Lenvima

Lenvatinib.

Each capsule contains 4 mg or 10 mg of Lenvatinib (equivalent to lenvatinib mesilate 4.90 mg or 12.25 mg).
Excipients/Inactive Ingredients: Contents: Calcium carbonate, Mannitol, Microcrystalline cellulose, Hydroxypropylcellulose, Low-substituted hydroxypropylcellulose, Talc.
Capsule: Hypromellose, Titanium dioxide (E171), Yellow iron oxide (E172), Red iron oxide (E172).
The printing ink contains: Shellac, Black iron oxide (E172), Potassium hydroxide, Propylene glycol.

Pharmacology: Pharmacodynamics: Mechanism of Action: Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor (PDGF) receptor PDGFRα; KIT; and RET.
In addition, lenvatinib had selective, direct antiproliferative activity in hepatocellular cell lines dependent on activated FGFR signaling, which is attributed to the inhibition of FGFR signaling by lenvatinib.
In syngeneic mouse tumor models, lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.
The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone.
QT Assessment: A single 32 mg dose of lenvatinib did not prolong the QTc interval based on results from a thorough QT study in healthy subjects.
Pharmacokinetics: Absorption: Lenvatinib is rapidly absorbed after oral administration with t_max typically observed from 1 to 4 hours post dose. Food does not affect the extent of absorption, but slows the rate of absorption. When administered to healthy subjects with food, peak plasma concentrations are delayed by 2 hours.
In subjects with solid tumors administered single and multiple doses of lenvatinib once daily, exposure to lenvatinib (C_max and AUC) increase in direct proportion to the administered dose over the range of 3.2 to 32 mg. Lenvatinib displays minimal accumulation at steady-state. Over this range, the median accumulation index (Rac) ranged from 0.96 (20 mg) to 1.54 (6.4 mg).
Distribution: In vitro binding of lenvatinib to human plasma proteins is high and ranged from 98% to 99% (0.3 - 30 μg/mL, mesilate). This binding was mainly to albumin with minor binding to α1-acid glycoprotein and γ-globulin. A similar plasma protein binding (97% to 99%) with no dependencies on lenvatinib concentrations (0.2 to 1.2 μg/mL) was observed in plasma from hepatically impaired renally impaired, and matching healthy subjects.
In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608 (0.1 - 10 μg/mL, mesilate).
Lenvatinib is a substrate for P-gp and BCRP. Lenvatinib is not a substrate for OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K or the BSEP.
Biotransformation: In vitro, cytochrome P450 3A4 was the predominant (>80%) cytochrome isoform involved in the P450-mediated metabolism of lenvatinib. In vivo, inducers and inhibitors of CYP3A4 had a minimal effect on lenvatinib exposure (see Interactions).
In human liver microsomes, the demethylated form of lenvatinib (M2) was identified as the main metabolite. M2' and M3', the major metabolites in human feces, were formed from M2 and lenvatinib, respectively, by AO. In plasma samples collected up to 24 hours after administration, lenvatinib constituted 97% of the radioactivity in plasma radiochromatograms while the M2 metabolite accounted for an additional 2.5%. Based on AUC_0-inf, lenvatinib accounted for 60% and 64% of the total radioactivity in plasma and blood, respectively.
Data from a human mass balance/excretion study indicate lenvatinib is extensively metabolized in humans. The main metabolic pathways in humans were identified as oxidation by AO, demethylation via CYP3A4, glutathione conjugation with elimination of the O-aryl group (chlorophenyl moiety), and combinations of these pathways followed by further biotransformations (eg, glucuronidation, hydrolysis of the glutathione moiety, degradation of the cysteine moiety, and intramolecular rearrangement of the cysteinylglycine and cysteine conjugates with subsequent dimerization). These in vivo metabolic routes align with the data provided in the in vitro studies using human biomaterials.
Elimination: Plasma concentrations decline bi-exponentially following C_max. The terminal exponential half-life of lenvatinib is about 28 hours.
Following administration of radiolabeled lenvatinib to 6 subjects with solid tumors, approximately two-thirds and one-fourth of the radiolabel were eliminated in the feces and urine, respectively. The M2 metabolite was the predominant analyte in excreta (~5% of the dose) with lenvatinib the second most prominent (~2.5%).
