Lenvima

Lenvatinib.

LENVIMA 4 mg: A yellowish-red body and yellowish-red cap, approximately 14.3 mm in length, marked in black ink with "Є" on the cap, and "LENV 4 mg" on the body.
Each hard capsule contains 4 mg of lenvatinib (as mesilate).
LENVIMA 10 mg: A yellow body and yellowish-red cap, approximately 14.3 mm in length, marked in black ink with "Є" on the cap, and "LENV 10 mg" on the body.
Each hard capsule contains 10 mg of lenvatinib (as mesilate).
Excipients/Inactive Ingredients: Calcium carbonate, Mannitol, Microcrystalline cellulose, Hydroxypropylcellulose, Low-substituted hydroxypropylcellulose, Talc, Hypromellose, Titanium dioxide (E171), Yellow iron oxide (E172), Red iron oxide (E172), Shellac, Black iron oxide (E172), Potassium hydroxide, Propylene glycol.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors. ATC code: L01EX08.
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. The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumour activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signalling in vitro and tumour volume in mouse xenograft models of human renal cell cancer greater than each drug alone.
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.
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 downregulation of VEGFR1 and VEGFR2 in the podocytes of the glomerulus.
The mechanism of action for the worsening of hypercholesterolemia with the combination of lenvatinib and everolimus has not been studied directly and is not fully elucidated.
Although not studied directly, the MOA for the worsening of diarrhoea with the combination of lenvatinib and everolimus is postulated to be mediated by the impairment of intestinal function related to the MOAs for the individual agents - VEGF/VEGFR and c-KIT inhibition by lenvatinib coupled with mTOR/NHE3 inhibition by everolimus.
Clinical efficacy: Radioiodine-refractory differentiated thyroid cancer: A multicentre, randomised, double-blind, placebo-controlled trial (SELECT, Study 303) that was conducted in 392 patients with radioiodine-refractory differentiated thyroid cancer with independent, centrally reviewed, radiographic evidence of disease progression within 12 months (+1 month window) prior to enrollment. Radioiodine-refractory was defined as one or more measurable lesions either with a lack of iodine uptake or with progression in spite of radioactive-iodine (RAI) therapy, or having a cumulative activity of RAI of >600 mCi or 22 GBq with the last dose at least 6 months prior to study entry. Randomisation was stratified by geographic region (Europe, North America, and Other), prior VEGF/VEGFR-targeted therapy (patients may have received 0 or 1 prior VEGF/VEGFR-targeted therapy), and age (≤65 years or >65 years). The main efficacy outcome measure was progression-free survival (PFS) as determined by blinded independent radiologic review using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Secondary efficacy outcome measures included overall response rate and overall survival. Patients in the placebo arm could opt to receive lenvatinib treatment at the time of confirmed disease progression.
Eligible patients with measurable disease according to RECIST 1.1 were randomised 2:1 to receive lenvatinib 24 mg once daily (n=261) or placebo (n=131). Baseline demographics and disease characteristics were well balanced for both treatment groups. Of the 392 patients randomised, 76.3% were naïve to prior VEGF/VEGFR-targeted therapies, 49.0% were female, 49.7% were European, and the median age was 63 years. Histologically, 66.1% had a confirmed diagnosis of papillary thyroid cancer and 33.9% had follicular thyroid cancer which included Hürthle cell 14.8% and clear cell 3.8%. Metastases were present in 99% of the patients: lungs in 89.3%, lymph nodes in 51.5%, bone in 38.8%, liver in 18.1%, pleura in 16.3%, and brain in 4.1%. The majority of patients had an ECOG performance status of 0; 42.1% had a status of 1; 3.9% had a status above 1. The median cumulative RAI activity administered prior to study entry was 350 mCi (12.95 GBq).
A statistically significant prolongation in PFS was demonstrated in lenvatinib-treated patients compared with those receiving placebo (p <0.0001) (see Figure 1). The positive effect on PFS was seen across the subgroups of age (above or below 65 years), sex, race, histological subtype, geographic region, and those who received 0 or 1 prior VEGF/VEGFR-targeted therapy. Following independent review confirmation of disease progression, 109 (83.2%) patients randomised to placebo had crossed over to open-label lenvatinib at the time of the primary efficacy analysis.
The objective response rate (complete response [CR] plus partial response [PR]) per independent radiological review was significantly (p <0.0001) higher in the lenvatinib-treated group (64.8%) than in the placebo-treated group (1.5%). Four (1.5%) subjects treated with lenvatinib attained a CR and 165 subjects (63.2%) had a PR, while no subjects treated with placebo had a CR and 2 (1.5%) subjects had a PR.
The median time to first dose reduction was 2.8 months. The median time to objective responsive was 2.0 (95% CI: 1.9, 3.5) months; however, of the patients who experienced a complete or partial response to lenvatinib, 70.4% were observed to develop the response on or within 30 days of being on the 24-mg dose.
An overall survival analysis was confounded by the fact that placebo-treated subjects with confirmed disease progression had the option to cross over to open-label lenvatinib. There was no statistically significant difference in overall survival between the treatment groups at the time of the primary efficacy analysis (HR=0.73; 95% CI: 0.50, 1.07, p=0.1032). The median OS had not been reached for either the lenvatinib group or the placebo crossover group. (See Table 1 and Figure 1.)

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Advanced Renal Cell Carcinoma: Combination With Pembrolizumab First-Line Treatment (Study 307): The efficacy of lenvatinib in combination with pembrolizumab was investigated in (CLEAR, Study 307), a multicenter, open-label, randomized trial that enrolled 1069 patients with advanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomization was stratified by geographic region. (North America and Western Europe versus "Rest of the World") and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups (favorable, intermediate, and poor risk).
Patients were randomized to lenvatinib 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every 3 weeks (n=355), or lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=357), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=357). All patients on the lenvatinib plus pembrolizumab arm were started on lenvatinib 20 mg orally once daily. The median time to first dose reduction for lenvatinib was 1.9 months. The median average daily dose for lenvatinib was 14 mg. Treatment continued until unacceptable toxicity or disease progression as determined by the investigator and confirmed by independent radiologic review committee (IRC) using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1).
Administration of lenvatinib with pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Pembrolizumab dosing was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every 8 weeks.
The overall study population characteristics were: median age of 62 years (range: 29 to 88 years); 42% age 65 or older, 75% male; 74% White, 21% Asian, 1% Black, and 2% other races; 18% and 82% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; patient distribution by IMDC (International Metastatic RCC Database Consortium) risk categories was 33% favorable, 56% intermediate and 10% poor, and MSKCC risk categories was 27% favorable, 64% intermediate and 9% poor. Common sites of metastases in patients were lung (68%), lymph node (45%), and bone (25%).
The primary efficacy outcome measure was progression free survival (PFS) based on RECIST 1.1 per IRC. Key secondary efficacy outcome measures included overall survival (OS) and objective response rate (ORR). Lenvatinib in combination with pembrolizumab demonstrated statistically significant improvements in PFS, OS and ORR compared with sunitinib. Efficacy results for CLEAR are summarized in Table 2 and Figures 2, 3 and 4, at a median OS follow-up time of 26.6 months. Progressive disease as best overall response was observed in 5.4% of patients treated with lenvatinib in combination with pembrolizumab compared with 14.0% of patients treated with sunitinib. Consistent results were observed across pre-specified subgroups, MSKCC prognostic groups and PD-L1 tumor expression status (see Figure 4). (See Table 2, Figures 2, 3 and 4.)

