LENVIMA 4mg capsules medication leaflet

LENVIMA 4 mg hard capsules

LENVIMA 10 mg hard capsules

LENVIMA 4 mg hard capsules

Each hard capsule contains 4 mg of lenvatinib (as mesilate).

LENVIMA 10 mg hard capsules

Each hard capsule contains 10 mg of lenvatinib (as mesilate).

For the full list of excipients, see section 6.1.

Hard capsule.

LENVIMA 4 mg hard capsules

A yellowish-red body and yellowish-red cap, approximately 14.3 mm in length, marked in black inkwith “Є” on the cap, and “LENV 4 mg” on the body.

LENVIMA 10 mg hard capsules

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.

Differentiated Thyroid Carcinoma (DTC)

LENVIMA as monotherapy is indicated for the treatment of adult patients with progressive, locallyadvanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma (DTC),refractory to radioactive iodine (RAI).

Hepatocellular Carcinoma (HCC)

LENVIMA as monotherapy is indicated for the treatment of adult patients withadvanced or unresectable hepatocellular carcinoma (HCC) who have received no prior systemictherapy (see section 5.1).

Endometrial Carcinoma (EC)

LENVIMA in combination with pembrolizumab is indicated for the treatment of adult patients withadvanced or recurrent endometrial carcinoma (EC) who have disease progression on or following priortreatment with a platinum-containing therapy in any setting and are not candidates for curative surgeryor radiation.

LENVIMA treatment should be initiated and supervised by a healthcare professional experienced inthe use of anticancer therapies.

Optimal medical management (i.e., treatment or therapy) for nausea, vomiting, and diarrhoea shouldbe initiated prior to any lenvatinib therapy interruption or dose reduction; gastrointestinal toxicityshould be actively treated in order to reduce the risk of development of renal impairment or failure(see section 4.4).

If a patient misses a dose, and it cannot be taken within 12 hours, then that dose should be skipped andthe next dose should be taken at the usual time of administration.

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

Differentiated thyroid cancer (DTC)

The recommended daily dose of lenvatinib is 24 mg (two 10-mg capsules and one 4-mg capsule) oncedaily. The daily dose is to be modified as needed according to the dose/toxicity management plan.

Dose adjustments and discontinuations for DTC

Management of adverse reactions may require dose interruption, adjustment, or discontinuation oflenvatinib therapy (see section 4.4). Mild to moderate adverse reactions (e.g., Grade 1 or 2) generallydo not warrant interruption of lenvatinib, unless intolerable to the patient despite optimal management.

Severe (e.g., Grade 3) or intolerable adverse reactions require interruption of lenvatinib untilimprovement of the reaction to Grade 0 to 1 or baseline.

For lenvatinib-related toxicities (see Table 4), upon resolution/improvement of an adverse reaction to

Grade 0 to 1 or baseline, treatment should be resumed at a reduced dose of lenvatinib as suggested in

Table 1.

Table 1 Dose modifications from recommended lenvatinib daily dose in DTC patientsa

Dose level Daily dose Number of capsules

Recommended daily24 mg orally once daily Two 10-mg capsules plus one 4-mg capsuledose

First dose reduction 20 mg orally once daily Two 10-mg capsules

Second dose reduction 14 mg orally once daily One 10-mg capsule plus one 4-mg capsule

Third dose reduction 10 mg orally once dailya One 10-mg capsulea: Further dose reductions should be considered on an individual patient basis as limited data are availablefor doses below 10 mg.

Treatment should be discontinued in case of life-threatening reactions (e.g., Grade 4) with theexception of laboratory abnormalities judged to be non-life-threatening, in which case they should bemanaged as severe reactions (e.g., Grade 3).

Hepatocellular Carcinoma

The recommended daily dose of lenvatinib is 8 mg (two 4 mg capsules) once daily for patients with abody 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 changesduring treatment. The daily dose is to be modified, as needed, according to the dose/toxicitymanagement plan.

Dose adjustments and Discontinuation for HCC

Management of some adverse reactions may require dose interruption, adjustment, or discontinuationof lenvatinib therapy. Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not warrantinterruption of lenvatinib, unless intolerable to the patient despite optimal management. Forlenvatinib-related toxicities, see Table 4. Details for monitoring, dose adjustment and discontinuationare provided in Table 2.

Table 2 Dose modifications from recommended lenvatinib daily dose in HCC patients≥60 kg BW <60 kg BW12 mg (three 4-mg 8 mg (two 4-mg

Starting Dosecapsules orally once capsules orallydaily) once daily)

Persistent and Intolerable Grade 2 or Grade 3 Toxicitiesa

Adverse Adjusted Doseb Adjusted Doseb

Reaction Modification (≥60 kg BW) (<60 kg BW)8 mg 4 mgc Interrupt until resolved to

First occurrence d (two 4-mg capsules) (one 4-mg capsule)

Grade 0-1 or baselineorally once daily orally once daily

Second 4 mg4 mgoccurrence Interrupt until resolved to (one 4-mg capsule)(one 4-mg capsule)(same reaction or Grade 0-1 or baselined orally every otherorally once dailynew reaction) day

Third occurrence 4 mg

Interrupt until resolved to(same reaction or (one 4-mg capsule) Discontinue

Grade 0-1 or baselinednew reaction) orally every other day

Life-threatening toxicities (Grade 4): Discontinueea: Initiate medical management for nausea, vomiting, or diarrhoea prior to interruption or dose reduction.b: Reduce dose in succession based on the previous dose level (12 mg, 8 mg, 4 mg or 4 mg every other day).c: Haematologic toxicity or proteinuria: no dose adjustment required for first occurrence.d: For haematologic toxicity, dosing can restart when resolved to Grade 2; proteinuria, resume when resolvesto less than 2 g/24 hours.e: Excluding laboratory abnormalities judged to be nonlife-threatening, which should be managed as

Grade 3.