Special Populations: Hepatic Impairment: The PK of lenvatinib following a single 10 mg dose were evaluated in 6 subjects with mild and moderate hepatic impairment (Child-Pugh A and Child-Pugh B, respectively). A 5 mg dose was evaluated in 6 subjects with severe hepatic impairment (Child-Pugh C). Eight healthy, demographically matched subjects served as controls and received a 10 mg dose.
The median half-life was comparable in subjects with mild, moderate, and severe hepatic impairment as well as those with normal hepatic function and ranged from 26 hr to 31 hr.
The percentage of the dose of lenvatinib excreted in urine was low in all cohorts (<2.16% across treatment cohorts).
Lenvatinib exposure, based on dose-adjusted AUC_0-t and AUC_0-inf data, was 119%, 107%, and 180% of normal for subjects with mild, moderate, and severe hepatic impairment, respectively. It is unknown whether there is a change in the plasma protein binding in hepatically impaired subjects. See Dosage & Administration for dosing recommendation.
Renal Impairment: The PK of lenvatinib following a single 24 mg dose were evaluated in 6 subjects each with mild, moderate, and severe renal impairment, and compared to 8 healthy, demographically matched subjects. Creatinine clearance ranges were defined as follows: creatinine clearance of ≥81 mL/min for normal, creatinine clearance of 50 to 80 mL/min for mild renal impairment, creatinine clearance of 30 to 49 mL/min for moderate renal impairment, and creatinine clearance of 15 to 29 mL/min for severe renal impairment. Subjects with end stage renal disease were not studied. Lenvatinib exposure, based on AUC_0-inf data, was 101%, 90%, and 122% of normal for subjects with mild, moderate and severe renal impairment, respectively, compared to normal subjects. It is unknown whether there is a change in the plasma protein binding in renally impaired subjects. See Dosage & Administration for dosing recommendation.
Gender: Based on a population pharmacokinetic analysis of patients receiving up to 24 mg lenvatinib once daily as monotherapy (DTC), up to 18 mg once daily in combination with 5 mg everolimus (RCC), and up to 20 mg once daily in combination with pembrolizumab (RCC and EC), gender had no significant effects on apparent clearance Cl/F.
Elderly (65 years of age and above): Based on a population pharmacokinetic analysis of patients receiving up to 24 mg lenvatinib once daily as monotherapy (DTC), up to 18 mg once daily in combination with 5 mg everolimus (RCC), and up to 20 mg once daily in combination with pembrolizumab (RCC and EC), age had no significant effects on Cl/F.
Race: Based on a population pharmacokinetic analysis of patients receiving up to 24 mg lenvatinib once daily as monotherapy (DTC), up to 18 mg once daily in combination with 5 mg everolimus (RCC), and up to 20 mg once daily in combination with pembrolizumab (RCC and EC), race (Japanese vs. other, Caucasian vs other) had no significant effects on Cl/F.
Tumor Type: Tumor type had no significant effect on clearance (Cl/F), based on population pharmacokinetic analysis of patients receiving: up to 24 mg levatinib once daily as monotherapy (DTC), up to 18 mg once daily in combination with 5 mg everolimus (RCCC), and up to 20 mg once daily in combination with pembrolizumab (RCC and EC).
Pediatric Population: Based on a population pharmacokinetic analysis of patients receiving up to 24 mg lenvatinib once daily as monotherapy (DTC), up to 18 mg once daily in combination with 5 mg everolimus (RCC), and up to 20 mg once daily in combination with pembrolizumab (RCC and EC), age had no significant effects on Cl/F in pediatric patients.
Genomic Assessment of Lenvatinib Pharmacokinetic Parameters: Because of lenvatinib's extensive metabolism, the effect of selected drug metabolizing enzyme phenotypes on lenvatinib clearance was investigated using data derived from the Affymetrix drug-metabolizing enzyme and transporter (DMET Plus) microarray genotyping platform. None of the phenotypes for CYP3A5, CYP1A2, CYP2A6, and CYP2C19 had a significant impact on lenvatinib clearance.

For the treatment of patients with unresectable thyroid cancer.
In combination with pembrolizumab, for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
In combination with everolimus, for the treatment of patients with advanced renal cell carcinoma (RCC) following one prior antiangiogenic therapy.
For the treatment of patients with hepatocellular carcinoma (HCC).
In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.