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Assessment of Quality of Life (QoL) in Patients with RCC: Patient-reported outcomes (PRO) were assessed using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-30 and Kidney Cancer Symptom Index (FKSI-DRS). From baseline to a mean follow-up time of 46 weeks, patients treated with lenvatinib in combination with pembrolizumab had better physical functioning, fatigue, dyspnea, and constipation scores compared to the sunitinib group.
Compared to sunitinib, lenvatinib in combination with pembrolizumab showed a more than 12 week delay in median time to worsening in global health status (GHS), physical functioning and patient reported symptoms with no subsequent recovery: EORTC QLQ-C30 GHS (114 vs. 75 weeks, HR=0.6 [95%CI: 0.47, 0.77]), physical functioning (134 vs 78 weeks, HR=0.52 [95% CI: 0.41, 0.67]), fatigue (110 vs. 59 weeks, HR=0.54 [95% CI: 0.43, 0.67]), insomnia (156 vs. 126 weeks, HR=0.63 [95% CI: 0.47. 0.85]), dyspnea (153 vs. 126 weeks, HR=0.56 [95% CI: 0.41, 0.76]), nausea and vomiting (147 vs 131 weeks, (HR=0.53 [95% CI: 0.39, 0.74]), pain (119 vs. 105 weeks, HR=0.68 [95% CI: 0.53, 0.87]) and FKSI-DRS (134 vs. 117 weeks, HR=0.7 [95% CI: 0.53, 0.92]).
Combination With Everolimus Second-Line Treatment (Study 205): A multicenter, randomised, 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 1b portion included 11 patients who received the combination of 18 mg of lenvatinib plus 5 mg of everolimus. The Phase 2 portion enrolled a total of 153 patients with unresectable advanced or metastatic RCC following 1 prior VEGF-targeted treatment. A total of 62 patients received the combination of lenvatinib and everolimus at the recommended dose. Patients were required, among others, to have histological confirmation of predominant clear cell RCC, radiographic evidence of disease progression according to Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST 1.1), one prior VEGF-targeted therapy and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
Patients were randomly allocated to one of 3 arms: 18 mg of lenvatinib plus 5 mg of everolimus, 24 mg of lenvatinib or 10 mg of everolimus using a 1:1:1 ratio. Patients were stratified by hemoglobin level (≤13 g/dL vs. >13 g/dL for males and ≤11.5 g/dL vs >11.5 g/dL for females) and corrected serum calcium (≥10 mg/dL vs. <10 mg/dL). The median of average daily dose in the combination arm per subject was 13.5 mg of lenvatinib (75.0% of the intended dose of 18 mg) and 4.7 mg of everolimus (93.6% of the intended dose of 5 mg). The final dose level in the combination arm was 18 mg for 29% of patients, 14 mg for 31% of patients, 10 mg for 23% of patients, 8 mg for 16% of patients and 4 mg for 2% of patients.
Of the 153 patients randomly allocated, 73% were male, the median age was 61 years, 37% were 65 years or older, 7% were 75 years or older, and 97% were Caucasian. Metastases were present in 95% of the patients and unresectable advanced disease was present in 5%. All patients had a baseline ECOG PS of either 0 (55%) or 1 (45%) with similar distribution across the 3 treatment arms. Memorial Sloan Kettering Cancer Center (MSKCC) poor risk was observed in 39% of patients in the lenvatinib plus everolimus arm, 44% in the lenvatinib arm and 38% in the everolimus arm. International mRCC Database Consortium (IMDC) poor risk was observed in 20% of patients in the lenvatinib plus everolimus arm, 23% in the lenvatinib arm, and 24% in the everolimus arm, The median time from diagnosis to first dose was 32 months in the lenvatinib plus everolimus-treatment arm, 33 months the lenvatinib arm and 26 months in the everolimus arm. All patients had been treated with 1 prior VEFG-inhibitor 65% with sunitinib, 23% with pazopanib, 4% with tivozanib, 3% with bevacizumab, and 2% each with sorafenib or axitinib.
The primary efficacy outcome measure, based on investigator assessed tumour response, was progression-free survival (PFS) of the lenvatinib plus everolimus arm vs the everolimus arm and of the lenvatinib arm vs the everolimus arm. Other efficacy outcome measures included overall survival (OS) and investigator-assessed objective response rate (ORR). Tumour assessments were evaluated according to RECIST 1.1.
The lenvatinib plus everolimus arm showed a statistically significant and clinically meaningful improvement in PFS compared with the everolimus arm (see Table 3 and Figure 5). Based on the results of a post-hoc exploratory analysis in a limited number of patients per subgroup, the positive effect on PFS was seen regardless of which prior VEGF-targeted therapy was used: sunitinib (Hazard ratio [HR]=0.356 [95% CI: 0.188, 0.674] or other therapies (HR=0.350 [95% CI: 0.148, 0.828]). The lenvatinib arm also showed an improvement in PFS compared with the everolimus arm. Overall survival was longer in the lenvatinib plus everolimus arm (see Table 3 and Figure 6). The study was not powered for the OS analysis.
The treatment effect of the combination on PFS and ORR was also supported by a post-hoc retrospective independent blinded review of scans. The lenvatinib plus everolimus arm showed a statistically significant and clinically meaningful improvement in PFS compared with the everolimus arm. Results for ORR were consistent with that of the investigators' assessments, 35.3% in the lenvatinib plus everolimus arm, with one complete response and 17 partial responses; no subject had an objective response in the everolimus arm (P<0.0001) in favor of the lenvatinib plus everolimus arm. (See Table 3, Figures 5 and 6.)

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Hepatocellular Carcinoma: The clinical efficacy and safety of lenvatinib have been evaluated in an international, multicenter, open-label, randomised phase 3 study (REFLECT) in patients with unresectable hepatocellular carcinoma (HCC).
In total, 954 patients were randomised 1:1 to receive either lenvatinib (12 mg [baseline body weight ≥60 kg] or 8 mg [baseline body weight <60 kg]) given orally once daily or sorafenib 400 mg given orally twice daily.
Patients were eligible to participate if they had a liver function status of Child-Pugh class A and Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1. Patients were excluded who had prior systemic anticancer therapy for advanced/unresectable HCC or any prior anti-VEGF therapy. Target lesions previously treated with radiotherapy or locoregional therapy had to show radiographic evidence of disease progression. Patients with ≥50% liver occupation, clear invasion into the bile duct or a main branch of the portal vein (Vp4) on imaging were also excluded.
Demographic and baseline disease characteristics were similar between the lenvatinib and the sorafenib groups and are shown as follows for all 954 randomised patients: Median age: 62 years; Male: 84%; White: 29%, Asian: 69%, Black or African American: 1.4%; Body weight: <60 kg -31%, 60-80 kg - 50%, >80 kg - 19%; Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0: 63%, ECOG PS of 1: 37%; Child-Pugh A: 99%, Child-Pugh B: 1%; Aetiology: Hepatitis B (50%), Hepatitis C (23%), alcohol (6%); Absence of macroscopic portal vein invasion (MPVI): 79%; Absence of MPVI, extra-hepatic tumour spread (EHS) or both: 30%; Underlying cirrhosis (by independent imaging review): 75%; Barcelona Clinic Liver Cancer (BCLC) stage B: 20%; BCLC stage C: 80%; Prior treatments: hepatectomy (28%), radiotherapy (11%), loco-regional therapies including transarterial (chemo) embolisation (52%), radiofrequency ablation (21%) and percutaneous ethanol injection (4%).
The primary efficacy endpoint was Overall Survival (OS). Lenvatinib was non-inferior for OS to sorafenib with HR=0.92 [95% CI of (0.79, 1.06)] and a median OS of 13.6 months vs 12.3 months (see Table 4 and Figure 7). The results for surrogate endpoints (PFS and ORR) are presented in Table 4 as follows. (See Table 4 and Figure 7.)

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In subgroup analyses by stratification factors (presence or absence of MPVI or EHS or both, ECOG PS 0 or 1, BW <60 kg or ≥60 kg and region) the HR consistently favoured lenvatinib over sorafenib, with the exception of Western region [HR of 1.08 (95% CI 0.82, 1.42], patients without EHS [HR of 1.01 (95% CI 0.78, 1.30)] and patients without MPVI, EHS or both [HR of 1.05 (0.79, 1.40)]. The results of subgroup analyses should be interpreted with caution.
The median duration of treatment was 5.7 months (Q1: 2.9, Q3: 11.1) in the lenvatinib arm and 3.7 months (Q1: 1.8, Q3: 7.4) in the sorafenib arm.
In both treatment arms in the REFLECT study, median OS was approximately 9 months longer in subjects who received post-treatment anticancer therapy than in those who did not. In the lenvatinib arm, median OS was 19.5 months (95% CI: 15.7, 23.0) for subjects who received post-treatment anticancer therapy (43%) and 10.5 months (95% CI: 8.6, 12.2) for those who did not. In the sorafenib arm, median OS was 17.0 months (95% CI: 14.2, 18.8) for subjects who received post-treatment anticancer therapy (51%) and 7.9 months (95% CI: 6.6, 9.7) for those who did not. Median OS was longer by approximately 2.5 months in the lenvatinib compared with the sorafenib arm in both subsets of subjects (with or without post-treatment anticancer therapy).
Endometrial Carcinoma (EC): The efficacy of lenvatinib in combination with pembrolizumab was investigated in Study 309, a randomized, multicenter, open-label, active-controlled study conducted in patients with advanced EC who had been previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Participants may have received up to 2 platinum-containing therapies in total, as long as one was given in the neoadjuvant or adjuvant treatment setting. The study excluded patients with endometrial sarcoma (including carcinosarcoma), or patients who had active autoimmune disease or a medical condition that required immunosuppression. Randomization was stratified by MMR status (dMMR or pMMR [not dMMR]) using a validated IHC test. The pMMR stratum was further stratified by ECOG performance status, geographic region, and history of pelvic radiation. Patients were randomised (1:1) to one of the following treatment arms: lenvatinib 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every 3 weeks; investigator's choice consisting of either doxorubicin 60 mg/m² every 3 weeks, or paclitaxel 80 mg/m² given weekly, 3 weeks on/1 week off.
Treatment with lenvatinib and pembrolizumab continued until RECIST v1.1-defined progression of disease as verified by blinded independent central review (BICR), unacceptable toxicity, or for pembrolizumab, a maximum of 24 months. Administration of study treatment was permitted beyond RECIST-defined disease progression if the treating investigator considered the patient to be deriving clinical benefit and the treatment was tolerated. A total of 121/411 (29%) of the lenvatinib and pembrolizumab-treated patients received continued study therapy beyond RECIST-defined disease progression. The median duration of postprogression therapy was 2.8 months. Assessment of tumor status was performed every 8 weeks.
A total of 827 patients were enrolled and randomized to lenvatinib in combination with pembrolizumab (n=411) or investigator's choice of doxorubicin (n=306) or paclitaxel (n=110). The baseline characteristics of these patients were: median age of 65 years (range 30 to 86), 50% age 65 or older; 61% White, 21% Asian, and 4% Black; ECOG PS of 0 (59%) or 1 (41%), and 84% with pMMR tumor status, and 16% with dMMR tumour status. The histologic subtypes were endometrioid carcinoma (60%), serous (26%), clear cell carcinoma (6%), mixed (5%), and other (3%). All 827 of these patients received prior systemic therapy for EC: 69% had one, 28% had two, and 3% had three or more prior systemic therapies. Thirty-seven percent of patients received only prior neoadjuvant or adjuvant therapy.
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).
The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). Secondary efficacy outcome measures included ORR, as assessed by BICR using RECIST 1.1. At the prespecified interim analysis, with a median follow-up time of 11.4 months (range: 0.3 to 26.9 months), the study demonstrated a statistically significant improvement in OS and PFS in the all-comer population.
Efficacy results by MMR subgroups were consistent with overall study results.
The pre-specified final OS analysis with approximately 16 months of additional follow-up duration from the interim analysis (overall median follow-up time of 14.7 months [range: 0.3 to 43.0 months]) was performed without multiplicity adjustment. The efficacy results in the all-comer population are summarised in Table 5. Kaplan-Meier curves for final OS and interim PFS analyses are shown in Figures 8 and 9, respectively. (See Table 5, Figures 8 and 9.)

