Bdfoie 4/Bdfoie 10

Bdfoie 4: White to off-white granular powder filled into size "4" hard gelatin capsules with opaque white cap and body.
Each hard gelatin capsule contains: Lenvatinib Mesylate 4.90 mg eq. to Lenvatinib 4.0 mg, Excipients q.s.
Approved colours used in capsule shells.
Bdfoie 10: White opaque/white opaque hard gelatin capsules size "01" containing white to off white granules.
Each hard gelatin capsule contains: Lenvatinib Mesylate 12.25 mg eq. to Lenvatinib 10 mg, Excipients q.s.
Approved colours used in capsule shells.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors.
Pharmacology: Pharmacodynamics: Lenvatinib is a multikinase inhibitor which has shown mainly antiangiogenic properties in vitro and in vivo, and direct inhibition of tumour growth was also observed in in vitro models.
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 signalling, which is attributed to the inhibition of FGFR signalling by Lenvatinib.
Although not studied directly with Lenvatinib, the mechanism of action (MOA) for hypertension is postulated to be mediated by the inhibition of VEGFR2 in vascular endothelial cells. Similarly, although not studied directly, the MOA for proteinuria is postulated to be mediated by down regulation of VEGFR1 and VEGFR2 in the podocytes of the glomerulus.
The mechanism of action for hypothyroidism is not fully elucidated.
Pharmacokinetics: Pharmacokinetic parameters of Lenvatinib have been studied in healthy adult subjects, adult subjects with hepatic impairment, renal impairment, and solid tumours.
Absorption: Lenvatinib is rapidly absorbed after oral administration with tmax typically observed from 1 to 4 hours postdose. Food does not affect the extent of absorption, but slows the rate of absorption. When administered with food to healthy subjects, peak plasma concentrations are delayed by 2 hours. Absolute bioavailability has not been determined in humans; however, data from a mass-balance study suggest that it is in the order of 85%. Lenvatinib exhibited good oral bioavailability in dogs (70.4%) and monkeys (78.4%).
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.
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 bile salt export pump BSEP.
In patients, the median apparent volume of distribution (Vz/F) of the first dose ranged from 50.5 L to 92 L and was generally consistent across the dose groups from 3.2 mg to 32 mg. The analogous median apparent volume of distribution at steady-state (Vz/Fss) was also generally consistent and ranged from 43.2 L to 121 L.
Biotransformation: In vitro, cytochrome P450 3A4 was demonstrated as the predominant (>80%) isoform involved in the P450-mediated metabolism of Lenvatinib. However, in vivo data indicated that non-P450-mediated pathways contributed to a significant portion of the overall metabolism of Lenvatinib. Consequently, in vivo, inducers and inhibitors of CYP 3A4 had a minimal effect on Lenvatinib exposure.
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 aldehyde oxidase.
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 metabolised in humans. The main metabolic pathways in humans were identified as oxidation by aldehyde oxidase, demethylation via CYP3A4, glutathione conjugation with elimination of the O-aryl group (chlorophenyl moiety), and combinations of these pathways followed by further biotransformations (e.g., glucuronidation, hydrolysis of the glutathione moiety, degradation of the cysteine moiety, and intramolecular rearrangement of the cysteinylglycine and cysteine conjugates with subsequent dimerisation). These in vivo metabolic routes align with the data provided in the in vitro studies using human biomaterials.
In vitro transporter studies: For the following transporters, OAT1, OAT3, OATP1B1, OCT1, OCT2, and BSEP, clinically relevant inhibition was excluded based on a cutoff of IC50 > 50 x Cmax,unbound.
Lenvatinib showed minimal or no inhibitory activities toward P-gp-mediated and breast cancer resistance protein (BCRP)-mediated transport activities. Similarly, no induction of P-gp mRNA expression was observed.
Lenvatinib showed minimal or no inhibitory effect on OATP1B3 and MATE2-K. Lenvatinib weakly inhibits MATE1. In human liver cytosol, Lenvatinib did not inhibit aldehyde oxidase activity.
Elimination: Plasma concentrations decline bi-exponentially following Cmax. The mean terminal exponential half-life of Lenvatinib is approximately 28 hours.
Following administration of radiolabelled Lenvatinib to 6 patients with solid tumours, approximately two-thirds and one-quarter of the radiolabel were eliminated in the feces and urine, respectively. The M3 metabolite was the predominant analyte in excreta (~17% of the dose), followed by M2' (~11% of the dose) and M2 (~4.4 of the dose).
Linearity/non-linearity: Dose proportionality and accumulation: In patients with solid tumours administered single and multiple doses of Lenvatinib once daily, exposure to Lenvatinib (Cmax and AUC) increased in direct proportion to the administered dose over the range of 3.2 to 32 mg once-daily.