If a dose is missed and cannot be taken within 12 hours, then that dose should be skipped and the next dose should be taken at the usual time of administration.
Treatment should continue as long as there is clinical benefit.
Optimal medical management for nausea, vomiting, and/or diarrhea should be initiated prior to any lenvatinib therapy interruption or dose reduction; however, gastrointestinal toxicity should be actively managed in order to reduce the risk of development of renal impairment or renal failure.
Management of some adverse reactions may require dose interruption, adjustment (modification), or discontinuation of lenvatinib therapy. Mild to moderate adverse reactions (eg., Grade 1 or 2) generally do not warrant interruption of lenvatinib unless intolerable to the patient despite optimal management. Severe (e.g., Grade 3) or intolerable adverse reactions until improvement of the reaction to Grade 0-1 or baseline, followed by dose reduction of lenvatinib once resumed.
Treatment should be discontinued in case of life-threatening reactions (eg., Grade 4) with the exception of laboratory abnormality judged to be non-life-threatening, in which case they should be managed as severe reactions (eg, Grade 3). For asymptomatic laboratory abnormalities, such as Grade >3 elevations of amylase and lipase that are not considered clinically relevant, lenvatinib continuation without dose modification may be considered. Grades are based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).
Specific recommendations for dose modification due to adverse reactions are provided as follows in Table 1, following specific information for each indication.
Posology: Thyroid Cancer: Initial dose regimen: The recommended starting daily dose of lenvatinib is 24 mg (two 10 mg capsules and one 4 mg capsule) taken once daily.
Monitoring and dose modification and discontinuation: For lenvatinib-related toxicities, upon resolution/improvement of an adverse reaction, treatment should be resumed at a reduced dose as suggested in Table 1. (See Table 1.)
Renal Cell Carcinoma: Lenvatinib in combination with pembrolizumab.
Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information.
Initial dose regimen: The recommend starting daily dose of lenvatinib is 20 mg (two 10-mg capsules) once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks.
Monitoring and dose modification and discontinuation For lenvatinib-related toxicities, upon resolution/improvement of an adverse reaction, treatment should be resumed at a reduced dose as suggested in Table 1. When used in combination with pembrolizumab, one or both medicines should be interrupted as appropriate. Lenvatinib should be withheld, dose reduced, or discontinued as appropriate. Withhold or discontinue pembrolizumab in accordance with the instructions in the prescribing information from pembrolizumab. No dose reductions are recommended for pembrolizumab.
Lenvatinib in combination with everolimus: Initial dose regimen: The recommended starting dose of lenvatinib is 18 mg (one 10 mg capsule and two 4 mg capsules) once daily in combination with 5 mg everolimus once daily. Or as prescribed by the physician.
Refer to the everolimus prescribing information for other everolimus dosing information.
Lenvatinib and everolimus are to be taken at the same time each day with or without food (see Pharmacology: Pharmacokinetics under Actions).
Monitoring and dose modification and discontinuation: For lenvatinib related toxicities, upon resolution/improvement of an adverse reaction to Grade 0-1 or baseline, treatment should be resumed at a reduced dose of lenvatinib as suggested in Table 1.
For toxicities thought to be related to everolimus, treatment should be interrupted, reduced to alternate day dosing, or discontinued. See the everolimus prescribing information for dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.
For toxicities thought to be related to both lenvatinib and everolimus, lenvatinib should be reduced (see Table 1) prior to reducing everolimus.
Hepatocellular Carcinoma (HCC): Initial dose regimen: The recommended starting daily dose of lenvatinib is 8 mg (two 4 mg capsules) once daily for patients with a body weight of < 60 kg and 12 mg (three 4 mg capsules) once daily for patients with a bodyweight of ≥ 60 kg. Or as prescribed by the physician.
Monitoring, dose modification and discontinuation: For lenvatinib-related toxicities, upon resolution/improvement of an adverse reaction, treatment should be resumed at a reduced dose as suggested in Table 1.
Posology: Endometrial Carcinoma (EC): Initial dose regimen: The recommended starting dosage of lenvatinib is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until unacceptable toxicity or disease progression. Or as prescribed by the physician.
Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information.
Monitoring, dose modification and discontinuation: For lenvatinib-related toxicities, upon resolution/improvement of an adverse reaction, treatment should be resumed at a reduced dose as suggested in Table 1. When administering lenvatinib in combination with pembrolizumab, interrupt, dose reduce, or discontinue lenvatinib as appropriate. With-hold or discontinue pembrolizumab in accordance with the instructions in the prescribing information for pembrolizumab. No dose reductions are recommended for pembrolizumab. (See Table 1.)