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QT interval prolongation: A single 32-mg dose of lenvatinib did not prolong the QT/QTc interval based on results from a thorough QT study in healthy volunteers; however, QT/QTc interval prolongation has been reported at a higher incidence in patients treated with lenvatinib than in patients treated with placebo (see Precautions and Adverse Reactions).
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 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 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 suggests 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. 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.
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 (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 faeces, 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 C_max,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 C_max. 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-fourth of the radiolabel were eliminated in the faeces 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 (C_max 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 was 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. See Dosage & Administration for dosing recommendation.
There are not sufficient data for HCC patients with Child-Pugh B (moderate hepatic impairment, 3 patients treated with lenvima 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. See Dosage & Administration for dosing recommendation.
Age, sex, weight, 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), age, sex, weight, and race (Japanese vs. other, Caucasian vs. other) had no significant effects on clearance (see Dosage & Administration).
Tumour Type: Tumour type had no significant effect on clearance (Cl/F), based on 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).
Paediatric Population: Based on population pharmacokinetic analysis of patients receiving up to 24 mg lenvatinib once daily as monotherapy, in the presence of body weight effect on Cl/F age had no significant effect on Cl/F in paediatric patients.
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 haemorrhage) 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 (foetal external and skeletal anomalies) at exposures below the clinical exposure (based on AUC) at the maximum tolerated human dose, and rabbits (foetal 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.

LENVIMA is indicated 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).
LENVIMA in combination with pembrolizumab is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
LENVIMA is indicated in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF)-targeted therapy.
LENVIMA is indicated as monotherapy for the treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have received no prior systemic therapy (see Pharmacology: Pharmacodynamics under Actions).
LENVIMA, 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 platinum-containing therapy in any setting and are not candidates for curative surgery or radiation.

LENVIMA treatment should be initiated and supervised by a health care professional experienced in the use of anticancer therapies.
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.
Optimal medical management (i.e. treatment or therapy) for nausea, vomiting, and diarrhoea should be initiated prior to any lenvatinib therapy interruption or dose reduction; however, gastrointestinal toxicity should be actively treated in order to reduce the risk of development of renal impairment or failure (see Renal failure and impairment/Gastrointestinal Toxicity under Precautions).
Posology: 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.
Renal Cell Carcinoma (RCC): Lenvatinib in combination with pembrolizumab: Initial dosing regimen: The recommended 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. Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information.
Lenvatinib in combination with everolimus: Initial dosing regimen: The recommended daily dose of lenvatinib is 18 mg (one 10 mg capsule and two 4 mg capsules) once daily in combination with 5 mg of everolimus once daily. The daily doses of lenvatinib and, if necessary, everolimus are to be modified as needed according to the dose/toxicity management plan.
Hepatocellular Carcinoma (HCC): 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.
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 every 3 weeks, until unacceptable toxicity or disease progression.
Refer to the pembrolizumab prescribing information for additional dosing information.
Monitoring, dose medication and discontinuation: Management of adverse reactions may require dose interruption, adjustment, or discontinuation of lenvatinib therapy or the combination therapy (see Precautions). Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not warrant interruption of lenvatinib or of the combination, unless intolerable to the patient despite optimal management. Severe (e.g., Grade 3) or intolerable adverse reactions require interruption of lenvatinib or of the combination of medicines until improvement of the reaction to Grade 0-1 or baseline.
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 reactions (e.g., Grade 3).
Dose adjustment and discontinuations for DTC: For lenvatinib related toxicities (see Table 6), 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 7.
Dose adjustment and discontinuations for RCC: In combination with pembrolizumab: For lenvatinib-related toxicities, upon resolution/improvement of an adverse reaction, treatment should be resumed at a reduced dose as suggested in Table 8. 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 for pembrolizumab. No dose reductions are recommended for pembrolizumab.
In combination with everolimus: 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 advice on specific adverse reactions).
For toxicities thought to be related to both lenvatinib and everolimus, lenvatinib should be reduced (see Table 8) prior to reducing everolimus.
Dose adjustment 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 9.
Dose adjustment and Discontinuation for EC: For lenvatinib-related toxicities see Table 6. When administering lenvatinib in combination with pembrolizumab, interrupt, dose reduce, or discontinue lenvatinib as appropriate (see table 10). Withhold or discontinue pembrolizumab in accordance with the instructions in the prescribing information for pembrolizumab. No dose reductions are recommended for pembrolizumab. (See Tables 6, 7, 8, 9 and 10.)

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Special populations: 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 (see Other special populations under Adverse Reactions). 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.
RCC: No data for the combination of lenvatinib and everolimus are available for most of the special populations. The following information is derived from the clinical experience on single agent lenvatinib in patients with differentiated thyroid cancer (DTC).
All patients other than those with severe hepatic or renal impairment (see as follows) should initiate treatment at the recommended dose of 20 mg of lenvatinib daily with pembrolizumab or 18 mg of lenvatinib with 5 mg of everolimus taken once daily as indicated, 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 (see Precautions). Refer also to Other special populations under Adverse Reactions.
Patients with hepatic impairment: DTC, 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: DTC: 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. 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: DTC, RCC and 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: DTC: 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 individual tolerability. Patients with end-stage renal disease have not been studied, therefore the use of lenvatinib in these patients is not recommended.
Limited data are available for the combination of lenvatinib with pembrolizumab or everolimus in patients with renal impairment. 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. Limited data are available on use in patients aged ≥75 years (see also Other special populations under Adverse Reactions).
Paediatric population: Lenvatinib should not be used in children younger than 2 years of age because of safety concerns identified in animal studies (see Pharmacology: Toxicology: Preclinical safety data under Actions). The safety and efficacy of lenvatinib in children aged 2 to <18 years have not yet been established (see Pharmacology: Pharmacodynamics under Actions). No data are available.
Race: No adjustment of starting dose is required on the basis of race (see Pharmacology: Pharmacokinetics under Actions). Limited data are available on use in patients from ethnic origins other than Caucasian or Asian (see also Other special populations under Adverse Reactions).
Body weight below 60 kg in RCC: No adjustment of starting dose is required on the basis of body weight. Limited data are available on treatment with lenvatinib in combination with everolimus in patients with a body weight below 60 kg with RCC (see also Other special populations under Adverse Reactions).
Patients with high ECOG performance status in RCC: Patients with an ECOG (Eastern Cooperative Oncology Group) performance status of 2 or higher were excluded from the RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions). Patients with a KPS (Karnofsky Performance Status) <70 were excluded from Study 307 (CLEAR). Benefit-risk in these patients has not been evaluated.
Method of administration: Lenvatinib is for oral use. The capsules should be taken at about the same time each day, with or without food (see Pharmacology: Pharmacokinetics under Actions). 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 also occurred in clinical trials. The most frequently observed adverse drug reactions at these doses were hypertension, nausea, diarrhoea, 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 listed in Description.
Breast-feeding (see Use in Pregnancy & Lactation).

Hypertension: Hypertension has been reported in patients treated with lenvatinib, usually occurring early in the course of treatment (see Description of selected adverse reactions under Adverse Reactions). 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 minimise 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 individualised 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 antihypertensive medication, 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 11. (See Table 11.)