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). The Rac in HCC subjects with mild and moderate liver impairment was similar to that reported for other solid tumours.
Special populations: Hepatic impairment: The pharmacokinetics of Lenvatinib following a single 10-mg dose were evaluated in 6 subjects each 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.
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 has been determined that plasma protein binding in plasma from hepatically impaired subjects was similar to the respective matched healthy subjects and no concentration dependency was observed.
There are no sufficient data for HCC patients with Child-Pugh B (moderate hepatic impairment, 3 patients treated with Lenvatinib in the pivotal trial) and no data available in Child-Pugh C HCC patients (severe hepatic impairment). Lenvatinib is mainly eliminated via the liver and exposure might be increased in these patient populations.
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 hours to 31 hours. The percentage of the dose of Lenvatinib excreted in urine was low in all cohorts (<2.16% across treatment cohorts).
Renal impairment: The pharmacokinetics of Lenvatinib following a single 24-mg dose were evaluated in 6 subjects each with mild, moderate, and severe renal impairment, and compared with 8 healthy, demographically matched subjects. 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. It has been determined that plasma protein binding in plasma from renally impaired subjects was similar to the respective matched healthy subjects and no concentration dependency was observed.
Age, sex, weight, race: Based on a population pharmacokinetic analysis of patients receiving up to 24 mg Lenvatinib once daily, age, sex, weight, and race (Japanese vs. other, Caucasian vs. other) had no significant effects on clearance.
Pediatric Population: Pediatric patients have not been studied.
Toxicology: Preclinical Safety Data: In the repeated-dose toxicity studies (up to 39 weeks), Lenvatinib caused toxicologic changes in various organs and tissues related to the expected pharmacologic effects of Lenvatinib including glomerulopathy, testicular hypocellularity, ovarian follicular atresia, gastrointestinal changes, bone changes, changes to the adrenals (rats and dogs), and arterial (arterial fibrinoid necrosis, medial degeneration, or hemorrhage) lesions in rats, dogs, and cynomolgus monkeys. Elevated transaminase levels associated with signs of hepatotoxicity, were also observed in rats, dogs and monkeys. Reversibility of the toxicologic changes was observed at the end of a 4-week recovery period in all animal species investigated.
Genotoxicity: Lenvatinib was not genotoxic.
Carcinogenicity studies have not been conducted with Lenvatinib.
Reproductive and developmental toxicity: No specific studies with Lenvatinib have been conducted in animals to evaluate the effect on fertility. However, testicular (hypocellularity of the seminiferous epithelium) and ovarian changes (follicular atresia) were observed in repeated-dose toxicity studies in animals at exposures 11 to 15 times (rat) or 0.6 to 7 times (monkey) the anticipated clinical exposure (based on AUC) at the maximum tolerated human dose. These findings were reversible at the end of a 4-week recovery period.
Administration of Lenvatinib during organogenesis resulted in embryolethality and teratogenicity in rats fetal external and skeletal anomalies) at exposures below the clinical exposure (based on AUC) at the maximum tolerated human dose, and rabbits (fetal external, visceral or skeletal anomalies) based on body surface area; mg/m² at the maximum tolerated human dose. These findings indicate that Lenvatinib has a teratogenic potential, likely related to the pharmacologic activity of Lenvatinib as an antiangiogenic agent.
Lenvatinib and its metabolites are excreted in rat milk.
Juvenile animal toxicity studies: Mortality was the dose-limiting toxicity in juvenile rats in which dosing was initiated on postnatal day (PND) 7 or PND21 and was observed at exposures that were respectively 125- or 12-fold lower compared with the exposure at which mortality was observed in adult rats, suggesting an increasing sensitivity to toxicity with decreasing age. Therefore, mortality may be attributed to complications related to primary duodenal lesions with possible contribution from additional toxicities in immature target organs.
The toxicity of Lenvatinib was more prominent in younger rats (dosing initiated on PND7) compared with those with dosing initiated on PND21 and mortality and some toxicities were observed earlier in the juvenile rats at 10 mg/kg compared with adult rats administered the same dose level. Growth retardation, secondary delay of physical development, and lesions attributable to pharmacologic effects (incisors, femur [epiphyseal growth plate], kidneys, adrenals, and duodenum) were also observed in juvenile rats.

