Lenvacent(Lenvatinib)

Therapeutic Group: Oncology

Presentation

Lenvacent 4: Each capsule contains Lenvatinib mesylate INN equivalent to Lenvatinib 4 mg.

Lenvacent 10: Each capsule contains Lenvatinib mesylate INN equivalent to Lenvatinib 10mg.

Description

Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases 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; platelet-derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation. The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumor activity as demonstrated by decreases in human endothelial cell proliferation, tube formation, and VEGF signaling in vitro, and by decreases in tumor volume in mouse xenograft models of human renal cell cancer that were greater than those with either drug alone.

Indications

Lenvatinib is a kinase inhibitor that is indicated:

• 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 anti-angiogenic therapy.

• For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC).

Dosage & Administration

• DTC: The recommended dosage is 24 mg orally once daily.
• RCC: The recommended dosage is 18 mg orally once daily with everolimus 5 mg orally once daily.
• 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, palmar-plantar 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.

Precautions

• Hypertension: Blood pressure should be controlled and monitered prior to treatment and during treatment. Lenvatinib should be withheld for Grade 3 hypertension despite optimal antihypertensive therapy. For Grade 4 hypertension Lenvatinib should be discontinued.
• Cardiac Dysfunction: Patients should be monitored for clinical symptoms or signs of cardiac dysfunction. Lenvatinib should be withheld or discontinued for Grade 3 cardiac dysfunction. For Grade 4 cardiac dysfunction Lenvatinib should be discontinued.
• Arterial Thromboembolic Events: Lenvatinib should be discontinued following an arterial thromboembolic event.
• Hepatotoxicity: Liver function should be monitored prior to treatment and periodically during treatment. Lenvatinib should be withheld or discontinued for Grade 3 or 4
hepatotoxicity. For hepatic failure, Lenvatinib should be discontinued.
• Renal Failure or Impairment: Lenvatinib should be withheld or discontinued for Grade 3 or 4 renal failure or impairment.
• Proteinuria: Proteinuria should be monitored prior to treatment and periodically during treatment. Lenvatinib should be withheld for 2 or more grams of proteinuria per 24 hours. For nephrotic syndrome Lenvatinib should be discontinued.
• Diarrhea: May be severe and recurrent. Promptly management for severe diarrhea
should be initiated. Lenvatinib should be withheld or discontinued based on severity.
• Fistula Formation and Gastrointestinal Perforation: Lenvatinib should be discontinued in patients who develop Grade 3 or 4 fistula or any Grade gastrointestinal perforation.
• QT Interval Prolongation: Electrolyte abnormalities should be monitored and corrected. Lenvatinib should be withheld for QT interval greater than 500 ms or for 60 ms or a greater increase in baseline QT interval.
• Hypocalcemia: Blood calcium levels should be monitored at least monthly and calcium should be replaced as necessary. Lenvatinib should be withheld or discontinued
based on severity.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Lenvatinib should be withheld for RPLS until fully resolved or should be discontinued.
• Hemorrhagic Events: Lenvatinib should be withheld or discontinued based on severity.
• Impairment of Thyroid Stimulating Hormone
Suppression/Thyroid Dysfunction:
Thyroid function should be monitored prior to treatment and monthly during treatment.

Wound Healing Complications: Lenvatinib should be withheld before surgery. Lenvatinib should be discontinued in patients with wound healing complications.
• Embryo-Fetal Toxicity: Lenvatinib can cause fetal harm. Patients should be advised of the potential risks to a fetus and the use of effective contraception.

Use in Pregnancy & Lactation

There are no available human data informing the drug-associated risk. Pregnant women should be advised of the potential risk to a fetus. It is not known whether lenvatinib is present in human milk. Because of the potential for serious adverse reactions in breastfed infants, women should be advised to discontinue breastfeeding during treatment with lenvatinib and for at least 1 week after the last dose.

Drug Interaction

Drugs That Prolong the QT Interval: Lenvatinib has been reported to prolong the QT/QTc interval. Coadministration of Lenvatinib shoud be avoided with medicinal products with a known potential to prolong the QT/QTc interval

Storage

Do not store above 30 0C. Keep away from light and out of the reach of children

Commercial Pack

Lenvacent 4: Each bottle contains 30 capsules.
Lenvacent 10:Each bottle contains 30 capsules.
Lenvacent 4: Each box contains 3 blister strips of 4 capsules.
Lenvacent 10: Each box contains 3 blister strips of 4 capsules

Others

Pediatric Use
The safety and effectiveness of lenvatinib in pediatric patients have not been established.

Geriatric Use
No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Hepatic Impairment
Dose adjustment is not recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate or severe hepatic impairment. Dose adjustment is not recommended for patients with DTC or RCC and mild or moderate hepatic impairment (Child-Pugh A or B). Lenvatinib concentrations may increase in patients with DTC or RCC and severe hepatic impairment (Child-Pugh C).
The dose should be reduced for patients with DTC or RCC and severe hepatic impairment.

Renal Impairment
Dose adjustment is not recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. Lenvatinib concentrations may increase
in patients with DTC or RCC and severe (CLcr 15-29 mL/min) renal impairment. The dose should be reduced for patients with RCC or DTC and severe renal impairment. There is no recommended dose of Lenvatinib for patients with HCC and severe renal impairment. Lenvatinib has not been studied in patients with end-stage renal disease.