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Special Populations: Patients With Hepatic Impairment: Thyroid Cancer, RCC and EC: No dose adjustments are required on the basis of hepatic function in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.
The recommended dosage of lenvatinib for patients with severe hepatic impairment (Child-Pugh C) is: TC: 14 mg taken orally once daily.
RCC: 10 mg taken orally once daily.
EC: 10 mg taken orally once daily.
Further dose adjustments may be necessary on the basis of individual tolerability.
Limited data are available for the combination of lenvatinib with pembrolizumab or everolimus in patients with hepatic impairment. Please refer to the respective prescribing information for pembrolizumab or everolimus for dosing in patients with hepatic impairment.
HCC: No dose adjustments are required on the basis of hepatic function in patients with HCC and mild hepatic impairment (Child-Pugh A). There are limited data in patients with HCC and moderate hepatic impairment (Child-Pugh B). On the basis of that data, the recommended starting dose in patients with moderate hepatic impairment (Child-Pugh B) is 8 mg, regardless of body weight. Patients with moderate hepatic impairment may require additional monitoring for adverse reactions requiring dose adjustments. The available data do not allow for a dosing recommendation for patients with HCC and severe hepatic impairment (Child-Pugh C).
Patients with Renal Impairment: Thyroid Cancer, RCC & EC: No dose adjustments are required on the basis of renal function in patients with mild or moderate renal impairment.
The recommended dosage of lenvatinib for patients with severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is: TC: 14 mg taken orally once daily.
RCC: 10 mg taken orally once daily.
EC: 10 mg taken orally once daily.
Further dose adjustments may be necessary on the basis of individual tolerability.
Limited data are available for the combination of lenvatinib with pembrolizumab or everolimus in patients with renal impairment. Please refer to the respective prescribing information for pembrolizumab or everolimus for dosing in patients with renal impairment.
HCC: No dose adjustments are required on the basis of renal function in HCC patients with mild or moderate renal impairment. The available data do not allow for a dosing recommendation for patients with HCC and severe renal impairment.
Elderly Population: No adjustment of starting dose is required on the basis of age.
Pediatric Patients: The safety and efficacy of lenvatinib in children and adolescents <18 years have not been established. No data are available.
Method of Administration: Take lenvatinib at the same time each day with or without food (see Pharmacology: Pharmacokinetics under Actions).
The lenvatinib capsules should be swallowed whole with water.
Alternatively, add the lenvatinib capsules (without breaking or crushing the capsules) to a tablespoon of water or apple juice in a small glass to produce a suspension. Leave the capsules in the liquid for at least 10 minutes. Stir for at least 3 minutes. Drink the mixture. After drinking, add the same amount of water or apple juice (one tablespoon) to the glass. Swirl the contents of the glass a few times and swallow the additional liquid.

There have been reports of overdose with lenvatinib involving single administrations of 6 to 10 times the recommended daily dose. These cases were associated with adverse reactions consistent with the known safety profile of lenvatinib or were without adverse reactions.
There is no specific antidote for overdose with lenvatinib. In case of suspected overdose, lenvatinib should be withheld and supportive care initiated.

None.

Hypertension: Hypertension has been reported in patients treated with lenvatinib (see Adverse Reactions). The median time to onset was 16 days in the Thyroid Cancer Study, 34 days in the RCC Study and 26 days in the HCC Study.
Blood pressure should be well controlled prior to treatment with lenvatinib. The early detection and effective management of hypertension are important to minimize the need for lenvatinib dose interruptions and reductions. Serious complications of poorly controlled hypertension, including aortic dissection, have been reported. Blood pressure should be monitored after 1 week of treatment with lenvatinib, then every 2 weeks for the first 2 months and monthly thereafter while on treatment. If a patient develops systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg active management is indicated (see Table 2).