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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 (see Description of selected adverse reactions under Adverse Reactions). Urine protein should be monitored regularly. If urine dipstick proteinuria ≥2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration). Cases of nephrotic syndrome have been reported in patients using lenvatinib. Lenvatinib should be discontinued in the event of nephrotic syndrome.
Renal failure and impairment/Gastrointestinal Toxicity: Renal impairment and renal failure have been reported in patients treated with lenvatinib (see Description of selected adverse reactions under Adverse Reactions). 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. In RCC, caution should be taken in patients receiving agents acting on the renin-angiotensin aldosterone system given a potentially higher risk for acute renal failure with the combination treatment. Dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
If patients have severe renal impairment, the initial dose of lenvatinib should be adjusted (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Cardiac dysfunction: Cardiac failure (<1%) and decreased left ventricular ejection fraction have been reported in patients treated with lenvatinib (see Description of selected adverse reactions under 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).
Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior leucoencephalopathy syndrome (RPLS): PRES, also known as RPLS, has been reported in patients treated with lenvatinib (<1%; see Description of selected adverse reactions under Adverse Reactions). 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 (see Hypertension as previously mentioned). In patients with signs or symptoms of PRES, dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
Hepatotoxicity: In DTC and RCC patients, 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 (<1%; see Description of selected adverse reactions under Adverse Reactions) 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 REFLECT trial, liver-related adverse reactions including hepatic encephalopathy and hepatic failure (including fatal reactions) were reported at a higher frequency (see Adverse Reactions) 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 (see also Dosage & Administration and Pharmacology: Pharmacokinetics under Actions). 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 Dosage & Administration).
Arterial thromboembolisms: Arterial thromboembolisms (cerebrovascular accident, transient ischaemic attack, and myocardial infarction) have been reported in patients treated with lenvatinib (see Description of selected adverse reactions under Adverse Reactions). 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.
Haemorrhage: Serious tumour related bleeds, including fatal haemorrhagic events have occurred in clinical trials and have been reported in post-marketing experience (see Description of selected adverse reactions under Adverse Reactions). In post-marketing surveillance, serious and fatal carotid artery haemorrhages 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 haemorrhage associated with tumour shrinkage/necrosis following lenvatinib therapy. Some cases of bleeding have occurred secondarily to tumour shrinkage and fistula formation, e.g. tracheooesophageal fistula. Cases of fatal intracranial haemorrhage 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 haemorrhage in a patient with HCC has been reported.
Screening for and subsequent treatment of oesophageal varices in patients with liver cirrhosis should be performed as per standard of care before starting treatment with lenvatinib.
In RCC, serious cases of haemorrhage have been reported in patients treated with lenvatinib (see Description of selected adverse reactions under Adverse Reactions). Cases of fatal intracranial haemorrhage have been reported in some patients with or without brain metastases.
In the case of bleeding, dose interruptions, adjustments, or discontinuation may be required (see Table 6 under Dosage & Administration).
Gastrointestinal perforation and fistulae formation: Gastrointestinal perforation or fistula has been reported in patients treated with lenvatinib (see Adverse Reactions). 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 (see Dosage & Administration).
Non-Gastrointestinal fistula: Patients may be at increased risk for the development of fistula when treated with lenvatinib in DTC. Cases of fistula formation or enlargement that involve other areas of the body than stomach or intestines were observed in clinical trials and in post-marketing experience (e.g. tracheal, tracheo-oesophageal, oesophageal, cutaneous, female genital tract fistulae). 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. Lenvatinib should not be started in patients with fistula to avoid worsening and lenvatinib should be permanently discontinued in patients with oesophageal or tracheobronchial tract involvement and any Grade 4 fistula (see Dosage & Administration); 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 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 (see Description of selected adverse reactions under Adverse Reactions). Electrocardiograms should be monitored at baseline and periodically during treatment in all patients with a special attention for 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 hypokalaemia, hypocalcaemia, or hypomagnesaemia increase the risk of QT prolongation, therefore electrolyte abnormalities should be monitored and corrected in all patients before starting treatment. Periodic monitoring of ECG and electrolytes (magnesium, potassium and calcium) should be considered 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 hypocalcaemia.
Impairment of thyroid stimulating hormone suppression/Thyroid dysfunction: Hypothyroidism has been reported in patients treated with lenvatinib (see Description of selected adverse reactions under Adverse Reactions). 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 (see Description of selected adverse reactions under Adverse Reactions). 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.
Diarrhoea: Diarrhoea has been reported frequently in patients treated with lenvatinib, usually occurring early in the course of treatment (see Description of selected adverse reactions under Adverse Reactions). Prompt medical management of diarrhoea should be instituted in order to prevent dehydration. Lenvatinib should be discontinued in the event of persistence of Grade 4 diarrhoea despite medical management.
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.
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 (see Other special populations under Adverse Reactions).
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 of 4 weeks.
Effects on ability to drive and use machines: Lenvatinib has a 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.
Women of childbearing potential: Women of childbearing potential must use highly effective contraception while taking lenvatinib and for one month after stopping treatment (see Use in Pregnancy & Lactation). It is currently unknown if lenvatinib increases the risk of thromboembolic events when combined with oral contraceptives.

Information on fertility, pregnancy and lactation as follows is relevant to use of lenvatinib monotherapy. When using lenvatinib in combination with everolimus or pembrolizumab, see as follows and also refer to the manufacturer's prescribing information for everolimus or pembrolizumab.
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 (see Pharmacology: Toxicology: Preclinical safety data under Actions).
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 foetus.
Breast-feeding: It is not known whether lenvatinib is excreted in human milk. Lenvatinib and its metabolites are excreted in rat milk (see Pharmacology: Toxicology: Preclinical safety data under Actions). A risk to newborns or infants cannot be excluded and, therefore, lenvatinib is contraindicated during breast-feeding (see Contraindications).
Fertility: Effects in humans are unknown. However, testicular and ovarian toxicity has been observed in rats, dogs, and monkeys (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: The safety profile of lenvatinib is based on pooled data from 497 RCC patients treated with lenvatinib in combination with pembrolizumab, including Study 307 (CLEAR), 62 RCC patients treated with lenvatinib in combination with everolimus in Study 205; 458 DTC patients and 496 HCC patients treated with lenvatinib as single-agent therapy.
Lenvatinib in combination with pembrolizumab in RCC: The safety profile of lenvatinib in combination with pembrolizumab is based on data from 497 RCC patients. The most frequently reported adverse reactions (occurring in ≥30% of patients) were diarrhoea (61.8%), hypertension (51.5%) fatigue (47.1%), hypothyroidism (45.1%), decreased appetite (42.1%), nausea (39.6%), stomatitis (36.6%), proteinuria (33.0%), dysphonia (32.8%), and arthralgia (32.4%).
The most common severe (Grade ≥3) adverse reactions (≥5%) were hypertension (26.2%), lipase increased (12.9%), diarrhoea (9.5%), proteinuria (8.0%), amylase increased (7.6%), weight decreased (7.2%), and fatigue (5.2%).
Discontinuation of lenvatinib, pembrolizumab, or both due to an adverse reaction occurred in 33.4% of patients; 23.7% lenvatinib, and 12.9 % both drugs. The most common adverse reactions (≥1%) leading to discontinuation of lenvatinib, pembrolizumab, or both were myocardial infarction (2.4%), diarrhoea (2.0%), proteinuria (1.8%), and rash (1.4%). Adverse reactions that most commonly led to discontinuation of lenvatinib (≥1%) were myocardial infarction (2.2%), proteinuria (1.8%), and diarrhoea (1.0%).
Dose interruptions of lenvatinib, pembrolizumab, or both due to an adverse reaction occurred in 80.1% of patients; lenvatinib was interrupted in 75.3%, and both drugs in 38.6% of patients. Lenvatinib was dose reduced in 68.4% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of lenvatinib were diarrhoea (25.6%), hypertension (16.1%), proteinuria (13.7%), fatigue (13.1%), appetite decreased (10.9%), palmar-plantar erythrodysaesthesia syndrome (PPE) (10.7%), nausea (9.7%), asthenia (6.6%), stomatitis (6.2%), lipase increased (5.6%), and vomiting (5.6%).
Lenvatinib in combination with everolimus in RCC: The safety profile of lenvatinib in combination with everolimus is based on data from 62 subjects-patients, allowing characterisation only of common adverse drug reactions in RCC patients from Study 205. The adverse reactions presented as follows are based on the combined safety data of 62 RCC patients from Study 205 (see Pharmacology: Pharmacodynamics under Actions) and 458 DTC patients.
The most frequently reported adverse reactions in the DTC and Study 205 RCC patient population (occurring in ≥30% of patients) are diarrhoea (80.6%), hypertension (70.1%)*, fatigue (59.7%), decreased appetite (53.7%), weight decreased (52.6%)*, vomiting (48.4%), nausea (45.2%), proteinuria 38.9%)*, stomatitis (36.9%)*, headache (35.8%)*, dysphonia (35.6%)*, palmar-plantar erythrodysaesthesia syndrome (PPE) (34.1%)* peripheral oedema (33.9%), and hypercholesterolemia (30.6%). Hypertension and proteinuria tend to occur early during lenvatinib treatment (see Description of selected adverse reactions as follows; the asterisked frequencies are from the DTC patient population). In DTC, the majority of Grade 3 to 4 adverse reactions occurred during the first 6 months of treatment except for diarrhoea, which occurred throughout treatment, and weight loss, which tended to be cumulative over time.
The most important serious adverse reactions included renal failure and impairment (11.3%), arterial thromboembolisms (3.9%)*, cardiac failure (1.6%), cerebral haemorrhage (1.6%), intracranial tumour haemorrhage (0.7%)*, PRES/RPLS (0.2%)*, and hepatic failure (0.2%)* (the asterisked frequencies are from the DTC patient population).
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, diarrhoea, fatigue, PPE, weight decreased, and decreased appetite. Adverse reactions that most commonly led to discontinuation of lenvatinib were proteinuria, asthenia, hypertension, cerebrovascular accident, diarrhoea, and pulmonary embolism.
In RCC Study 205, adverse reactions led to dose reductions in 67.7% of patients and 18 (29.0%) patients discontinued the treatment. The most common adverse reactions (≥5%) resulting in dose reductions in the lenvatinib plus everolimus treated group were diarrhoea (21.0%), thrombocytopenia (6.5%), and vomiting (6.5%).
HCC: The most frequently reported adverse reactions (occurring in ≥30% of patients) are hypertension (44.0%), diarrhoea (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%), oesophageal varices haemorrhage (1.4%), cerebral haemorrhage (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, diarrhoea, 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%), diarrhoea (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 erythrodysaesthesia syndrome (23%), stomatitis (23%), anaemia (22%), and hypomagnesaemia (20%).
The most common (occurring in ≥5% of patients) severe (Grade ≥3) adverse reactions were hypertension (37.2%), decreased weight (9.1%), diarrhoea (8.1%), increased lipase (7.7%), decreased appetite (6.4%), asthenia (6%), fatigue (6%), hypokalaemia (5.7%), anaemia (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%), diarrhoea (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%), diarrhoea (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%), diarrhoea (12.5%), palmar-plantar erythrodysaesthesia 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 for DTC, RCC, HCC and EC studies: Similar adverse reactions were observed in clinical trials in DTC, RCC and HCC. Adverse reactions that occur more frequently with lenvatinib and everolimus combination therapy compared to lenvatinib monotherapy are hypothyroidism, (including increased blood thyroid stimulating hormone), hypercholesterolaemia, and severe diarrhoea.
Adverse reactions that occured more frequently with lenvatinib and pembrolizumab combination therapy compared to lenvatinib monotherapy were hypothyroidism (including increased blood thyroid stimulating hormone), hypercholesterolaemia, diarrhoea, lipase increased, amylase increased, rash (including maculopapular rash), and blood creatinine increased.
The safety profile of lenvatinib as combination therapy is based on data from 530 EC patients treated with lenvatinib in combination with pembrolizumab (see Pharmacology: Pharmacodynamics under Actions).
Adverse reactions observed in clinical trials and reported from post-marketing use of lenvatinib are listed in Table 12. The adverse reaction frequency category represents the most conservative estimate of frequency from the individual populations. Adverse reactions known to occur with lenvatinib or combination therapy components given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical studies with combination therapy.
For additional safety information when lenvatinib is administered in combination, refer to the package insert for the respective combination therapy components.
Frequencies are defined as: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).
Within each frequency category, undesirable effects are presented in order of decreasing seriousness. (See Tables 12a and 12b.)