Lenvatinib "Bdfoie 4/Bdfoie 10" is indicated as monotherapy for the treatment of adult patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine (RAI). Lenvatinib "Bdfoie 4/Bdfoie 10" is indicated as monotherapy for the treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have received no prior systemic therapy. Lenvatinib "Bdfoie 4/Bdfoie 10" in combination with pembrolizumab is indicated for the treatment of adult patients with advanced or recurrent endometrial carcinoma (EC) who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and are not candidates for curative surgery or radiation.

Lenvatinib "Bdfoie 4/Bdfoie 10" treatment should be initiated and supervised by a healthcare professional experienced in the use of anticancer therapies. Optimal medical management (i.e. treatment or therapy) for nausea, vomiting, and diarrhea should be initiated prior to any Lenvatinib therapy interruption or dose reduction; gastrointestinal toxicity should be actively treated in order to reduce the risk of development of renal impairment or failure.
Posology: If a patient misses a dose, and it 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 clinical benefit is observed or until unacceptable toxicity occurs.
Differentiated thyroid cancer (DTC): The recommended daily dose of Lenvatinib is 24 mg (two 10 mg capsules and one 4 mg capsule) once daily. The daily dose is to be modified as needed according to the dose/toxicity management plan.
Dose adjustments and discontinuations for DTC: Management of adverse reactions may require dose interruption, adjustment, or discontinuation of Lenvatinib therapy. Mild to moderate adverse reactions (e.g., 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 require interruption of Lenvatinib until improvement of the reaction to Grade 0-1 or baseline.
For Lenvatinib related toxicities (see Table 3), 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. (See Table 1.)

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Treatment should be discontinued in case of life-threatening reactions (e.g., Grade 4) with the exception of laboratory abnormality judged to be non-life-threatening, in which case they should be managed as severe reaction (e.g., Grade 3).
Hepatocellular Carcinoma: The recommended 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 body weight of ≥60 kg. Dose adjustments are based only on toxicities observed and not on body weight changes during treatment. The daily dose is to be modified, as needed, according to the dose/toxicity management plan.
Dose adjustments and Discontinuation for HCC: Management of some adverse reactions may require dose interruption, adjustment, or discontinuation of Lenvatinib therapy. Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not warrant interruption of Lenvatinib, unless intolerable to the patient despite optimal management. Details for monitoring, dose adjustment and discontinuation are provided in Table 2. (See Table 2.)

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Grades are based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).
Endometrial Carcinoma (EC): The recommended dosage of Lenvatinib is 20 mg orally once daily, in combination with pembrolizumab either 200 mg every 3 weeks or 400 mg every 6 weeks, administered as an intravenous infusion over 30 minutes, until unacceptable toxicity or disease progression.
Refer to the Summary of Product Characteristics (SmPC) for pembrolizumab for additional dosing information.
Dose adjustments and Discontinuation for EC: For lenvatinib-related toxicities see Table 4. When administering Lenvatinib "Bdfoie 4/Bdfoie 10" in combination with pembrolizumab, interrupt, dose reduce, or discontinue Lenvatinib "Bdfoie 4/Bdfoie 10" as appropriate. Withhold or discontinue pembrolizumab in accordance with the instructions in the SmPC for pembrolizumab. No dose reductions are recommended for pembrolizumab. (See Tables 3 and 4.)

