Lenvatinib (Capsules) Instructions for Use

ATC Code

L01EX08 (Lenvatinib)

Active Substance

Lenvatinib (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; other protein kinase inhibitors

Pharmacological Action

Lenvatinib is an antitumor agent, a tyrosine kinase inhibitor. It selectively inhibits the kinase activity of vascular endothelial growth factor (VEGF) receptors – VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also exerts an inhibitory effect on other receptor tyrosine kinases involved in proangiogenic and oncogenic mechanisms, including fibroblast growth factor receptors (FGFR1, 2, 3, and 4), the platelet-derived growth factor receptor alpha (PDGFRα), as well as the KIT and RET receptor tyrosine kinases.

Enhanced antiangiogenic and antitumor activity was observed in preclinical models studying the combination of lenvatinib with everolimus.

The relationship between the onset of arterial hypertension during lenvatinib treatment and the features of its mechanism of action has not been specifically studied, but the development of hypertension is presumably associated with inhibition of the vascular endothelial growth factor receptor (VEGFR) type 2, VEGFR2. Similarly, the relationship between the features of lenvatinib’s mechanism of action and the development of proteinuria has not been studied; its occurrence is presumably due to inhibition of VEGFR1 and VEGFR2 receptors in the podocytes of the renal glomerulus.

The mechanism of lenvatinib’s effect on hypothyroidism is not fully understood.

Pharmacokinetics

Lenvatinib is rapidly absorbed after oral administration. C_max in blood plasma is reached approximately 1-4 hours after administration. Food intake does not affect the extent of absorption but slows the rate of this process. When the drug was taken with food by healthy volunteers, the time to reach C_max of the drug in blood plasma was delayed by 2 hours. The absolute bioavailability of lenvatinib in humans has not been determined, but mass balance study data suggest it is about 85%. Lenvatinib showed good bioavailability upon oral administration in dogs (70.4%) and monkeys (78.4%).

Under in vitro conditions, Lenvatinib demonstrated a high degree of binding to human plasma proteins, ranging from 98% to 99%. It binds primarily to albumin and to a lesser extent to alpha-1-acid glycoprotein and gamma-globulin. The ratio of lenvatinib concentration in vitro in whole blood to plasma ranged from 0.589 to 0.608 (0.1-10 µg/ml mesylate).

Lenvatinib is a substrate of P-glycoprotein and breast cancer resistance protein (BCRP) and is not a substrate of organic anion and cation transporter proteins (OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2) and the bile salt export pump (BSEP).

The median apparent V_d of the first dose in patients ranged from 50.5 L to 92 L and was generally dose-proportional in groups from 3.2 mg to 32 mg. Similarly, the median apparent V_d at steady state was generally dose-proportional and ranged from 43.2 L to 121 L.

In vitro studies have shown that the CYP3A4 isoenzyme is the predominant (>80%) cytochrome P450 isoform involved in the metabolism of lenvatinib. However, in vivo experiments have shown that the contribution of metabolic pathways other than P450-mediated is significant. Accordingly, in vivo inducers and inhibitors of the CYP3A4 isoenzyme had minimal impact on lenvatinib exposure.

A demethylated form of lenvatinib (M2), which is the main metabolite of the drug, was found in human liver cell microsomes. Metabolites M2′ and M3′ (found in human feces) are formed from M2 and lenvatinib, respectively, with the participation of aldehyde oxidase.

According to radiochromatographic analysis of blood plasma samples collected up to 24 hours after lenvatinib administration, unchanged Lenvatinib accounted for 97% of the radioactivity, while the M2 metabolite accounted for only 2.5%. Analysis of AUC_(0-inf) showed that lenvatinib radioactivity accounted for 60% and 64% of the total radioactivity in plasma and whole blood, respectively.

