection, have been reported secondary to poorly controlled hypertension.
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. Arterial thromboembolic events were reported as well, including fatal cases.
Severe cases of artery dissection (with or without hypertension) and artery aneurysm (including rupture) have been reported in patients using VEGFR TKIs.
QT prolongation has been reported and may lead to severe ventricular arrhythmias, including Torsades de pointes.
Grade 3 or 4 renal failure was reported in up to 3% of patients, with the primary risk factor being dehydration secondary to diarrhea or vomiting. HCC Patients with baseline renal impairment had a higher incidence of fatigue, hypothyroidism, dehydration, diarrhea, decreased appetite, proteinuria and hepatic encephalopathy. These patients also had a higher incidence of renal reactions and arterial thromboembolic events.
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 perforation or fistulas have been reported, mainly in patients with prior surgery or radiotherapy. Reports of non-GI fistulae (e.g. respiratory, genitourinary, cutaneous) have been observed across various indications.
Wound healing complications, including fistula formation and wound dehiscence, may occur.
Severe tumour-related hemorrhage, including fatal intracranial hemorrhage in patients with brain metastases has been reported. Epistaxis and hematuria were the most frequently reported hemorrhagic events.
Posterior-reversible encephalopathy syndrome (PRES) has been reported rarely and may be associated with hypertension.
Refer to protocol by which the patient is being treated.
Lenvatinib is associated with a moderate emetic potential; antiemetics may be considered to prevent nausea and vomiting.
Blood pressure should be well controlled and electrolyte abnormalities should be corrected prior to starting treatment.
Adequate washout period is required between lenvatinib and other systemic anticancer treatments (e.g. sorafenib). In DTC and RCC studies, the minimum washout period was 3 weeks. In HCC, washout period from prior locoregional therapies was 4 weeks.
DTC patients:
lenvatinib 24 mg PO daily
RCC patients:
lenvatinib 18 mg PO daily in combination with everolimus 5 mg PO daily
HCC patients:
In patients with body weight (BW) of ≥60 kg: lenvatinib 12 mg PO daily
In patients with body weight (BW) of <60 kg: lenvatinib 8 mg PO daily
The dosing and dose modifications described here relate to lenvatinib use only.
Refer to the everolimus drug monograph for dosage modifications for RCC patients. For toxicities related to both lenvatinib and everolimus, reduce the lenvatinib dose first and then the everolimus dose.
Reduced doses should not be increased.
Dose Levels:
| Dose level |
Lenvatinib DTC / RCC monotherapy dose (mg daily) |
Lenvatinib RCC dose when in combination with everolimus (mg daily) |
≥60 kg BW Lenvatinib HCC dose (mg daily, unless otherwise stated) |
<60 kg BW Lenvatinib HCC dose (mg daily, unless otherwise stated) |
| 0 | 24 | 18 | 12 | 8 |
| -1 | 20 | 14 | 8+ | 4+ |
| -2 | 14 | 10 | 4 | 4 every other day |
| -3 | 10 | 8 | 4 every other day | Discontinue |
| -4 | Discontinue | N/A | ||
+ No dose adjustment required for first occurrence of hematologic toxicity or proteinuria
No recommendations are available for resuming lenvatinib in patients with grade 4 adverse reactions that resolve.
| 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 1 dose level ↓.* | |
| Grade 4, life-threatening | Discontinue | |
| Cardiotoxicity or hemorrhage | Grade 3 | Hold until recovery to ≤ grade 1 or baseline; resume at 1 dose level ↓* or discontinue depending on severity and persistence. |
| Grade 4 | Discontinue | |
| Nephrotoxicity or hepatotoxicity | Grade 3 | Hold until recovery to ≤ grade 1 or baseline; resume at 1 dose level ↓* or discontinue depending on severity and persistence. |
| Grade 4 | Discontinue | |
| Hepatic failure | Grade 3 or 4 | Discontinue |
| Proteinuria | ≥ 2 g proteinuria / 24 h (≥ 2+ on urine dipstick) | Hold until proteinuria < 2 g / 24 h; resume at 1 dose level ↓.*† |
| Nephrotic syndrome | Discontinue | |
| Nausea, vomiting, diarrhea** |
Persistent and intolerable Grade 2 or Grade 3 |
Hold until recovery to ≤ grade 1 or baseline; resume at 1 dose level ↓. |
| Grade 4 despite medical management | Discontinue | |
| QT prolongation | Grade 3 or 4 | Hold until recovery to ≤ grade 1 or baseline; resume at 1 dose level ↓.* |
| PRES | Any | Hold until resolved; resume at 1 dose level ↓* or discontinue depending on the severity and persistence of neurologic symptoms. |
| Arterial thromboembolism | Discontinue | |
| GI perforation or fistula | ||
| Wound healing complications | ||
| Other treatment-related toxicity |
Persistent and intolerable Grade 2 Or Grade 3 Or Grade 4 lab abnormalities considered non-life-threatening |
Medically manage. Hold until recovery to ≤ grade 1 or baseline; resume at 1 dose level ↓.*† |
|
Grade 4 (except lab abnormalities considered non-life-threatening) |
Discontinue | |
| Major surgery | Hold at least 6 days prior to scheduled surgery, 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 in order to reduce the risk of development of renal impairment or failure.
†For patients with HCC and hematologic toxicity or proteinuria, may restart when recovery to ≤ Grade 2.
