Levat10 mg

Levat is an oral multi-targeted tyrosine kinase inhibitor used in oncology. Its approved and guideline-supported indications, classified by evidence strength, are as follows.

FDA-approved / established indications

• Differentiated thyroid cancer (DTC): Treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, as a single agent.
• Hepatocellular carcinoma (HCC): First-line treatment of unresectable hepatocellular carcinoma, as a single agent.
• Renal cell carcinoma (RCC) - requires combination therapy:
  • First-line treatment of advanced renal cell carcinoma, in combination with pembrolizumab.
  • Treatment of advanced renal cell carcinoma following one prior anti-angiogenic therapy, in combination with everolimus.
• Endometrial carcinoma - requires combination therapy: Treatment of advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), in patients who have disease progression following prior systemic therapy and who are not candidates for curative surgery or radiation, in combination with pembrolizumab.

Levat is not indicated as monotherapy for renal cell carcinoma or endometrial carcinoma; it must be used together with the specified partner agent for these indications. Use outside these established indications should only occur within a clinical trial or under specialist oncology guidance.

Each capsule contains Lenvatinib Mesylate equivalent to Lenvatinib base (commonly available as 4 mg and 10 mg strengths, expressed as lenvatinib). Inactive ingredients vary by manufacturer; refer to the specific product's package insert for the complete excipient list.

Levat is the mesylate salt form of lenvatinib, an orally administered receptor tyrosine kinase inhibitor developed as an antineoplastic (anticancer) agent. It is formulated as oral capsules and is used in the treatment of several solid tumors, including differentiated thyroid cancer, hepatocellular carcinoma, renal cell carcinoma, and endometrial carcinoma.

Levat works primarily by inhibiting angiogenesis (new blood vessel formation) and tumor cell proliferation through blockade of multiple receptor tyrosine kinases.

Antineoplastic agent - Multi-targeted receptor tyrosine kinase inhibitor (anti-angiogenic agent)

Pharmacodynamics

Lenvatinib Mesylate inhibits the kinase activities of vascular endothelial growth factor receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic receptor tyrosine kinases including fibroblast growth factor receptors FGFR1, 2, 3, and 4, platelet-derived growth factor receptor alpha (PDGFRα), KIT, and RET. By blocking these pathways, Lenvatinib Mesylate reduces tumor angiogenesis and inhibits tumor cell growth.

Pharmacokinetics

• Absorption: Peak plasma concentrations are reached approximately 1 to 4 hours after oral dosing; can be taken with or without food.
• Distribution: Highly protein bound (approximately 98-99%).
• Metabolism: Primarily metabolized by CYP3A4 and by non-CYP mediated pathways (aldehyde oxidase).
• Elimination: Mean effective half-life is approximately 28 hours; eliminated mainly via feces, with a smaller portion via urine.

Levat capsules should be taken orally once daily at approximately the same time each day, with or without food, and swallowed whole with water. Capsules should not be opened or crushed unless the patient is unable to swallow capsules, in which case a physician-guided dispersion method may be used. Patients should be advised not to double the dose if a dose is missed and more than 12 hours have passed.

Levat has clinically significant interactions with the following classes of drugs.

• Strong CYP3A4/P-glycoprotein inhibitors (e.g. ketoconazole, itraconazole, ritonavir): may increase lenvatinib exposure and the risk of adverse reactions when co-administered with Levat; monitor closely and adjust dose if toxicity occurs.
• Strong CYP3A4/P-glycoprotein inducers (e.g. rifampin, carbamazepine, phenytoin, St. John's Wort): may decrease lenvatinib plasma concentrations and reduce efficacy; concomitant use should generally be avoided.
• QT-interval-prolonging drugs (e.g. certain antiarrhythmics, some antipsychotics, some antibiotics): additive risk of QT prolongation when used with Levat; electrocardiographic monitoring is advised with concomitant use.
• Other antihypertensive agents: since Levat itself commonly causes hypertension, concomitant antihypertensive therapy may need dose adjustment; conversely, uncontrolled hypertension may require additional antihypertensive medication during treatment.

Side effects of Levat are common, and many patients require dose modification. Reported reactions include the following.

Very common (may affect more than 1 in 10 people)

• Hypertension
• Diarrhea
• Fatigue and asthenia
• Decreased appetite and weight loss
• Nausea and vomiting
• Stomatitis and oral mucositis
• Palmar-plantar erythrodysesthesia (hand-foot syndrome)
• Proteinuria
• Hypothyroidism / increased thyroid-stimulating hormone
• Headache
• Dysphonia

Common but less frequent

• Abdominal pain, constipation
• Arthralgia/myalgia
• Rash, dry skin
• Dizziness
• Hemorrhagic events (e.g. epistaxis)

Serious reactions such as cardiac dysfunction, hepatotoxicity, renal failure, gastrointestinal perforation/fistula, and reversible posterior leukoencephalopathy syndrome can also occur; see Precautions and Warnings.