Mass balance and excretion studies of lenvatinib have shown that the drug undergoes active metabolism in the human body. The main identified metabolic pathways of the drug in humans include: aldehyde oxidase-mediated oxidation; demethylation involving the CYP3A4 isoenzyme; conjugation with glutathione upon elimination of the O-aryl (chlorobenzyl) group; and combinations of these mechanisms with further biotransformation, including glucuronidation, hydrolysis of the glutathione group, cleavage of the cysteine residue, and intramolecular rearrangement of cysteinyl-glycine and cysteine conjugates followed by dimerization. The identification of these metabolic mechanisms in vivo is consistent with the results of in vitro studies using human-derived biomaterials.

Lenvatinib showed minimal or absent inhibitory activity against P-glycoprotein-mediated and BCRP-mediated transport. Similarly, induction of P-glycoprotein and mRNA expression was not observed.

Lenvatinib showed minimal or no inhibitory effect on OATP1B3. Lenvatinib does not inhibit aldehyde oxidase activity in human liver cytosol.

After reaching C_max, the concentration of lenvatinib in blood plasma decreases biexponentially. The T_1/2 of lenvatinib in the elimination phase is approximately 28 hours.

After administration of labeled lenvatinib to 6 patients with solid tumors, approximately 2/3 of the administered dose was excreted via the intestine and 1/4 via the kidneys.

The predominant metabolite in excreta was metabolite M3 (about 17% of the dose), followed by metabolites M2′ (about 11% of the dose) and M2 (about 4.4% of the dose).

In patients with solid tumors receiving single and multiple doses of lenvatinib once daily, systemic exposure parameters (C_max and AUC) of the drug increased in direct proportion to the dose increase from 3.2 to 32 mg once daily.

Minimal accumulation of lenvatinib was observed at steady state.

Indications

Progressive locally advanced or metastatic differentiated (papillary, follicular, Hürthle cell) thyroid carcinoma refractory to radioactive iodine.

In combination with everolimus for the treatment of advanced renal cell carcinoma after one prior course of targeted therapy with vascular endothelial growth factor receptor inhibitors.

ICD codes

Dosage Regimen

Capsules

The drug is taken orally once a day. A single dose is 18-24 mg, depending on the indications and treatment regimen.

The daily dose may be revised depending on the manifestations of toxicity.

In patients with severe renal impairment, adjustment of the initial dose of lenvatinib is required.

Treatment continues as long as a clinical benefit is observed or until unacceptable toxicity manifests.

Adverse Reactions

Definition of frequency categories of adverse reactions: very common (≥1/10), common (≥1/100 <1/10), and uncommon (≥1/1000 <1/100).

Infections and infestations Very common – urinary tract infection; Uncommon – perineal abscess.

Blood and lymphatic system disorders Very common – thrombocytopenia (including decreased platelet count in blood); Common – lymphopenia (including decreased lymphocyte count in blood); Uncommon – splenic infarction.

Endocrine disorders Very common – hypothyroidism; increased blood TSH level.

Metabolism and nutrition disorders Very common – hypocalcemia, hypercholesterolemia (including increased blood cholesterol level), hypokalemia, decreased appetite, weight loss; Common – dehydration, hypomagnesemia (including decreased blood magnesium level).

Nervous system disorders Very common – dizziness, headache, insomnia; Common – cerebrovascular accident; Uncommon – reversible posterior leukoencephalopathy syndrome, monoparesis, transient ischemic attack.

Cardiac disorders Very common – bleeding (including epistaxis, hemoptysis, hematuria, contusion, hematochezia, gingival bleeding, petechiae, pulmonary hemorrhage, rectal bleeding, urine blood present, hematoma, vaginal bleeding, conjunctival hemorrhage, hemorrhoidal hemorrhage, hemorrhage into intracranial tumor, laryngeal hemorrhage, ecchymosis, increased tendency to bruise, post procedural hemorrhage, purpura, skin hemorrhage, ruptured aneurysm, arterial hemorrhage, eye hemorrhage, gastric hemorrhage, gastroduodenal hemorrhage, gastrointestinal hemorrhage, hematemesis, hemorrhagic stroke, melena, metrorrhagia, nail bed bleeding, pleural hemorrhage, postmenopausal hemorrhage, hemorrhagic proctitis, renal hematoma, splenic hemorrhage, subungual hemorrhage, subarachnoid hemorrhage, tracheal hemorrhage, tumor hemorrhage), arterial hypertension (including hypertensive crisis, increased diastolic blood pressure and increased blood pressure), arterial hypotension; Common – myocardial infarction (including acute myocardial infarction), heart failure, QT interval prolongation, decreased left ventricular ejection fraction, pulmonary embolism.