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Special Populations: Elderly Population: DTC: Patients of age ≥75 years, of Asian race, with comorbidities (such as hypertension, and hepatic or renal impairment), or body weight below 60 kg appear to have reduced tolerability to Lenvatinib. All patients other than those with severe hepatic or renal impairment (see as follows) should initiate treatment at the recommended 24 mg dose, following which the dose should be further adjusted on the basis of individual tolerability.
HCC: Patients ≥75 years, of white race or female sex or those with worse baseline hepatic impairment (Child-Pugh A score of 6 compared to score of 5) appear to have reduced tolerability to Lenvatinib.
HCC patients other than those with moderate and severe hepatic impairment or severe renal impairment should initiate treatment at the recommended starting dose of 8 mg (two 4 mg capsules) for body weight <60 kg and 12 mg (three 4 mg capsules) for body weight ≥60 kg, following which the dose should be further adjusted on the basis of individual tolerability.
Patients with hypertension: Blood pressure should be well controlled prior to treatment with Lenvatinib, and should be regularly monitored during treatment.
Patients with hepatic impairment: DTC: No adjustment of starting dose is required on the basis of hepatic function in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. In patients with severe (Child-Pugh C) hepatic impairment, the recommended starting dose is 14 mg taken once daily. Further dose adjustments may be necessary on the basis of individual tolerability.
HCC: In the patient populations enrolled in the HCC study, no dose adjustments were required on the basis of hepatic function in those patients who had mild hepatic impairment (Child-Pugh A). The available very limited data are not sufficient to allow for a dosing recommendation for HCC patients with moderate hepatic impairment (Child-Pugh B). Close monitoring of overall safety is recommended in these patients. Lenvatinib has not been studied in patients with severe hepatic impairment (Child-Pugh C) and is not recommended for use in these patients.
EC: Limited data are available for the combination of lenvatinib with pembrolizumab in patients with hepatic impairment. No adjustment of starting dose of the combination is required on the basis of hepatic function in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. In patients with severe (Child-Pugh C) hepatic impairment, the recommended starting dose of lenvatinib is 10 mg taken once daily. Please refer to the SmPC for pembrolizumab for dosing in patients with hepatic impairment. Further dose adjustments may be necessary on the basis of individual tolerability.
Patients with renal impairment: DTC: No adjustment of starting dose is required on the basis of renal function in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended starting dose is 14 mg taken once daily. Further dose adjustments may be necessary based on individual tolerability. Patients with end-stage renal disease were not studied, therefore the use of Lenvatinib in these patients is not recommended.
HCC: No dose adjustments are required on the basis of renal function in 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.
EC: No adjustment of starting dose is required on the basis of renal function in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended starting dose is 10 mg of lenvatinib taken once daily. Please refer to the SmPC for pembrolizumab for dosing in patients with renal impairment. Further dose adjustments may be necessary based on individual tolerability. Patients with end-stage renal disease have not been studied, therefore the use of lenvatinib in these patients is not recommended.
Elderly population: No adjustment of starting dose is required on the basis of age. Limited data are available on use in patients aged ≥75 years.
Pediatric population: Lenvatinib should not be used in children younger than 2 years of age because of safety concerns identified in animal studies. The safety and efficacy of Lenvatinib in children aged 2 to <18 years have not yet been established. No data are available.
Race: No adjustment of starting dose is required on the basis of race. Limited data are available on use in patients from ethnic origins other than Caucasian or Asian.
Method of administration: Lenvatinib is for oral use. The capsules should be taken at about the same time each day, with or without food. The capsules should be swallowed whole with water. Caregivers should not open the capsule, in order to avoid repeated exposure to the contents of the capsule.
Alternatively, the Lenvatinib capsules may be added without breaking or crushing them to a tablespoon of water or apple juice in a small glass to produce a suspension. The capsules must be left in the liquid for at least 10 minutes and stirred for at least 3 minutes to dissolve the capsule shells. The suspension is to be swallowed. After drinking, the same amount of water or apple juice (one tablespoon) must be added to the glass and swirled a few times. The additional liquid must be swallowed.

The highest doses of Lenvatinib studied clinically were 32 mg and 40 mg per day. Accidental medication errors resulting in single doses of 40 to 48 mg have occurred in clinical trials. The most frequently observed adverse drug reactions at these doses were hypertension, nausea, diarrhea, fatigue, stomatitis, proteinuria, headache, and aggravation of PPE. There have also 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 (i.e., renal and cardiac failure), or were without adverse reactions.
Symptoms and Management: There is no specific antidote for overdose with Lenvatinib. In case of suspected overdose, Lenvatinib should be withheld and appropriate supportive care given as required.

Hypersensitivity to the active substance or to any of the excipients.