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Proteinuria: Proteinuria has been reported in patients treated with lenvatinib (see Adverse Reactions). Monitor urine protein regularly. If urine dipstick proteinuria ≥2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration). Discontinue in the event of nephrotic syndrome.
Renal Failure and Impairment/Gastrointestinal toxicity: Renal impairment (including renal failure) has been reported in patients treated with lenvatinib (see Adverse Reactions). The primary risk factor identified was dehydration/hypovolemia due to gastrointestinal toxicity. Gastrointestinal toxicity should be actively managed in order to reduce the risk of development of renal impairment or renal failure. Dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
Cardiac Failure: Cardiac failure and decreased left ventricular ejection fraction have been reported in patients treated with lenvatinib (see Adverse Reactions).
Patients should be monitored for clinical symptoms or signs of cardiac decompensation, as dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Events of reversible posterior leukoencephalopathy syndrome (RPLS) also known as posterior reversible encephalopathy syndrome (PRES) have been reported (<1%) in patients treated with lenvatinib (see Adverse Reactions). RPLS is a neurological disorder that can present with headache, seizure, lethargy, confusion, altered mental function, blindness, and other visual or neurological disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Appropriate measures should be taken to control blood pressure (see Table 2 as previously mentioned). In patients with signs or symptoms of RPLS, dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
Hepatotoxicity: In Thyroid cancer and RCC liver-related adverse reactions most commonly reported in patients treated with lenvatinib included increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood bilirubin (see Adverse Reactions). Hepatic failure and acute hepatitis (<1%) have been reported in patients with Thyroid cancer and RCC treated with lenvatinib. The hepatic failure events were generally reported in patients with progressive metastatic liver disease.
Liver-related adverse reactions including hepatic encephalopathy and hepatic failure (including fatal reactions) were reported at a higher frequency in lenvatinib treated patients with HCC (see Table 7 under Adverse Reactions) than with Thyroid Cancer and RCC. Patients with worse hepatic impairment and/or greater liver tumor burden at baseline had a higher risk of developing hepatic encephalopathy and hepatic failure. Hepatic encephalopathy also occurred more frequently in patients aged 75 years and older. Approximately half of the events of hepatic failure were reported in patients with disease progression.
Liver function tests should be monitored before initiation of treatment, then every 2 weeks for the first 2 months and monthly thereafter during treatment. Patients with HCC should be monitored for worsening liver function including hepatic encephalopathy. In the case of hepatotoxicity, dose interruptions, adjustments, or discontinuation may be necessary (see Table 3 Thyroid Cancer, Table 4 RCC, Table 5 HCC and Table 6 EC under Dosage & Administration).
Hemorrhagic Events: Serious hemorrhagic events have been reported in patients treated with lenvatinib (see Adverse Reactions). The most frequently reported hemorrhagic event was mild epistaxis. However, serious tumor related bleeds were reported, including fatal hemorrhagic events in lenvatinib-treated patients. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
In the case of bleeding, dose interruptions, adjustments, or discontinuation may be required (see Dosage & Administration).
Arterial Thromboembolic Events (ATEs): Arterial thromboembolic events have been reported in patients treated with lenvatinib (see Adverse Reactions). Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.
Fistula Formation and Gastrointestinal Perforation: Events of fistula formation or gastrointestinal perforation and their sequelae have been reported in patients treated with lenvatinib (see Adverse Reactions). Fistulas (e.g. gastrointestinal, bronchopleural, tracheo-oesophageal, oesophageal, cutaneous, pharyngeal, female genital tract fistula) have been reported in lenvatinib clinical trials and in post-marketing experience. In addition, pneumothorax has been reported with and without clear evidence of a bronchopleural fistula. Some reports of gastrointestinal perforation, fistula and pneumothorax occurred in association with tumor regression or necrosis. In most cases of fistula formation or gastrointestinal perforation, risk factors such as prior surgery or radiotherapy were present. In the case of fistula formation or gastrointestinal perforation, dose interruptions, adjustments, or discontinuation may be required (see Dosage & Administration).
QT Interval Prolongation: The effect of a single 32 mg dose of lenvatinib on the QT/QTc interval was evaluated in a thorough QT study in healthy subjects. In this study lenvatinib did not prolong the QT/QTc interval. QT/QTc interval prolongation has been reported at a higher rate in patients treated with lenvatinib. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, and drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Monitor and correct electrolyte abnormalities in all patients (see Adverse Reactions and Pharmacology: Pharmacodynamics under Actions).
Hypocalcaemia: Hypocalcaemia has been reported in patients treated with lenvatinib (see Adverse Reactions). Monitor blood calcium levels periodically and replace calcium as necessary during lenvatinib treatment. Interrupt and adjust lenvatinib dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia.
Thyroid Dysfunction and Impairment of Thyroid Stimulating Hormone Suppression: Hypothyroidism has been reported in patients treated with lenvatinib. Thyroid function, T3, T4 and TSH should be monitored before initiation of, and periodically throughout treatment with lenvatinib. Hypothyroidism should be treated according to standard medical practice to maintain euthyroid state (see Adverse Reactions).
Wound Healing Complications: No formal studies of the effect of lenvatinib on wound healing have been conducted. Impaired wound healing has been reported in patients receiving lenvatinib. Temporary interruption of lenvatinib should be considered in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of lenvatinib following a major surgical procedure. Therefore, the decision to resume lenvatinib following a major surgical procedure should be based on clinical judgment of adequate wound healing.
Osteonecrosis of the Jaw (ONJ): Events of osteonecrosis of the jaw (ONJ) have been observed with lenvatinib. Invasive dental procedures are an identified risk factor for the development of ONJ. An oral dental examination and appropriate preventive dentistry should be considered prior to initiation of lenvatinib. Patients should be advised regarding periodic dental examinations and oral hygiene practice during lenvatinib therapy. Avoid invasive dental procedures during lenvatinib treatment, if possible. Use caution in patients receiving agents associated with ONJ, such as bisphosphonates and denosumab.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed.