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Description of selected adverse reactions: Hypertension (see Precautions): In CLEAR (see Pharmacology: Pharmacodynamics under Actions), hypertension was reported in 56.3% of patients in the lenvatinib plus pembrolizumab-treated group and 42.6% of patients in the sunitinib-treated group. The exposure-adjusted frequency of hypertension was 0.65 episodes per patient year in the lenvatinib plus pembrolizumab-treated group and 0.73 episodes per patient year in the sunitinib-treated group. The median time to onset in lenvatinib plus pembrolizumab-treated patients was 0.7 months. Reactions of Grade 3 or higher occurred in 28.7% of lenvatinib plus pembrolizumab-treated group compared with 19.4% of the sunitinib-treated group. 16.8% of patients with hypertension had dose modifications of lenvatinib (9.1% dose interruption and 11.9% dose reduction). In 0.9% of patients, hypertension led to permanent treatment discontinuation of lenvatinib.
In DTC Study 303 (see Pharmacology: Pharmacodynamics under Actions), hypertension (including hypertension, hypertensive crisis, blood pressure diastolic increased, and blood pressure increased) was reported in 72.8% of lenvatinib-treated patients and 16.0% of patients in the placebo-treated group. The median time to onset in lenvatinib-treated patients was 16 days. Reactions of Grade 3 or higher (including 1 reaction of Grade 4) occurred in 44.4% of lenvatinib-treated patients compared with 3.8% of placebo-treated patients. The majority of cases recovered or resolved following dose interruption or reduction, which occurred in 13.0% and 13.4% of patients, respectively. In 1.1% of patients, hypertension led to permanent treatment discontinuation.
In RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), hypertension was reported in 41.9% of patients in the lenvatinib plus everolimus-treated group (the incidence of Grade 3 or Grade 4 hypertension was 12.9%) and 10.0% of patients in the everolimus-treated group (the incidence of Grade 3 or Grade 4 hypertension was 2.0%). The median time to onset was 4.9 weeks (any grade) and 6.9 weeks (Grade ≥3) in the lenvatinib plus everolimus-treated group.
In the HCC study (see Pharmacology: Pharmacodynamics under Actions), hypertension (including hypertension, increased blood pressure, increased diastolic blood pressure and orthostatic hypertension) was reported in 44.5% of lenvatinib-treated patients and Grade 3 hypertension occurred in 23.5%. The median time to onset was 26 days. The majority of cases recovered following dose interruption or reduction, which occurred in 3.6% and 3.4% of patients respectively. One subject (0.2%) discontinued lenvatinib due to hypertension.
In the EC Study 309 (see Pharmacology: Pharmacodynamics under Actions), hypertension was reported in 65% of patients in the lenvatinib plus pembrolizumab group. Reactions of Grade 3 or higher occurred in 38.4% of patients in the lenvatinib plus pembrolizumab group. The median time to onset in the lenvatinib plus pembrolizumab group was 15 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in 11.6%, 17.7% and 2.0% of patients, respectively.
Proteinuria (see Precautions): In the DTC study (see Pharmacology: Pharmacodynamics under Actions), proteinuria was reported in 33.7% of lenvatinib-treated patients and 3.1% of patients in the placebo-treated group. The median time to onset was 6.7 weeks. Grade 3 reactions occurred in 10.7% of lenvatinib-treated patients and none in placebo-treated patients. The majority of cases had an outcome of recovered or resolved following dose interruption or reduction, which occurred in 16.9% and 10.7% of patients, respectively. Proteinuria led to permanent treatment discontinuation in 0.8% of patients.
In RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), proteinuria was reported in 30.6% of patients in the lenvatinib plus everolimus-treated group (8.1% were Grade ≥3) and 14.0% of patients in the everolimus-treated group (2.0% were Grade ≥3). The median time to onset of proteinuria was 6.1 weeks (any grade) and 20.1 weeks (Grade ≥3) in the lenvatinib plus everolimus-treated group. Proteinuria led to permanent treatment discontinuation in 4.8% of patients.
In the HCC study (see Pharmacology: Pharmacodynamics under Actions), proteinuria was reported in 26.3% of lenvatinib-treated patients and Grade 3 reactions occurred in 5.9%. The median time to onset was 6.1 weeks. The majority of cases recovered following dose interruption or reduction, which occurred in 6.9% and 2.5% of patients respectively. Proteinuria led to permanent treatment discontinuation in 0.6% of patients.
In the EC Study 309 (see Pharmacology: Pharmacodynamics under Actions), proteinuria was reported in 29.6% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 5.4% of patients. The median time to onset was 34.5 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in 6.2%, 7.9% and 1.2% of patients, respectively.
Renal failure and impairment (see Precautions): In the DTC study (see Pharmacology: Pharmacodynamics under Actions), 5.0% of patients developed renal failure and 1.9% developed renal impairment (3.1% of patients had a Grade ≥3 event of renal failure or impairment). In the placebo group 0.8% of patients developed renal failure or impairment (0.8% were Grade ≥3).
In RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), 8.1% of patients in the lenvatinib plus everolimus treated group developed renal failure and 3.2% developed renal impairment, (9.7% of patients had a Grade 3 event of renal failure or impairment). In the everolimus monotherapy group 2.0% of patients developed renal failure (2.0% were Grade 3).
In the HCC study (see Pharmacology: Pharmacodynamics under Actions), 7.1% of lenvatinib-treated patients developed a renal failure/impairment event. Grade 3 or greater reactions occurred in 1.9% of lenvatinib-treated patients.
In the EC Study 309 (see Pharmacology: Pharmacodynamics under Actions), 18.2% of lenvatinib plus pembrolizumab-treated patients developed a renal failure/impairment event. Grade ≥3 reactions occurred in 4.2% of patients. The median time to onset was 86.0 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in 3.0%, 1.7% and 1.2% of patients, respectively.
Cardiac dysfunction (see Precautions): In the DTC study (see Pharmacology: Pharmacodynamics under Actions), decreased ejection fraction/cardiac failure was reported in 6.5% of patients (1.5% were Grade ≥3) in the lenvatinib treated group, and 2.3% in the placebo group (none were Grade ≥3).
In RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), decreased ejection fraction/cardiac failure was reported in 4.8% of patients (3.2% were Grade ≥3) in the lenvatinib plus everolimus treated group, and 4.0% in the everolimus group (2.0% were Grade ≥3). The median time to onset of decreased ejection fraction and cardiac failure was 15.7 weeks (any grade) and 32.8 weeks (Grade ≥3) in the lenvatinib plus everolimus-treated group.
In the HCC study (see Pharmacology: Pharmacodynamics under Actions), cardiac dysfunction (including congestive cardiac failure, cardiogenic shock, and cardiopulmonary failure) was reported in 0.6% of patients (0.4% were Grade ≥3) in the lenvatinib-treated group.
In the EC Study 309 (see Pharmacology: Pharmacodynamics under Actions), cardiac dysfunction was reported in 1.0% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 0.5% of patients. The median time to onset was 112.0 days. Dose reduction and discontinuation of lenvatinib both occurred in 0.2% of patients.
Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior leucoencephalopathy syndrome (RPLS) (see Precautions): In the DTC study (see Pharmacology: Pharmacodynamics under Actions), there was 1 event of PRES (Grade 2) in the lenvatinib-treated group and no reports in the placebo group.
In RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), there was 1 event of PRES (Grade 3) in the lenvatinib-treated group, occurring after 18.4 weeks of treatment. There were no reports in the lenvatinib plus everolimus or everolimus monotherapy groups.
In the HCC study (see Pharmacology: Pharmacodynamics under Actions), there was 1 event of PRES (Grade 2) in the lenvatinib-treated group.
Amongst 1,823 patients treated with lenvatinib monotherapy in clinical trials, there were 5 cases (0.3%) of PRES (0.2% were Grade 3 or 4), all of which resolved after treatment and/or dose interruption, or permanent discontinuation.