Respiratory, thoracic and mediastinal disorders Very common – dysphonia.

Gastrointestinal disorders Very common – diarrhea, abdominal pain (including abdominal discomfort, lower abdominal pain, upper abdominal pain, abdominal tenderness, epigastric discomfort), vomiting, nausea, stomatitis (including aphthous ulcer, stomatitis, glossitis, mouth ulceration, mucosal inflammation), oral pain (including glossodynia, oropharyngeal pain), constipation, dyspepsia, dry mouth, dysgeusia; Common – rectal fistula, flatulence.

Hepatobiliary disorders Common – increased AST activity, hypoalbuminemia, increased ALT activity, increased alkaline phosphatase activity, impaired liver function, increased GGT activity, increased blood bilirubin level; Uncommon – hepatic cellular damage/hepatitis (including drug-induced liver injury, hepatic steatosis, cholestatic liver injury).

Skin and subcutaneous tissue disorders Very common – palmar-plantar erythrodysesthesia syndrome, palmar erythema, rash, alopecia; Common – hyperkeratosis.

Musculoskeletal and connective tissue disorders Very common – back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain.

Renal and urinary disorders Very common – proteinuria; Common – renal failure events (including acute prerenal failure, acute renal failure, renal tubular necrosis), impaired renal function, increased blood creatinine level, increased blood urea level.

General disorders and administration site conditions Very common – fatigue, asthenia, peripheral edema; Common – malaise.

Contraindications

End-stage chronic kidney disease, pregnancy, lactation (breastfeeding); age under 18 years (data on efficacy and safety for this category of patients are lacking); hypersensitivity to lenvatinib.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Women of childbearing potential should use effective methods of contraception during lenvatinib use and for at least 1 month after completion of treatment. It is currently unknown whether Lenvatinib reduces the effectiveness of hormonal contraception, so it is recommended to additionally use barrier methods of contraception.

Experimental studies have shown that administration of Lenvatinib to rats and rabbits had embryotoxic and teratogenic effects. Administration of the drug to rats, dogs, and monkeys was accompanied by toxic effects on the testes and ovaries. Lenvatinib and its metabolites are excreted in the milk of lactating rats.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

The drug should be prescribed with caution to patients with arterial hypertension, hepatic insufficiency, renal insufficiency, after surgical operations or radiation therapy, patients over 75 years of age, patients with congenital long QT syndrome, congestive heart failure or bradyarrhythmia, as well as patients simultaneously receiving drugs that prolong the QT interval (monitoring of ECG parameters is necessary).

Arterial hypertension was reported in patients receiving Lenvatinib, which typically developed in the early stages of treatment. Before starting treatment with lenvatinib, blood pressure should be normalized. Patients prone to arterial hypertension should be on a stable dose of antihypertensive therapy for at least 1 week before starting lenvatinib therapy. Early detection and effective treatment of arterial hypertension is important to minimize the need for temporary interruption of lenvatinib treatment or dose reduction of the drug. Antihypertensive medications should be started immediately after elevated blood pressure is confirmed. Examination for arterial hypertension should be performed 1 week after starting lenvatinib, every 2 weeks during the first 2 months of treatment, and then monthly. The choice of antihypertensive therapy should be individualized according to the patient’s condition and follow standard medical practice. For patients with normal blood pressure prior to treatment, in case of elevated blood pressure, antihypertensive monotherapy with a drug from one of the classes of antihypertensive drugs should be initiated. For patients taking antihypertensive drugs prior to starting lenvatinib, an increase in the dose of this antihypertensive drug or the addition of a drug from another class may be required. For patients with arterial hypertension and proteinuria, treatment with ACE inhibitors or angiotensin II receptor antagonists is preferred.