Information on fertility, pregnancy and lactation as follows is relevant to use of lenvatinib monotherapy.
When using lenvatinib in combination with everolimus or pembrolizumab, please see as follows and also refer to the manufacturer's prescribing information for everolimus or pembrolizumab.
Fertility: Effects in humans are unknown. No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility; however, results from general toxicology studies in rats, monkeys, and dogs suggest there is a potential for lenvatinib to impair fertility.
Pregnancy: There is insufficient information on the use of lenvatinib in pregnant women. Oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity and teratogenicity in rats and rabbits.
Lenvatinib should not be used during pregnancy unless clearly necessary and after a careful consideration of the needs of the mother and the risk to the fetus. Women should avoid becoming pregnant and use effective contraception while on treatment with lenvatinib.
Lactation: It is not known whether lenvatinib is excreted in human milk. Lenvatinib and its metabolites are excreted in rat milk. A risk to newborn or infants cannot be excluded, and therefore lenvatinib should not be used during breastfeeding.

The incidence rates of treatment-emergent adverse events observed in clinical studies are presented in the respective tables listed as follows.
Table 3: DTC monotherapy; Table 4: RCC combination with pembrolizumab; Table 6: RCC combination with everolimus; Table 7: HCC monotherapy; Table 8: EC combination with pembrolizumab; Table 10: Postmarketing adverse drug reactions, monotherapy.
Events are included as Adverse Drug Reactions (ADRs) based on the incidence rates of treatment emergent adverse events (TEAEs) in the placebo-controlled DTC study together with events from other indications assessed in the context of TEAE incidence rates across study treatment arms, the known pharmacology of lenvatinib and the underlying indication.
Thyroid Cancer: The safety of lenvatinib was evaluated in 392 patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) randomized to receive lenvatinib 24 mg once daily (n=261) or placebo (n=131).
Table 3 presents the incidence rates of treatment-emergent adverse events observed in the double-blind phase of the DTC study. All adverse events occurring with a treatment difference of at least 5% over placebo are included in the Table. Clinically significant events (CSEs) that were observed more frequently than placebo are also included based on an assessment of the known pharmacology of lenvatinib and class effects. (See Tables 3a and 3b.)

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RCC 1L Combination With Pembrolizumab: The safety of lenvatinib was evaluated in Study 307, in which patients with advanced renal cell carcinoma (RCC) were randomized (1:1:1) to lenvatinib 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks(n=352), lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily(n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=340).
The median duration of study treatment was 17.0 months (range 2 days to 39.1 months). The median duration of exposure to lenvatinib was 16.1 months (range 2 days to 39.1 months).
Tables 4 and 5 summarize treatment emergent adverse events and laboratory abnormalities, respectively, in patients receiving lenvatinib in combination with pembrolizumab in Study 307. (See Tables 4 and 5.)

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RCC 2L Combination With Everolimus: A multicenter, randomized, open-label, trial was conducted to determine the safety and efficacy of lenvatinib administered alone or in combination with everolimus in subjects with unresectable, advanced or metastatic RCC. The study consisted of a Phase 1b dose finding and a Phase 2 portion.
The Phase 2 portion enrolled a total of 153 patients with advanced or metastatic renal cell carcinoma(RCC) following 1 prior VEGF-targeted treatment who were randomized to receive the combination of 18 mg lenvatinib plus 5 mg everolimus (n=51), lenvatinib 24 mg (n=52) or everolimus 10 mg(n=50) once daily).
Table 6 presents the incidence rates of treatment-emergent adverse events observed in the RCC study.
All adverse events occurring with a frequency of at least 10% all Grades or 3% Grade 3 or 4. (See Table 6.)