Hypertension: Hypertension has been reported in patients treated with Lenvatinib, usually occurring early in the course of treatment. Blood pressure (BP) should be well-controlled prior to treatment with Lenvatinib and, if patients are known to be hypertensive, they should be on a stable dose of antihypertensive therapy for at least 1 week prior to treatment with Lenvatinib. Serious complications of poorly controlled hypertension, including aortic dissection, have been reported. The early detection and effective management of hypertension are important to minimize the need for Lenvatinib dose interruptions and reductions. Antihypertensive agents should be started as soon as elevated BP is confirmed. BP should be monitored after 1 week of treatment with Lenvatinib, then every 2 weeks for the first 2 months, and monthly thereafter. The choice of antihypertensive treatment should be individualized to the patient's clinical circumstances and follow standard medical practice. For previously normotensive subjects, monotherapy with one of the classes of antihypertensives should be started when elevated BP is observed. For those patients already on an antihypertensive medicinal product, the dose of the current agent may be increased, if appropriate, or one or more agents of a different class of antihypertensive should be added. When necessary, manage hypertension as recommended in Table 5. (See Table 5.)

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Aneurysms and artery dissections: The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Lenvatinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.
Proteinuria: Proteinuria has been reported in patients treated with Lenvatinib, usually occurring early in the course of treatment. Urine protein should be monitored regularly. If urine dipstick proteinuria ≥2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary. Cases of nephrotic syndrome have been reported in patients using Lenvatinib. Lenvatinib should be discontinued in the event of nephrotic syndrome.
Diarrhea: Diarrhea has been reported frequently in patients treated with Lenvatinib, usually occurring early in the course of treatment. Prompt medical management of diarrhea should be instituted in order to prevent dehydration. Lenvatinib should be discontinued in the event of persistence of Grade 4 diarrhea despite medical management.
Cardiac dysfunction: Cardiac failure (<1%) and decreased left ventricular ejection fraction have been reported in patients treated with Lenvatinib. Patients should be monitored for clinical symptoms or signs of cardiac decompensation, as dose interruptions, adjustments, or discontinuation may be necessary.
Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior leucoencephalopathy syndrome (RPLS): PRES, also known as RPLS, has been reported in patients treated with Lenvatinib. PRES is a neurological disorder which 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 PRES. Appropriate measures should be taken to control blood pressure. In patients with signs or symptoms of PRES, dose interruptions, adjustments, or discontinuation may be necessary.
Arterial thromboembolisms: Arterial thromboembolisms (cerebrovascular accident, transient ischemic attack, and myocardial infarction) have been reported in patients treated with Lenvatinib. Lenvatinib has not been studied in patients who have had an arterial thromboembolism within the previous 6 months, and therefore should be used with caution in such patients. A treatment decision should be made based upon an assessment of the individual patient's benefit/risk. Lenvatinib should be discontinued following an arterial thrombotic event.
Hemorrhage: Serious tumour related bleeds, including fatal hemorrhagic events have occurred in clinical trials and have been reported in post-marketing experience. In post-marketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than in DTC or other tumour types. The degree of tumour invasion/infiltration of major blood vessels (e.g., carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumour shrinkage/necrosis following Lenvatinib therapy. Some cases of bleeding have occurred secondarily to tumour shrinkage and fistula formation, e.g., tracheo-esophageal fistula. Cases of fatal intracranial hemorrhage have been reported in some patients with or without brain metastases. Bleeding in sites other than the brain (e.g., trachea, intra-abdominal, lung) has also been reported. One fatal case of hepatic tumour hemorrhage in a patient with HCC has been reported.
Screening for and subsequent treatment of esophageal varices in patients with liver cirrhosis should be performed as per standard of care before starting treatment with Lenvatinib.
In the case of bleeding, dose interruptions, adjustments, or discontinuation may be required.
Gastrointestinal perforation and fistula formation: Gastrointestinal perforation or fistula have been reported in patients treated with Lenvatinib. In most cases, gastrointestinal perforation and fistula occurred in patients with risk factors such as prior surgery or radiotherapy. In the case of a gastrointestinal perforation or fistula, dose interruptions, adjustments, or discontinuation may be necessary.
Non-gastrointestinal fistula: Patients may be at increased risk for the development of fistula when treated with Lenvatinib. Cases of fistula formation or enlargement that involve areas of the body other than stomach or intestines were observed in clinical trials and in post-marketing experience (e.g., tracheal, tracheoesophageal, esophageal, cutaneous, female genital tract fistula). In addition, pneumothorax has been reported with and without clear evidence of a bronchopleural fistula. Some reports of fistula and pneumothorax occurred in association with tumour regression or necrosis. Prior surgery and radiotherapy may be contributing risk factors. Lung metastases may also increase the risk of pneumothorax. Lenvatinib should not be started in patients with fistula to avoid worsening and Lenvatinib should be permanently discontinued in patients with esophageal or tracheobronchial tract involvement and any Grade 4 fistula; limited information is available on the use of dose interruption or reduction in management of other events, but worsening was observed in some cases and caution should be taken. Lenvatinib may adversely affect the wound healing process as for other agents of the same class.