In patients receiving Lenvatinib, regular urine testing for protein should be performed. If significant amounts of protein are detected in the urine by rapid test (≥2+), interruption of lenvatinib treatment, dose adjustment, or complete discontinuation of the drug may be required.

The main identified risk factor for impaired renal function was dehydration and/or hypovolemia due to gastrointestinal toxicity. Gastrointestinal toxicities should be actively managed to reduce the risk of impaired renal function or renal failure. Temporary interruption of lenvatinib treatment, dose adjustment, or complete discontinuation of the drug may be required.

Patients should be examined for symptoms and clinical signs of cardiac decompensation, the presence of which may require temporary interruption of treatment, dose adjustment, or complete discontinuation of the drug.

Reversible posterior leukoencephalopathy syndrome is a neurological disorder whose clinical picture may include headache, seizures, lethargy, confusion, impaired thinking ability, pallor, visual impairment, and other neurological symptoms. Moderate to severe arterial hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis. Appropriate measures should be taken to control blood pressure.

In patients with symptoms and clinical signs of reversible posterior leukoencephalopathy syndrome, temporary discontinuation of lenvatinib treatment, dose adjustment, or complete discontinuation of the drug may be required.

Liver function tests should be performed before starting lenvatinib, every 2 weeks during the first 2 months of treatment, and then monthly throughout the treatment period. If signs of hepatotoxicity occur, temporary discontinuation of lenvatinib treatment, dose adjustment, or complete discontinuation of the drug may be required.

Due to the potential risk of serious bleeding associated with tumor shrinkage or necrosis during lenvatinib therapy, the degree of tumor invasion and infiltration of large blood vessels (e.g., carotid artery) should be considered. In case of bleeding, temporary discontinuation of lenvatinib treatment, dose adjustment, or complete discontinuation of the drug may be required.

If arterial thromboembolism occurs, lenvatinib therapy should be discontinued.

Cases of gastrointestinal perforation or fistula formation have been reported in patients receiving Lenvatinib. In most cases, they occurred in patients with risk factors, which included prior surgery or radiation therapy. Temporary discontinuation of lenvatinib treatment, dose adjustment, or complete discontinuation of the drug may be required.

ECG monitoring should be performed in patients with congenital long QT syndrome, congestive heart failure or bradyarrhythmia, as well as in patients receiving drugs known to prolong the QT interval (including class IA and III antiarrhythmic drugs). Electrolyte imbalances such as hypokalemia, hypocalcemia, and hypomagnesemia increase the risk of QT interval prolongation, so electrolyte balance should be controlled and corrected in all patients before starting treatment. Periodic monitoring of ECG and electrolytes (magnesium, potassium, and calcium) should be performed during treatment.

Thyroid function should be monitored before starting and during treatment with lenvatinib. Treatment of hypothyroidism should be carried out in accordance with accepted treatment standards until a euthyroid state is achieved.

Lenvatinib disrupts exogenous TSH suppression. Regular monitoring of TSH levels should be performed, and the dose of thyroid hormones should be adjusted to achieve an acceptable TSH level, taking into account the therapeutic target for the specific patient.

Data on the use of lenvatinib in patients of races other than Caucasian and Asian, as well as in patients older than 75 years, are insufficient. Treatment with lenvatinib in such patients should be carried out with caution, taking into account the reduced tolerance of lenvatinib in patients of Asian race and elderly patients.

Drug Interactions

There are no data to rule out the risk of induction of the CYP3A4 isoenzyme or P-glycoprotein in the gastrointestinal tract by lenvatinib. This may potentially lead to a decrease in exposure to substrates of the CYP3A4 isoenzyme or P-glycoprotein upon oral administration, which must be considered when using these drugs concomitantly, for which maintaining efficacy is very important. Substrates of the CYP3A4 isoenzyme with a known narrow therapeutic index (e.g., astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, or ergot alkaloids (ergotamine, dihydroergotamine)) should be used with caution in patients receiving Lenvatinib.

It is currently unknown whether Lenvatinib reduces the effectiveness of hormonal contraception; therefore, women taking oral hormonal contraceptives are advised to additionally use barrier methods of contraception.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.