Lenvatinib exposure increases in severe hepatic impairment.
|
Childs classification of hepatic impairment |
Starting dose DTC / RCC monotherapy (mg daily) |
Starting dose RCC when in combination with everolimus (mg daily) |
Starting Dose HCC (≥60 kg BW) (mg daily) |
Starting Dose HCC (<60 kg BW) (mg daily) |
|
A |
24 |
18 | 12 | 8 |
|
B |
24 |
18 | No data | |
|
C |
14 |
10 | No data: not recommended for use | |
Lenvatinib exposure increases with severe renal impairment.
|
Creatinine clearance (ml/min) |
Starting dose DTC / RCC monotherapy (mg daily) |
Starting dose RCC when in combination with everolimus (mg daily) |
Starting Dose HCC (≥60 kg BW) (mg daily) |
Starting Dose HCC (<60 kg BW) (mg daily) |
|
50-80 |
24 |
18 | 12 | 8 |
|
30-49 |
24 |
18 | 12 | 8 |
|
< 30 |
14 |
10 | No data | |
|
End stage renal failure |
No data: not recommended for use |
|||
No dosage adjustment is recommended. Use with caution and monitor patients closely.
In the DTC study, patients aged 75 and older had a higher incidence of toxicity, including severe and fatal adverse events, compared to younger patients, leading to treatment discontinuation (21% vs 14%). Patients 75 years or older were more likely to experience grade 3-4 hypertension, proteinuria, decreased appetite, and dehydration compared to patients < 65 years old.
In the RCC, study patients aged 65 and older had a higher incidence of cough, dyspnea, lethargy, nausea, peripheral swelling and vomiting compared to younger patients.
In the HCC study, patients ≥75 years appeared to have lower tolerability and were more likely to experience hypertension, proteinuria, decreased appetite, asthenia, dehydration, dizziness and hepatic encephalopathy. Arterial thromboembolic events also occurred at an increased incidence in this age group.
Body weight
In patients with DTC and RCC, no adjustment of starting dose is required based on body weight. In the DTC study, patients with body weight <60 kg had a higher incidence of hand-foot syndrome, proteinuria, severe electrolyte abnormalities and a trend towards severe anorexia.
Lenvatinib PK was affected by body weight in patients with HCC. Refer to the dosing section for starting doses.
No adjustment of starting dose is required 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.
In HCC patients, females had a higher incidence of hypertension, fatigue and ECG QT prolongation. Hepatic failure events were observed in male patients only.
No adjustment of starting dose is required based on race.
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.
In HCC patients, Asian patients had a higher incidence of proteinuria and hand-foot syndrome compared to Caucasian patients, while Caucasian patients had a higher incidence of fatigue, hepatic encephalopathy and acute kidney injury, anxiety, asthenia, thrombocytopenia, and vomiting.
Safety and efficacy have not been established in pediatric patients. Animal studies suggest the potential for impaired bone growth in children. Lenvatinib should not be used in children younger than 2 years of age.
-
Lenvatinib should be taken at the same time daily, with or without food.
-
Capsules should be swallowed whole with water.
-
If the patient has difficulty swallowing, capsule(s) may be added (without breaking or crushing) to a tablespoon of water or apple juice in a small glass. Capsule(s) should be left in the liquid for at least 10 minutes and stirred for at least 3 minutes to allow the capsule shell(s) to dissolve. The entire suspension should then be swallowed. After drinking, the glass should be filled with the same amount of water or apple juice, swirled a few times, then additional liquid should be swallowed.
-
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.
- Patients who have a hypersensitivity to this drug or to any ingredient in the formulation or component of the container.
-
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.
-
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.
-
Use lenvatinib with caution in patients who are at risk for, or have a history of cardiac events or arterial thromboembolism. 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.
-
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:
Likely
Observed in animal studies.
Breastfeeding is not recommended.
-
Fertility effects:
Likely
Animal studies suggest decreased male and female fertility.
Lenvatinib is extensively metabolized by CYP3A4. In vitro studies indicate that lenvatinib inhibits CYP 2C8, 1A2, 2B6, 2C9, 2C19, 2D6 and 3A4. 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 | For DTC and RCC, use a minimum washout period of 3 weeks. For HCC, use a minimum washout period of 4 weeks after locoregional therapies |
| 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 phosphate 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 |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Blood pressure |
Baseline, after 1 week, then every 2 weeks for the first 2 months, monthly thereafter while on treatment |
CBC |
Baseline and at each visit |
ECG |
Baseline and as clinically indicated |
Liver function tests |
Baseline, every 2 weeks for the first 2 months, then monthly during treatment |
Renal function tests |
Baseline and at each visit |
Urine protein |
Baseline and at each visit |
TSH levels |
Baseline and monthly during treatment |
Serum calcium and electrolytes |
Baseline, at least monthly and as clinically indicated |
Clinical toxicity assessment for GI effects, infection, wound healing complications, bleeding, hypertension, thromboembolism, cardiac and neurologic effects |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website)
- lenvatinib - For the treatment of patients with locally recurrent or metastatic, progressive, radioactive-iodine-refractory differentiated thyroid cancer (DTC) according to criteria
- lenvatinib - For the treatment of unresectable advanced hepatocellular carcinoma according to clinical criteria
- lenvatinib - In Combination with Pembrolizumab for First-Line Advanced or Metastatic Renal Cell Carcinoma
- lenvatinib - In Combination with Pembrolizumab for Advanced Endometrial Cancer
Lenvatinib product monograph, Eisai Limited. December 19, 2018
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.
Scott LJ. Lenvatinib: first global approval. Drugs 2015;75:553-560
Product Monograph Update: Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs). Health Canada InfoWatch, June 2020.
September 2023 Updated elimination section
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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