QT interval prolongation: QT/QTc interval prolongation has been reported at a higher incidence in patients treated with Lenvatinib than in patients treated with placebo. Electrocardiograms should be monitored at baseline and periodically during treatment in all patients with particular attention to those with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, and those taking medicinal products known to prolong the QT interval, including Class Ia and III antiarrhythmics. Lenvatinib should be withheld in the event of development of QT interval prolongation greater than 500 ms. Lenvatinib should be resumed at a reduced dose when QTc prolongation is resolved to <480 ms or baseline.
Electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia increase the risk of QT prolongation; therefore, electrolyte abnormalities should be monitored and corrected in all patients before starting treatment. Electrolytes (magnesium, potassium and calcium) should be monitored periodically during treatment. Blood calcium levels should be monitored at least monthly and calcium should be replaced as necessary during Lenvatinib treatment. Lenvatinib dose should be interrupted or dose adjusted as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia.
Impairment of thyroid stimulating hormone suppression/Thyroid dysfunction: Hypothyroidism has been reported in patients treated with Lenvatinib. Thyroid function 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.
Lenvatinib impairs exogenous thyroid suppression. Thyroid stimulating hormone (TSH) levels should be monitored on a regular basis and thyroid hormone administration should be adjusted to reach appropriate TSH levels, according to the patient's therapeutic target.
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): Cases of ONJ have been reported in patients treated with Lenvatinib. Some cases were reported in patients who had received prior or concomitant treatment with antiresorptive bone therapy, and/or other angiogenesis inhibitors, e.g., bevacizumab, TKI, mTOR inhibitors. Caution should therefore be exercised when Lenvatinib is used either simultaneously or sequentially with antiresorptive therapy and/or other angiogenesis inhibitors.
Invasive dental procedures are an identified risk factor. Prior to treatment with Lenvatinib, a dental examination and appropriate preventive dentistry should be considered. In patients who have previously received or are receiving intravenous bisphosphonates, invasive dental procedures should be avoided if possible.
Effects on ability to drive and use machines: Lenvatinib has minor influence on the ability to drive and use machines, due to undesirable effects such as fatigue and dizziness. Patients who experience these symptoms should use caution when driving or operating machines.
Hepatotoxicity: In DTC, liver-related adverse reactions most commonly reported in patients treated with Lenvatinib included increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood bilirubin. Hepatic failure and acute hepatitis have been reported in patients with DTC treated with Lenvatinib. The hepatic failure cases were generally reported in patients with progressive metastatic liver metastases disease.
In HCC patients treated with Lenvatinib in the trial, liver-related adverse reactions including hepatic encephalopathy and hepatic failure (including fatal reactions) were reported at a higher frequency compared to patients treated with sorafenib. Patients with worse hepatic impairment and/or greater liver tumour 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 and one third of the events of the hepatic encephalopathy were reported in patients with disease progression.
Data in HCC patients with moderate hepatic impairment (Child-Pugh B) are very limited and there are currently no data available in HCC patients with severe hepatic impairment (Child-Pugh C). Since Lenvatinib is mainly eliminated by hepatic metabolism, an increase in exposure in patients with moderate to severe hepatic impairment is expected.
Close monitoring of the overall safety is recommended in patients with mild or moderate hepatic impairment. 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.
Renal failure and impairment: Renal impairment and renal failure have been reported in patients treated with Lenvatinib. The primary risk factor identified was dehydration and/or 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.
If patients have severe renal impairment, the initial dose of Lenvatinib should be adjusted.
Special populations: Limited data are available for patients of ethnic origin other than Caucasian or Asian, and in patients aged ≥75 years. Lenvatinib should be used with caution in such patients, given the reduced tolerability of Lenvatinib in Asian and elderly patients.
There are no data on the use of Lenvatinib immediately following sorafenib or other anticancer treatments and there may be a potential risk for additive toxicities unless there is an adequate washout period between treatments. The minimal washout period in clinical trials was 4 weeks.
Women of childbearing potential: Women of childbearing potential must use highly effective contraception while taking Lenvatinib and for one month after stopping treatment. It is currently unknown if Lenvatinib increases the risk of thromboembolic events when combined with oral contraceptives.