In the EC Study 309 (see Pharmacology: Pharmacodynamics under Actions), there was one event of PRES (Grade 1) in the lenvatinib plus pembrolizumab-treated group for which lenvatinib was interrupted.
Hepatotoxicity (see Precautions): In CLEAR (see Pharmacology: Pharmacodynamics under Actions), the most commonly reported liver related adverse reactions in the lenvatinib plus pembrolizumab treated group were elevations of liver enzyme levels, including increases in alanine aminotransferase (11.9%), aspartate aminotransferase (11.1%) and blood bilirubin (4.0%). Similar events occurred in the sunitinib-treated group at rates of 10.3%, 10.9% and 4.4% respectively. The median time to onset of liver events was 3.0 months (any grade) in the lenvatinib plus pembrolizumab treated group and 0.7 months in the sunitinib-treated group. The exposure-adjusted frequency of hepatoxicity events was 0.39 episodes per patient year in the lenvatinib plus pembrolizumab-treated group and 0.46 episodes per patient year in the sunitinib-treated group. Grade 3 liver related reactions occurred in 9.9% of lenvatinib plus pembrolizumab treated patients and 5.3% of sunitinib-treated patients. Liver related reactions led to dose interruptions and reductions of lenvatinib in 8.5% and 4.3% of patients, respectively, and to permanent discontinuation of lenvatinib in 1.1% of patients.
In the DTC study (see Pharmacology: Pharmacodynamics under Actions), the most commonly reported liver-related adverse reactions were hypoalbuminaemia (9.6% lenvatinib vs. 1.5% placebo) and elevations of liver enzyme levels, including increases in alanine aminotransferase (7.7% lenvatinib vs. 0 placebo), aspartate aminotransferase (6.9% lenvatinib vs. 1.5% placebo), and blood bilirubin (1.9% lenvatinib vs. 0 placebo). The median time to onset of liver reactions in lenvatinib-treated patients was 12.1 weeks. Liver-related reactions of Grade 3 or higher (including 1 Grade 5 case of hepatic failure) occurred in 5.4% of lenvatinib-treated patients compared with 0.8% in placebo-treated patients. Liver-related reactions led to dose interruptions and reductions in 4.6% and 2.7% of patients, respectively, and to permanent discontinuation in 0.4%.
In RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), the most commonly reported liver-related adverse reactions in the lenvatinib plus everolimus-treated group were elevations of liver enzyme levels, including increases in alanine aminotransferase (9.7%), aspartate aminotransferase (4.8%), alkaline phosphatase (4.8%), and blood bilirubin (3.2%). The median time to onset of liver events was 6.7 weeks (any grade) and 14.2 weeks (Grade ≥3) in the lenvatinib plus everolimus-treated group. Grade 3 liver-related reactions occurred in 3.2% of lenvatinib plus everolimus-treated patients. Liver-related reactions led to dose interruptions and reductions in 1.6% and 1.6% of patients, respectively, and to permanent discontinuation in 3.2% of patients.
Amongst 1,166 patients treated with lenvatinib, there were 3 cases (0.3%) of hepatic failure, all with a fatal outcome. One occurred in a patient with no liver metastases. There was also a case of acute hepatitis in a patient without liver metastases.
In the Phase 3 REFLECT trial (see Pharmacology: Pharmacodynamics under Actions), the most commonly reported hepatotoxicity adverse reactions were increased blood bilirubin (14.9%), increased aspartate aminotransferase (13.7%), increased alanine aminotransferase (11.1%), hypoalbuminaemia (9.2%), hepatic encephalopathy (8.0%), increased gamma-glutamyltransferase (7.8%) and increased blood alkaline phosphatase (6.7%). The median time to onset of hepatotoxocity adverse reactions was 6.4 weeks. Hepatotoxicity reactions of ≥Grade 3 occurred in 26.1% of lenvatinib-treated patients. Hepatic failure (including fatal events in 12 patients) occurred in 3.6% of patients (all were ≥Grade 3). Hepatic encephalopathy (including fatal events in 4 patients) occurred in 8.4% of patients (5.5% were ≥Grade 3). There were 17 (3.6%) deaths due to hepatotoxicity events in the lenvatinib arm and 4 (0.8%) deaths in the sorafenib arm. Hepatotoxicity adverse reactions led to dose interruptions and reductions in 12.2% and 7.4% of lenvatinib-treated patients respectively, and to permanent discontinuation in 5.5%.
Across clinical studies in which 1327 patients received lenvatinib monotherapy in indications other than HCC, hepatic failure (including fatal events) was reported in 4 patients (0.3%), liver injury in 2 patients (0.2%), acute hepatitis in 2 patients (0.2%), and hepatocellular injury in 1 patient (0.1%).
In the EC Study 309 (see Pharmacology: Pharmacodynamics under Actions), hepatotoxicity was reported in 33.7% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 12.1% of patients. The median time to onset was 56.0 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in 5.2%, 3.0% and 1.2% of patients, respectively.
Arterial thromboembolisms (see Precautions): In CLEAR (see Pharmacology: Pharmacodynamics under Actions), 5.4% of patients in the lenvatinib plus pembrolizumab treated group reported arterial thromboembolic events (of which 3.7% were Grade ≥3) compared with 2.1% of patients in the sunitinib-treated group (of which 0.6% were Grade ≥3). No events were fatal. The exposure-adjusted frequency of arterial thromboembolic event episodes was 0.04 episodes per patient year in the lenvatinib plus pembrolizumab-treated group and 0.02 episodes per patient year in the sunitinib-treated group. The most commonly reported arterial thromboembolic event in the lenvatinib plus pembrolizumab treated group was myocardial infarction (3.4%). One event of myocardial infarction (0.3%) occurred in the sunitinib-treated group. The median time to onset of arterial thromboembolic events was 10.4 months in the lenvatinib plus pembrolizumab treated group.
In the DTC study (see Pharmacology: Pharmacodynamics under Actions), arterial thromboembolic events were reported in 5.4% of lenvatinib-treated patients and 2.3% of patients in the placebo group.
In RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), 1.6% of patients in the lenvatinib plus everolimus-treated group reported arterial thromboembolic events. The time to onset was 69.6 weeks. In the everolimus group, 6.0% of patients reported an arterial thromboembolism (4.0% were Grade ≥3).
In the HCC study (see Pharmacology: Pharmacodynamics under Actions), arterial thromboembolic events reported in 2.3% of patients treated with lenvatinib.
Amongst 1,823 patients treated with lenvatinib monotherapy in clinical studies, there were 10 cases (0.5%) of arterial thromboembolisms (5 cases of myocardial infarction and 5 cases of cerebrovascular accident) with a fatal outcome.
In the EC Study 309 (see Pharmacology: Pharmacodynamics under Actions), arterial thromboembolisms were reported in 3.7% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 2.2% of patients. The median time to onset was 59.0 days. Dose interruption and discontinuation of lenvatinib occurred in 0.2% and 2.0% of patients, respectively.
Haemorrhage (see Precautions): In the DTC study (see Pharmacology: Pharmacodynamics under Actions), haemorrhage was reported in 34.9% (1.9% were Grade ≥3) of lenvatinib-treated patients versus 18.3% (3.1% were Grade ≥3) of placebo-treated patients. Reactions that occurred at an incidence of ≥0.75% above placebo were: epistaxis (11.9%), haematuria (6.5%), contusion (4.6%), gingival bleeding (2.3%), haematochezia (2.3%), rectal haemorrhage (1.5%), haematoma (1.1%), haemorrhoidal haemorrhage (1.1%), laryngeal haemorrhage (1.1%), petechiae (1.1%), and intracranial tumour haemorrhage (0.8%). In this trial, there was 1 case of fatal intracranial haemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline.
In RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), haemorrhage was reported in 38.7% (8.1% were Grade ≥3) of patients in the lenvatinib plus everolimus-treated group. Reactions that occurred at an incidence of ≥2.0% were: epistaxis (22.6%), haematuria (4.8%), haematoma (3.2%), and gastric haemorrhage (3.2%). The median time to first onset of was 10.2 weeks (any grade) and 7.6 weeks (Grade ≥3) in the lenvatinib plus everolimus-treated group. The incidence of serious haemorrhage was 4.8% (cerebral haemorrhage, gastric haemorrhage and haemarthrosis). Discontinuation due to haemorrhagic events occurred in 3.2% of patients in the lenvatinib plus everolimus-treated group. There was one case of fatal cerebral haemorrhage in the lenvatinib plus everolimus-treated group and one case of fatal intracranial haemorrhage in the lenvatinib-treated group.