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HCC: A multicenter, randomized, open-label study was conducted to determine the safety and efficacy of lenvatinib compared to sorafenib in subjects with unresectable hepatocellular carcinoma (HCC). Subjects were randomized 1:1 to lenvatinib (12 mg [≥ 60 kg BW] or lenvatinib 8 mg [<60 kg BW]) orally, once daily, or sorafenib 400 mg orally, twice daily.
Table 7 presents the incidence rates of treatment emergent adverse events observed in the HCC study and includes all adverse events occurring with a frequency of at least 10% and of at least 3% ≥ CTCAE Grade 3. (See Table 7.)

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EC 2L Combination With Pembrolizumab: The safety of lenvatinib in combination with pembrolizumab was investigated in Study 309, a multicenter, open-label, randomized (1:1), active-controlled trial in 827 patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received lenvatinib 20 mg orally once daily with pembrolizumab 200 mg intravenously every 3 weeks (n=406) or treatment of investigator's choice (n=388), consisting of 60 mg/m2 doxorubicin every 3 weeks or 80 mg/m2 paclitaxel given weekly, 3 weeks on/1 week off.
The median duration of study treatment was 7.6 months (range 1 day to 26.8 months). The median duration of exposure to lenvatinib was 6.9 months (range 1 day to 26.8 months).
Tables 8 and 9 summarize treatment emergent adverse events and laboratory abnormalities, respectively, in patients receiving lenvatinib in combination with pembrolizumab in Study 30. (See Table 8 and 9.)

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Postmarketing adverse drug reactions: The incidence of adverse events observed in lenvatinib monotherapy datasets for reactions identified from post marketing use of lenvatinib are provided in Table 10. (See Table 10.)

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The following are considered to be Adverse Drug Reactions (ADRs) for lenvatinib: Blood and Lymphatic System Disorders: Lymphopenia, Thrombocytopenia, Leukopenia, Neutropenia.
Cardiac Disorders: Cardiac failure, QT interval prolongation.
Endocrine Disorders: Hypothyroidism.
Gastrointestinal Disorders: Abdominal pain, Amylase increased^*, Constipation, Diarrhea, Dry mouth, Dyspepsia, Flatulence, Gastrointestinal perforation and fistula, Lipase increased^*, Nausea, Oral pain, Pancreatitis^*, Stomatitis, Vomiting.
General Disorders and Administration Site Conditions: Asthenia, Edema peripheral, Fatigue, Malaise, Impaired Wound Healing^*.
Hepatobiliary Disorders: Cholecystitis^*, Hepatotoxicity, Hepatic failure^‡, Hepatic encephalopathy^‡.
Infections and Infestations: Urinary tract infection.
Investigations: Weight decreased.
Metabolism and Nutrition Disorders: Decreased appetite, Dehydration, Hypercholesterolemia, Hypocalcemia, Hypokalemia, Hypomagnesemia.
Musculoskeletal and Connective Tissue Disorders: Arthralgia, Back pain, Musculoskeletal pain, Myalgia, Pain in extremity, Osteonecrosis of the jaw^*.
Nervous System Disorders: Dizziness, Dysgeusia, Headache, Reversible posterior leukoencephalopathy syndrome.
Psychiatric Disorders: Insomnia.
Renal and Urinary Disorders: Nephrotic syndrome^*, Proteinuria, Renal failure^‡, Renal impairment.
Respiratory, Thoracic and Mediastinal Disorders: Cough, Dysphonia, Pneumothorax^*‡, Pulmonary embolism^‡.
Skin and Subcutaneous Tissue Disorders: Alopecia, Hyperkeratosis, Palmar-plantar erythrodysesthesia syndrome, Rash.
Vascular Disorders: Arterial thromboembolic events^‡, Hemorrhage^‡, Hypertension, Hypotension, Aortic Dissection^‡*.
^‡ Includes fatal events.
^* Identified from post-marketing of lenvatinib.