Women of childbearing potential: Women of childbearing potential should avoid becoming pregnant and use highly effective contraception while on treatment with Lenvatinib and for at least one month after finishing treatment. It is currently unknown whether Lenvatinib may reduce the effectiveness of hormonal contraceptives, and therefore women using oral hormonal contraceptives should add a barrier method.
Pregnancy: There are no data on the use of Lenvatinib in pregnant women. Lenvatinib was embryotoxic and teratogenic when administered to 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.
Breastfeeding: It is not known whether Lenvatinib is excreted in human milk. Lenvatinib and its metabolites are excreted in rat milk. A risk to newborns or infants cannot be excluded and, therefore, Lenvatinib is contraindicated during breastfeeding.
Fertility: Effects in humans are unknown. However, testicular and ovarian toxicity has been observed in rats, dogs, and monkeys.

Summary of the safety profile: The safety profile of Lenvatinib is based on data from 452 DTC patients and 496 HCC patients; allowing characterization only of common adverse drug reactions in DTC and HCC patients. The adverse reactions presented in this section are based on safety data of both DTC and HCC patients.
DTC: The most frequently reported adverse reactions (occurring in ≥30% of patients) are hypertension (68.6%), diarrhea (62.8%), decreased appetite (51.5%), decreased weight (49.1%), fatigue (45.8%), nausea (44.5%), proteinuria (36.9%), stomatitis (35.8%), vomiting (34.5%), dysphonia (34.1%), headache (34.1%), and palmar-plantar erythrodysesthesia syndrome (PPE) (32.7%). Hypertension and proteinuria tend to occur early during Lenvatinib treatment. The majority of Grade 3 to 4 adverse reactions occurred during the first 6 months of treatment except for diarrhea, which occurred throughout treatment, and weight loss, which tended to be cumulative over time.
The most important serious adverse reactions were renal failure and impairment (2.4%), arterial thromboembolisms (3.9%), cardiac failure (0.7%), intracranial tumour hemorrhage (0.7%), PRES/RPLS (0.2%), hepatic failure (0.2%), and arterial thromboembolisms (cerebrovascular accident (1.1%), transient ischemic attack (0.7%), and myocardial infarction (0.9%).
In 452 patients with RAI-refractory DTC, dose reduction and discontinuation were the actions taken for an adverse reaction in 63.1% and 19.5% of patients, respectively. Adverse reactions that most commonly led to dose reductions (in ≥5% of patients) were hypertension, proteinuria, diarrhea, fatigue, PPE, decreased weight, and decreased appetite. Adverse reactions that most commonly led to discontinuation of Lenvatinib were proteinuria, asthenia, hypertension, cerebrovascular accident, diarrhea, and pulmonary embolism.
HCC: The most frequently reported adverse reactions (occurring in ≥30% of patients) are hypertension (44.0%), diarrhea (38.1%), decreased appetite (34.9%), fatigue (30.6%), and decreased weight (30.4%).
The most important serious adverse reactions were hepatic failure (2.8%), hepatic encephalopathy (4.6%), esophageal varices hemorrhage (1.4%), cerebral hemorrhage (0.6%), arterial thromboembolic events (2.0%) including myocardial infarction (0.8%), cerebral infarction (0.4%) and cerebrovascular accident (0.4%) and renal failure/impairment events (1.4%). There was a higher incidence of decreased neutrophil count in patients with HCC (8.7% on Lenvatinib than in other non-HCC tumour types (1.4%)), which was not associated with infection, sepsis or bacterial peritonitis.
In 496 patients with HCC, dose modification (interruption or reduction) and discontinuation were the actions taken for an adverse reaction in 62.3% and 20.2% of patients, respectively. Adverse reactions that most commonly led to dose modifications (in ≥5% of patients) were decreased appetite, diarrhea, proteinuria, hypertension, fatigue, PPE and decreased platelet count. Adverse reactions that most commonly led to discontinuation of Lenvatinib were hepatic encephalopathy, fatigue, increased blood bilirubin, proteinuria and hepatic failure.