Levat can cause fetal harm based on its mechanism of action and findings in animal reproduction studies, which showed embryotoxicity, fetotoxicity, and teratogenicity at maternal exposures below the recommended human dose. Levat should not be used during pregnancy unless the potential benefit to the mother clearly justifies the potential risk to the fetus, and only under close specialist supervision. Females of reproductive potential should be advised to use effective contraception during treatment with Levat and for at least 30 days after the final dose; male patients with female partners of reproductive potential should also use effective contraception.

It is not known whether Levat or its metabolites pass into human breast milk. Because of the potential for serious adverse reactions in a breastfed infant, women should be advised not to breastfeed during treatment with Levat and for at least one week after the final dose. Always consult a physician before use in pregnancy or lactation.

Levat carries several serious risks that require close monitoring throughout treatment.

• Hypertension: Very common and can be severe; blood pressure should be well controlled before starting Levat and monitored regularly during treatment, with antihypertensive therapy or dose modification as needed.
• Cardiac dysfunction: Reduced left ventricular ejection fraction and heart failure have been reported; monitor for signs and symptoms of cardiac decompensation.
• Arterial thromboembolic events: Including myocardial infarction and stroke have occurred; use with caution in patients with prior thromboembolic events and discontinue after an arterial thrombotic event.
• Hepatotoxicity: Including hepatic failure and hepatic encephalopathy, some fatal; monitor liver function before and periodically during treatment.
• Renal failure and impairment: Monitor renal function during treatment; dose interruption or reduction may be required.
• Gastrointestinal perforation and fistula formation: Have been reported; discontinue Levat if this occurs.
• QT interval prolongation: Monitor electrocardiograms and electrolytes, particularly in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those taking drugs known to prolong the QT interval.
• Hemorrhagic events: Including severe and fatal hemorrhage have occurred; use with caution in patients at increased bleeding risk.
• Reversible posterior leukoencephalopathy syndrome (RPLS): A rare but serious neurological condition; if symptoms (headache, seizure, lethargy, confusion, visual disturbance) occur, discontinue temporarily or permanently as appropriate.
• Impairment of thyroid-stimulating hormone (TSH) suppression: Monitor TSH levels monthly and adjust thyroid replacement therapy as needed in thyroid cancer patients.
• Impaired wound healing: Withhold Levat for at least several days before scheduled surgery and until adequate wound healing has occurred.
• Embryo-fetal toxicity: See Pregnancy and Lactation.

There is no specific antidote for Levat overdose. In case of suspected overdose, discontinue Levat immediately and seek immediate medical attention or contact a poison control center. Management should include general supportive care and close monitoring for signs of toxicity such as severe hypertension, cardiac dysfunction, hepatotoxicity, or other adverse reactions, with treatment directed at the presenting symptoms as appropriate.

Store at room temperature (below 30°C), away from light and moisture. Keep out of reach of children.

• Hepatic impairment: Dose adjustment of Levat is recommended in patients with moderate to severe hepatic impairment; use with caution and enhanced monitoring.
• Renal impairment: Dose adjustment is recommended in patients with severe renal impairment; Levat has not been studied in patients with end-stage renal disease.
• Elderly patients: No overall differences in effectiveness were observed between elderly and younger patients, but elderly patients may be more susceptible to certain adverse reactions such as hypertension and fatigue; monitor closely.
• Women of reproductive potential: See Pregnancy and Lactation for contraception recommendations.
• Pediatric patients: See Pediatric Uses.

Antineoplastic agents; Multi-targeted receptor tyrosine kinase inhibitors (anti-angiogenic agents)

Lenvatinib Mesylate acts by inhibiting the kinase activity of vascular endothelial growth factor receptors (VEGFR1, VEGFR2, VEGFR3) as well as other receptor tyrosine kinases implicated in tumor growth and pathogenic angiogenesis, including fibroblast growth factor receptors (FGFR1-4), platelet-derived growth factor receptor alpha (PDGFRα), KIT, and RET. By simultaneously blocking these targets, Lenvatinib Mesylate suppresses new blood vessel formation that tumors require for growth and spread, and directly inhibits proliferation of tumor cells expressing these receptors, leading to reduced tumor growth.

The safety and effectiveness of Levat have not been established in pediatric patients for hepatocellular carcinoma, renal cell carcinoma, or endometrial carcinoma. Data in pediatric populations for other indications remain limited, and use in children should occur only within the context of a clinical trial or under the direct supervision of a pediatric oncology specialist, with careful individualized risk-benefit assessment. Levat is not recommended for routine use in children outside specialist oncology care.