Lenvatinib

Uses

Lenvatinib is a kinase inhibitor that is used for:

• 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 patients with advanced renal cell carcinoma (RCC) following one prior antiangiogenic therapy.
• For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC).

Lenvatinib is also used to associated treatment for these conditions: Advanced Renal Cell Carcinoma, Locally recurrent radioactive iodine-refractory Thyroid cancer, Metastatic radioactive iodine-refractory Thyroid cancer, Progressive radioactive iodine-refractory Thyroid cancer

How Lenvatinib works

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET.

Dosage

Lenvatinib dosage

Differentiated thyroid cancer (DTC): The recommended dosage is 24 mg orally once daily.

Renal cell carcinoma (RCC): The recommended dosage is 18 mg orally once daily with everolimus 5 mg orally once daily.

Hepatocellular carcinoma (HCC): The recommended dosage is based on actual body weight:

• 12 mg orally once daily for patients greater than or equal to 60 kg
• 8 mg orally once daily for patients less than 60 kg.

Modify the recommended daily dose for certain patients with renal or hepatic impairment.

Side Effects

In DTC, the most common adverse reactions (incidence ≥30%) for lenvatinib are hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmarplantar erythrodysesthesia syndrome, abdominal pain, and dysphonia.

In RCC, the most common adverse reactions (incidence ≥30%) for lenvatinib and everolimus are diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, decreased weight, hemorrhagic events, and proteinuria.

In HCC, the most common adverse reactions (incidence ≥20%) for lenvatinib are hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea.

Toxicity

The most common adverse events that occurred in lenvatinib recipients were hypertension (67.8 vs. 9.2 % in the placebo group), diarrhea (59.4 vs. 8.4 %), fatigue or asthenia (59.0 vs. 27.5 %), decreased appetite (50.2 vs. 11.5 %), decreased bodyweight (46.4 vs. 9.2 %), nausea (41.0 vs. 13.7 %), stomatitis (35.6 vs. 3.8 %), palmar-plantar erythrodysethesia syndrome (31.8 vs. 8.0 %) and proteinuria (31.0 vs. 1.5 %). Adverse events that occurred in clinical trials and for which there is a warning/precaution in US manufacturer’s pre- scribing information were hypertension, cardiac dysfunction (decreased left or right ventricular function, cardiac failure or pulmonary edema), arterial thromboembolic events, hepatotoxicity, proteinuria, renal failure and impairment, gastrointestinal perforation and fistula formation, QT interval prolongation, hypocalcaemia, reversible posterior leucoencephalopathy syndrome, haemorrhagic events, and impairment of thyroid stimulating hormone (TSH) suppression. Based on the mechanism of action of lenvatinib and results from animal reproduction studies, which showed embryotoxicity, foetotoxicity and teratogenicity at lenvatinib doses below the recommended dose in humans, females of reproductive potential should be advised to use effective contraception during treatment and for at least 2 weeks following completion of therapy.

Precaution

Hypertension: Control blood pressure prior to treatment and monitor during treatment. Withhold for Grade 3 hypertension despite optimal antihypertensive therapy. Discontinue for Grade 4 hypertension.

Cardiac Dysfunction: Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold or discontinue for Grade 3 cardiac dysfunction. Discontinue for Grade 4 cardiac dysfunction.

Arterial Thromboembolic Events: Discontinue following an arterial thromboembolic event.

Hepatotoxicity: Monitor liver function prior to treatment and periodically during treatment. Withhold or discontinue for Grade 3 or 4 hepatotoxicity. Discontinue for hepatic failure.

Renal Failure or Impairment: Withhold or discontinue for Grade 3 or 4 renal failure or impairment.

Proteinuria: Monitor for proteinuria prior to treatment and periodicallyduring treatment. Withhold for 2 or more grams of proteinuria per 24hours. Discontinue for nephrotic syndrome.

Diarrhea: May be severe and recurrent. Promptly initiate management for severe diarrhea. Withhold or discontinue based on severity.

Fistula Formation and Gastrointestinal Perforation: Discontinue in patients who develop Grade 3 or 4 fistula or any Grade gastrointestinal perforation.

QT Interval Prolongation: Monitor and correct electrolyte abnormalities. Withhold for QT interval greater than 500 ms or for 60 ms or greater increase in baseline QT interval.

Hypocalcemia: Monitor blood calcium levels at least monthly and replace calcium as necessary. Withhold or discontinue based on severity

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Withhold for RPLS until fully resolved or discontinue.

Hemorrhagic Events: Withhold or discontinue based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction: Monitor thyroid function prior to treatment and monthly during treatment.

Wound Healing Complications: Withhold lenvatinib before surgery.Discontinue in patients with wound healing complications.

Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception.

Food Interaction

• Avoid hypertensive herbs (e.g. bayberry, blue cohosh, cayenne, ephedra, and licorice). Lenvatinib may cause hypertension as an adverse effect; therefore, there may be additive blood pressure elevation when using hypertensive herbs.
• Take at the same time every day.
• Take with or without food.

Lenvatinib Hypertension interaction

[Moderate] The use of lenvatinib may cause hypertension.

It is recommended to control blood pressure prior to treatment with lenvatinib and monitor blood pressure regularly during treatment as medically indicated.

Withhold treatment with lenvatinib for Grade 3 hypertension despite optimal antihypertensive therapy.

If clinically appropriate, resume at a reduced dose when hypertension is controlled and discontinue treatment for hypertension that becomes life-threatening.

Care and close monitoring of blood pressure is recommended.

Lenvatinib Drug Interaction

Moderate: lithiumUnknown: charcoal, mometasone, aspirin, LAC , loratadine, pembrolizumab, arginine, levocarnitine, cysteine, pantoprazole, acetaminophen, valproic acid, thiamine, cyanocobalamin, pyridoxine, cholecalciferol, phytonadione, menaquinone, rivaroxaban

Lenvatinib Disease Interaction

Moderate: arterial thromboembolism, bleeding, cardiac dysfunction, diarrhea, GI perforation, hepatic impairment, hypertension, hypocalcemia, hypothyroidism, proteinuria, QT prolongation, renal impairment, RPL syndrome, lung toxicity

Elimination Route

Time to peak plasma concentration occurred from 1 to 4 hours post­dose. Administration with food did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.

Half Life

The terminal elimination half­life of lenvatinib is approximately 28 hours.

Elimination Route

Following administration of a radiolabeled dose, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.

Pregnancy & Breastfeeding use

Lactation: Advise not to breastfeed.

Contraindication

None

Storage Condition

Store at 25°C; excursions permitted to 15-30°C

Innovators Monograph

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