EC: The safety of lenvatinib in combination with pembrolizumab has been evaluated in 530 patients with advanced EC receiving 20 mg lenvatinib once daily and 200 mg pembrolizumab every 3 weeks. The most common (occurring in ≥20% of patients) adverse reactions were hypertension (63%), diarrhea (57%), hypothyroidism (56%), nausea (51%), decreased appetite (47%), vomiting (39%), fatigue (38%), decreased weight (35%), arthralgia (33%), proteinuria (29%), constipation (27%), headache (27%), urinary tract infection (27%), dysphonia (25%), abdominal pain (23%), asthenia (23%), palmar-plantar erythrodysesthesia syndrome (23%), stomatitis (23%), anemia (22%), and hypomagnesemia (20%). The most common (occurring in ≥5% of patients) severe (Grade ≥3) adverse reactions were hypertension (37.2%), decreased weight (9.1%), diarrhea (8.1%), increased lipase (7.7%), decreased appetite (6.4%), asthenia (6%), fatigue (6%), hypokalemia (5.7%), anemia (5.3%) and proteinuria (5.1%).
Discontinuation of lenvatinib occurred in 30.6% of patients, and discontinuation of both lenvatinib and pembrolizumab occurred in 15.3% of patients due to an adverse reaction. The most common (occurring in ≥1% of patients) adverse reactions leading to discontinuation of lenvatinib were hypertension (1.9%), diarrhea (1.3%), asthenia (1.3%), decreased appetite (1.3%), proteinuria (1.3%) and decreased weight (1.1%).
Dose interruption of lenvatinib due to an adverse reaction occurred in 63.2% of patients. Dose interruption of lenvatinib and pembrolizumab due to an adverse reaction occurred in 34.3% of patients. The most common (occurring in ≥5% of patients) adverse reactions leading to interruption of lenvatinib were hypertension (12.6%), diarrhea (11.5%), proteinuria (7.2%), vomiting (7%), fatigue (5.7%), and decreased appetite (5.7%).
Dose reduction of lenvatinib due to adverse reactions occurred in 67.0% of patients. The most common (occurring in ≥5% of patients) adverse reactions resulting in dose reduction of lenvatinib were hypertension (16.2%), diarrhea (12.5%), palmar-plantar erythrodysesthesia syndrome (9.1%), fatigue (8.7%), proteinuria (7.7%), decreased appetite (6.6%), nausea (5.5%), asthenia (5.1%), and decreased weight (5.1%).
Tabulated list of adverse reactions: Similar adverse reactions were observed in clinical trials in DTC and HCC.
Adverse reactions observed in clinical trials in DTC and HCC and reported from post-marketing use of Lenvatinib are listed in Table 6. The adverse reaction frequency category represents the most conservative estimate of frequency from the two individual populations.
Frequencies are defined as: Very Common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Not known (cannot be estimated from the available data).
Within each frequency category, undesirable effects are presented in order of decreasing seriousness. (See Table 6.)

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Effect of other medicinal products on Lenvatinib: Chemotherapeutic agents: Concomitant administration of Lenvatinib, carboplatin, and paclitaxel has no significant impact on the pharmacokinetics of any of these 3 substances.
Effect of Lenvatinib on other medicinal products: A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma concentrations of midazolam (a sensitive CYP3A and Pgp substrate) were not altered in the presence of Lenvatinib. No significant drug-drug interaction is therefore expected between Lenvatinib and other CYP3A4/Pgp substrates.
Oral contraceptives: It is currently unknown whether Lenvatinib may reduce the effectiveness of hormonal contraceptives, and therefore women using oral hormonal contraceptives should add a barrier method.

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Targeted Cancer Therapy

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

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