Interaction with other medicinal products and other forms of interaction as follows are relevant to the use of lenvatinib monotherapy. Population pharmacokinetic analysis demonstrated that lenvatinib does not significantly affect the pharmacokinetics of either everolimus or pembrolizumab. When using lenvatinib in combination with everolimus or pembrolizumab, also refer to the manufacturer's prescribing information for everolimus or pembrolizumab.
Effect on Cytochrome P450 or UGT Enzymes: Lenvatinib is not considered a strong inducer or inhibitor of cytochrome P450 or uridine 5'-diphospho-glucuronosyl transferase (UGT) enzymes.
Based on simulations from a physiologically based pharmacokinetic model developed for lenvatinib, there is no projected significant drug-drug interaction risk between lenvatinib and midazolam (a CYP3A4 substrate) or repaglinide (a CYP2C8 substrate) at a dose of 24 mg of lenvatinib. This has also been confirmed in a clinical study determining the effect of lenvatinib on midazolam, in subjects with advanced solid tumors.
Other Chemotherapeutic Agents: Concomitant administration of lenvatinib, carboplatin, and paclitaxel has no significant impact on the pharmacokinetics (PK) of any of these 3 drugs.
Effect of CYP3A, P-gp, and BCRP Inhibitors: Lenvatinib may be co-administered without dose adjustment with CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors.
Effect of P-gp Inhibitors: Lenvatinib may be co-administered without dose adjustment with P-gp inhibitors based on a study in healthy subjects.
Effect of CYP3A and P-gp Inducers: Lenvatinib may be co-administered without dose adjustment with CYP3A and P-gp inducers, based on a study in which healthy subjects were administered repeated doses of rifampicin (600 mg for 21 days) and a single dose of lenvatinib (24 mg, Day 15). The effect of CYP3A induction alone was estimated by comparing the PK parameters for lenvatinib following single and multiple doses of rifampicin. Lenvatinib AUC and C_max were predicted to decrease by 30% and 15%, respectively, after strong induction in the absence of acute P-gp inhibition. This is supported by a population PK analysis, which found CYP3A4 inducers increased Cl/F by 30%.
Gastric pH Altering Agents: In a population PK analysis of patients receiving lenvatinib up to 24 mg once daily, agents that increase gastric pH (H₂ receptor blockers, proton pump inhibitors, antacids) did not have a significant effect on lenvatinib exposure.
In Vitro Studies: Drug metabolizing enzyme and transporter inhibition: In vitro, lenvatinib exhibited an inhibitory effect on CYP2C8 (half-maximal inhibitory concentration [IC₅₀]: 10.1 μmol/L), weak inhibitory effects on CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A, and virtually no inhibitory effects on CYP2A6 and CYP2E1 in human liver microsomes. Time dependent inhibition of the formation of 1'-hydroxymidazolam from midazolam (CYP3A) by lenvatinib was observed. In human liver microsomes, lenvatinib directly inhibited UGT1A1 and UGT1A4 but showed little or no evidence of inhibition on UGT1A6, UGT1A9, and UGT2B7. Treatment of cultured human hepatocytes with up to 3 μmol/L lenvatinib did not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 enzyme activities or their mRNA expressions.
Lenvatinib showed minimal or no inhibitory activities toward P-gp-mediated and BCRP-mediated transport activities.
Lenvatinib showed inhibitory effects on organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transporting polypeptide (OATP) 1B1, and the bile salt export pump (BSEP), but minimal or no inhibitory effect on OATP1B3 and multidrug and toxin extrusion 2 (MATE2)-K. Lenvatinib weakly inhibits MATE1.
In human liver cytosol, lenvatinib did not inhibit aldehyde oxidase (AO) activity (IC₅₀>100 μmol/L).
Drug metabolizing enzyme and transporter induction: Treatment of cultured human hepatocytes with up to 3 μmol/L of lenvatinib slightly increased CYP3A enzyme activity (≤1.54-fold) and CYP3A4 mRNA expression (≤1.65-fold). No effects on CYP1A1, CYP1A2, CYP2B6, and CYP2C9 enzyme activities or mRNA expression were observed.
In vitro, lenvatinib did not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 enzyme activities or mRNA expressions.
Treatment of cultured human hepatocytes with up to 3 μmol/L of lenvatinib showed no induction potency on P-gp mRNA expression.

Incompatibilities: Not applicable.
Instructions for Use and Handling: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Do not open the capsule. Avoid repeat exposure to contents of the capsule.

Store at temperatures not exceeding 30°C.

Targeted Cancer Therapy

L01EX08 - lenvatinib ; Belongs to the class of other protein kinase inhibitors. Used in the treatment of cancer.

Rx