In the HCC study (see Pharmacology: Pharmacodynamics under Actions), haemorrhage was reported in 24.6% of patients and 5.0% were Grade ≥3. Grade 3 reactions occurred in 3.4%, Grade 4 reactions in 0.2% and 7 patients (1.5%) had a grade 5 reaction including cerebral haemorrhage, upper gastrointestinal haemorrhage, intestinal haemorrhage and tumour haemorrhage. The median time to first onset was 11.9 weeks. A haemorrhage event led to dose interruption or reduction in 3.2% and 0.8% patients respectively and to treatment discontinuation in 1.7% of patients.
Across clinical studies in which 1,327 patients received lenvatinib monotherapy in indications other than HCC, Grade ≥3 or greater haemorrhage was reported in 2% of patients, 3 patients (0.2%) had a Grade 4 haemorrhage and 8 patients (0.6%) had a Grade 5 reaction including arterial haemorrhage, haemorrhagic stroke, intracranial haemorrhage, intracranial tumour haemorrhage, haematemesis, melaena, haemoptysis and tumour haemorrhage.
In the EC Study 309 (see Pharmacology: Pharmacodynamics under Actions), haemorrhage was reported in 24.4% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 3.0% of patients. The median time to onset was 65.0 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in 1.7%, 1.2% and 1.7% of patients, respectively.
Hypocalcaemia (see QT interval prolongation under Precautions): In the DTC study (see Pharmacology: Pharmacodynamics under Actions), hypocalcaemia was reported in 12.6% of lenvatinib-treated patients vs. no cases in the placebo arm. The median time to first onset in lenvatinib-treated patients was 11.1 weeks. Reactions of Grade 3 or 4 severity occurred in 5.0% of lenvatinib-treated vs 0 placebo-treated patients. Most reactions resolved following supportive treatment, without dose interruption or reduction, which occurred in 1.5% and 1.1% of patients, respectively; 1 patient with Grade 4 hypocalcaemia discontinued treatment permanently.
In RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), hypocalcaemia was reported in 8.1% of patients in the lenvatinib plus everolimus-treated group (3.2% were Grade ≥3) and 4.0% of patients in the everolimus-treated group (none were Grade ≥3). The median time to onset of hypocalcaemia was 28.3 weeks (any grade) and 45.9 weeks (Grade ≥3) in the lenvatinib plus everolimus-treated group. There was one Grade 4 TEAE. No events of hypocalcaemia required dose reduction or interruption, and no patients discontinued treatment due to hypocalcaemia.
In the HCC study (see Pharmacology: Pharmacodynamics under Actions), hypocalcaemia was reported in 1.1% of patients, with grade 3 reactions occurring in 0.4%. Lenvatinib dose interruption due to hypocalcaemia occurred in one subject (0.2%) and there were no dose reductions or discontinuations.
In the EC Study 309 (see Pharmacology: Pharmacodynamics under Actions), hypocalcaemia was reported in 3.9% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 1.0% of patients. The median time to onset was 148.0 days. No lenvatinib dose modifications were reported.
Gastrointestinal perforation and fistula formation (see Precautions): In the DTC study (see Pharmacology: Pharmacodynamics under Actions), events of gastrointestinal perforation or fistula were reported in 1.9% of lenvatinib-treated patients and 0.8% of patients in the placebo group.
In RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), 1.6% of cases of perforated appendicitis (of Grade 3) occurred in the lenvatinib plus everolimus-treated group; there were no reports in the lenvatinib or everolimus groups.
In the HCC study (see Pharmacology: Pharmacodynamics under Actions), events of gastrointestinal perforation or fistula were reported in 1.9% of lenvatinib-treated patients.
In the EC Study 309 (see Pharmacology: Pharmacodynamics under Actions), events of fistula formation were reported in 2.5% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 2.5% of patients. The median time to onset was 117.0 days. Discontinuation of lenvatinib occurred in 1.0% of patients. Events of gastrointestinal perforation were reported in 3.9% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 3.0% of patients. The median time to onset was 42 days. Dose interruption and discontinuation of lenvatinib occurred in 0.5% and 3.0% of patients, respectively.
Non-Gastrointestinal fistula (see Precautions): Lenvatinib use has been associated with cases of fistula including reactions resulting in death. Reports of fistula that involve areas of the body other than stomach or intestines were observed across various indications. Reactions were reported at various time points during treatment ranging from two weeks to greater than 1 year from initiation of lenvatinib, with median latency of about 3 months.
QT interval prolongation (see Precautions): In the DTC study (see Pharmacology: Pharmacodynamics under Actions), QT/QTc interval prolongation was reported in 8.8% of lenvatinib-treated patients and 1.5% of patients in the placebo group. The incidence of QT interval prolongation of greater than 500 ms was 2% in the lenvatinib-treated patients compared to no reports in the placebo group.
In RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), QTc interval increases greater than 60 ms were reported in 11% of patients in the lenvatinib plus everolimus-treated group. The incidence of QTc interval greater than 500 ms was 6% in the lenvatinib plus everolimus-treated group. No reports of QTc interval prolongation greater than 500 ms or increases greater than 60 ms occurred in the everolimus-treated group.
In the HCC study (see Pharmacology: Pharmacodynamics under Actions), QT/QTc interval prolongation was reported in 6.9% of lenvatinib-treated patients. The incidence of QTcF interval prolongation of greater than 500 ms was 2.4%.
In the EC Study 309 (see Pharmacology: Pharmacodynamics under Actions), QT interval prolongation was reported in 3.9% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 0.5% of patients.
The median time to onset was 115.5 days. Dose interruption and reduction of lenvatinib occurred in 0.2% and 0.5% of patients, respectively.
Increased Blood thyroid stimulating hormone (see Precautions): In CLEAR (see Pharmacology: Pharmacodynamics under Actions), hypothyroidism occurred in 47.2% of patients in the lenvatinib plus pembrolizumab treated group and 26.5% of patients in the sunitinib treated group. The exposure-adjusted frequency of hypothyroidism was 0.39 episodes per patient year in the lenvatinib plus pembrolizumab-treated group and 0.33 episodes per patient year in the sunitinib-treated group. In general, the majority of hypothyroidism events in the lenvatinib plus pembrolizumab treated group were of Grade 1 or 2. Grade 3 hypothyroidism was reported in 1.4% of patients in the lenvatinib plus pembrolizumab treated group versus none in the sunitinib-treated group. At baseline, 90% of patients in the lenvatinib plus pembrolizumab-treated group and 93.1% of patients in the sunitinib-treated group had baseline TSH levels ≤ upper limit of normal.
Elevations of TSH > upper limit of normal were observed post baseline in 85.0% of lenvatinib plus pembrolizumab treated patients versus 65.6% of sunitinib-treated patients. In lenvatinib plus pembrolizumab-treated patients, hypothyroidism events resulted in dose modification of lenvatinib (reduction or interruption) in 2.6% patients and discontinuation of lenvatinib in 1 patient.
In the DTC study (see Pharmacology: Pharmacodynamics under Actions), 88% of all patients had a baseline TSH level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of lenvatinib-treated patients as compared with 14% of placebo-treated patients.
In RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), hypothyroidism occurred in 24% of patients in the lenvatinib plus everolimus-treated group and 2% of patients in the everolimus-treated group. All events of hypothyroidism in the lenvatinib plus everolimus-treated group were of Grade 1 or 2. In patients with a normal TSH at baseline, an elevation of TSH level was observed post baseline in 60.5% of lenvatinib plus everolimus-treated patients as compared with none in patients receiving everolimus alone.
In the HCC study (see Pharmacology: Pharmacodynamics under Actions), 89.6% of patients had a baseline TSH level of less than the upper limit of normal. Elevation of TSH above the upper limit of normal was observed post baseline in 69.6% of lenvatinib-treated patients.
In the EC Study 309 (see Pharmacology: Pharmacodynamics under Actions), hypothyroidism was reported in 68.2% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 1.2% of patients. The median time to onset was 62.0 days. Dose interruption and reduction of lenvatinib occurred in 2.2% and 0.7% of patients, respectively.
Blood TSH increased was reported in 12.8% of lenvatinib plus pembrolizumab-treated patients with no patients reporting Grade ≥3 reactions. Dose interruption occurred in 0.2% of patients.
Diarrhoea (see Precautions): In the DTC study (see Pharmacology: Pharmacodynamics under Actions), diarrhoea was reported in 67.4% of patients in the lenvatinib-treated group (9.2% were Grade ≥3) and in 16.8% of patients in the placebo group (none were Grade ≥3).
In RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), diarrhoea was reported in 80.6% of patients in the lenvatinib plus everolimus-treated group (21.0% were Grade ≥3) and in 34.0% of patients in the everolimus-treated group (2.0% were Grade ≥3). The median time to onset was 4.1 weeks (any grade) and 8.1 weeks (Grade ≥3) in the lenvatinib plus everolimus-treated group. Diarrhoea was the most frequent cause of dose interruption/reduction and recurred despite dose reduction. Diarrhoea resulted in discontinuation in one patient.
In the HCC study (see Pharmacology: Pharmacodynamics under Actions), diarrhoea was reported in 38.7% of patients treated with lenvatinib (4.2% were Grade ≥3).
In the EC Study 309 (see Pharmacology: Pharmacodynamics under Actions), diarrhoea was reported in 54.2% of lenvatinib plus pembrolizumabtreated patients (7.6% were Grade ≥3). Dose interruption, reduction and discontinuation of lenvatinib occurred in 10.6%, 11.1% and 1.2% of patients, respectively.
Paediatric population: Clinical data are not yet available in this population (see Dosage & Administration).
Other special populations: Elderly: In CLEAR, patients of age ≥75 years had a higher (≥10% difference) incidence of proteinuria than patients of age <65 years.
In DTC, patients of age ≥75 years were more likely to experience Grade 3 or 4 hypertension, proteinuria, decreased appetite, and dehydration.
In RCC study, there are limited data on patients of age ≥75 years with RCC.
In HCC, patients of age ≥75 years were more likely to experience hypertension, proteinuria, decreased appetite, asthenia, dehydration, dizziness, malaise, peripheral oedema, pruritus and hepatic encephalopathy. Hepatic encephalopathy occurred at more than twice the incidence in patients aged ≥75 years (17.2%) than in those <75 years (7.1%). Hepatic encephalopathy tended to be associated with adverse disease characteristics at baseline or with the use of concomitant medications. Arterial thromboembolic events also occurred at an increased incidence in this age group.
In EC, patients of age ≥75 years were more likely to experience urinary tract infections and Grade ≥3 hypertension (≥10% increase compared to patients of age <65 years).
Gender: In CLEAR, males had a higher (≥10% difference) incidence than females of diarrhoea.
In patients with DTC, females had a higher incidence of hypertension (including Grade 3 or 4 hypertension), proteinuria, and PPE, while males had a higher incidence of decreased ejection fraction and gastrointestinal perforation and fistula formation.
In HCC, females had a higher incidence of hypertension, fatigue, ECG QT prolongation and alopecia. Men had a higher incidence (26.5%) of dysphonia than women (12.3%), decreased weight and decreased platelet count. Hepatic failure events were observed in male patients only.
Ethnic origin: In CLEAR, Asian patients had a higher (≥10% difference) incidence than Caucasian patients of palmar-plantar erythrodysaesthesia syndrome, proteinuria and hypothyroidism (including blood thyroid hormone increased) while Caucasian patients had a higher incidence of fatigue, nausea, arthralgia, vomiting, and asthenia.
In patients with DTC, Asian patients had a higher (≥10% difference) incidence than Caucasian patients of peripheral oedema, hypertension, fatigue, PPE, proteinuria, stomatitis, thrombocytopenia, and myalgia; while Caucasian patients had a higher incidence of diarrhoea, weight decreased, nausea, vomiting, constipation, asthenia, abdominal pain, pain in extremity, and dry mouth. A larger proportion of Asian patients had a lenvatinib dose reduction compared to Caucasian patients. The median time to first dose reduction and the average daily dose taken were lower in Asian than in Caucasian patients.
In RCC Study 205, there are limited data on Asian patients.
In HCC, Asian patients had a higher incidence than Caucasian patients of proteinuria, decreased neutrophil count, decreased platelet count, decreased white blood count and PPE syndrome, while Caucasian patients had a higher incidence of fatigue, hepatic encephalopathy, acute kidney injury, anxiety, asthenia, nausea, thrombocytopenia and vomiting.
In EC, Asian patients had a higher (≥10% difference) incidence than Caucasian patients of anaemia, malaise, neutrophil count decrease, stomatitis, platelet count decreased, proteinuria and PPE while Caucasian patients had a higher incidence of mucosal inflammation, abdominal pain, diarrhoea, urinary tract infection, weight decreased, hypomagnesaemia, dizziness, asthenia and fatigue.
Baseline hypertension: In CLEAR, patients with baseline hypertension had a higher incidence of proteinuria than patients without baseline hypertension.
In DTC, patients with baseline hypertension had a higher incidence of Grade 3 or 4 hypertension, proteinuria, diarrhoea, and dehydration, and experienced more serious cases of dehydration, hypotension, pulmonary embolism, malignant pleural effusion, atrial fibrillation, and GI symptoms (abdominal pain, diarrhoea, vomiting).
In RCC Study 205, patients with baseline hypertension had a higher incidence of Grade 3 or 4 dehydration, fatigue, and hypertension.
Baseline diabetes: In RCC Study 205, patients with baseline diabetes had a higher incidence of Grade 3 or 4 hypertension, hypertriglyceridemia and acute renal failure.
Hepatic impairment: In DTC, patients with baseline hepatic impairment had a higher incidence of hypertension and PPE, and a higher incidence of Grade 3 or 4 hypertension, asthenia, fatigue, and hypocalcaemia compared with patients with normal hepatic function.
In RCC Study 205, there are limited data on patients with hepatic impairment.
In HCC, patients with a baseline Child Pugh (CP) score of 6 (about 20% patients in the REFLECT study) had a higher incidence of decreased appetite, fatigue, proteinuria, hepatic encephalopathy and hepatic failure compared to patients with a baseline CP score of 5. Hepatotoxicity events and haemorrhage events also occurred at a higher incidence in CP score 6 patients compared to CP score 5 patients.
Renal impairment: In DTC, patients with baseline renal impairment had a higher incidence of Grade 3 or 4 hypertension, proteinuria, fatigue, stomatitis, oedema peripheral, thrombocytopenia, dehydration, prolonged electrocardiogram QT, hypothyroidism, hyponatraemia, blood thyroid stimulating hormone increased, pneumonia compared with subjects with normal renal function. These patients also had a higher incidence of renal reactions and a trend towards a higher incidence of liver reactions.
In RCC Study 205, patients with baseline renal impairment had a higher incidence of Grade 3 fatigue.
In HCC, patients with baseline renal impairment had a higher incidence of fatigue, hypothyroidism, dehydration, diarrhoea, decreased appetite, proteinuria and hepatic encephalopathy. These patients also had a higher incidence of renal reactions and arterial thromboembolic events.
Patients with body weight <60 kg: In DTC, patients with low body weight (<60 kg) had a higher incidence of PPE, proteinuria, of Grade 3 or 4 hypocalcaemia and hyponatraemia, and a trend towards a higher incidence of Grade 3 or 4 decreased appetite. There are limited data on patients with body weight <60 kg in RCC.

Effect of other medicinal products on 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.
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 (see Use in Pregnancy & Lactation).

Store below 30°C. Store in the original blister in order to protect from moisture.

Targeted Cancer Therapy

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

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