Grades are based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse

Events (CTCAE).

Endometrial Carcinoma (EC)

The recommended dosage of LENVIMA is 20 mg orally once daily, in combination withpembrolizumab either 200 mg every 3 weeks or 400 mg every 6 weeks, administered as anintravenous infusion over 30 minutes, until unacceptable toxicity or disease progression (seesection 5.1).

Refer to the Summary of Product Characteristics (SmPC) for pembrolizumab for additional dosinginformation.

Dose adjustments and Discontinuation for EC

For lenvatinib-related toxicities see Table 4. When administering LENVIMA in combination withpembrolizumab, interrupt, dose reduce, or discontinue LENVIMA as appropriate (see Table 3).

Withhold or discontinue pembrolizumab in accordance with the instructions in the SmPC forpembrolizumab. No dose reductions are recommended for pembrolizumab.

Table 3 Dose modifications from recommended lenvatinib daily dose in EC patientsa

Starting Dose 20 mg orally once dailyin combination with pembrolizumab (two 10-mg capsules)

Persistent and Intolerable Grade 2 or Grade 3 Toxicities

Adverse

Reaction Modification Adjusted Dose

Interrupt until resolved to Grade 14 mg orally once daily

First occurrence0-1 or baseline (one 10-mg capsule + one 4-mg capsule)

Secondoccurrence Interrupt until resolved to Grade 10 mg orally once daily(same reaction or 0-1 or baseline (one 10-mg capsule)new reaction)

Third occurrence

Interrupt until resolved to Grade 8 mg orally once daily(same reaction or0-1 or baseline (two 4-mg capsules)new reaction)

Life-threatening toxicities (Grade 4): Discontinueba: Limited data are available for doses below 8 mg.b: Treatment should be discontinued in case of life-threatening reactions (e.g., Grade 4) with the exception oflaboratory abnormalities judged to be non-life-threatening, in which case they should be managed assevere reactions (e.g., Grade 3).

Table 4 Adverse reactions requiring dose modification of lenvatinib

Dose reduce and

Adverse reaction Severity Action resume lenvatinib

Hypertension Grade 3 Interrupt Resolves to Grade 0, 1 or(despite optimal 2.antihypertensive therapy) See detailed guidancein Table 5 in section 4.4.

Grade 4 Discontinue Do not resume.

Proteinuria ≥ 2 g/24 hours Interrupt Resolves to less than 2 g /24 hours.

Nephrotic syndrome ------- Discontinue Do not resume.

Renal impairment or Grade 3 Interrupt Resolves to Grade 0-1 orfailure baseline.

Grade 4* Discontinue Do not resume.

Cardiac dysfunction Grade 3 Interrupt Resolves to Grade 0-1 orbaseline.

Grade 4 Discontinue Do not resume.

Table 4 Adverse reactions requiring dose modification of lenvatinib

Dose reduce and

Adverse reaction Severity Action resume lenvatinib

Posterior reversible Any grade Interrupt Consider resuming atencephalopathy reduced dose if resolvessyndrome to Grade 0-1.(PRES)/reversibleposteriorleukoencephalopathysyndrome (RPLS)

Hepatotoxicity Grade 3 Interrupt Resolves to Grade 0-1 orbaseline.

Grade 4* Discontinue Do not resume.

Arterial Any grade Discontinue Do not resume.thromboembolisms

Haemorrhage Grade 3 Interrupt Resolves to Grade 0-1.

Grade 4 Discontinue Do not resume.

Gastrointestinal Grade 3 Interrupt Resolves to Grade 0-1 orperforation or fistula baseline.

Grade 4 Discontinue Do not resume.

Non-gastrointestinal Grade 4 Discontinue Do not resume.fistula

QT interval >500 ms Interrupt Resolves to <480 ms orprolongation baseline.

Diarrhoea Grade 3 Interrupt Resolves to Grade 0-1 orbaseline.

Grade 4 (despite medical Discontinue Do not resume.management)

*Grade 4 laboratory abnormalities judged to be non-life-threatening, may be managed as severe reactions(e.g., Grade 3).

DTC

Patients of age ≥75 years, of Asian race, with comorbidities (such as hypertension, and hepatic or renalimpairment), or body weight below 60 kg appear to have reduced tolerability to lenvatinib (seesection 4.8). All patients other than those with severe hepatic or renal impairment (see below) shouldinitiate treatment at the recommended 24-mg dose, following which the dose should be furtheradjusted 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 renalimpairment 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 whichthe 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 regularlymonitored during treatment (see sections 4.4 and 4.8).

DTC

No adjustment of starting dose is required on the basis of hepatic function in patients with mild (Child-

Pugh A) or moderate (Child-Pugh B) hepatic impairment. In patients with severe (Child-Pugh C)hepatic impairment, the recommended starting dose is 14 mg taken once daily. Further doseadjustments may be necessary on the basis of individual tolerability. Refer also to section 4.8.

HCC

In the patient populations enrolled in the HCC study no dose adjustments were required on the basis ofhepatic function in those patients who had mild hepatic impairment (Child-Pugh A). The availablevery limited data are not sufficient to allow for a dosing recommendation for HCC patients withmoderate hepatic impairment (Child-Pugh B). Close monitoring of overall safety is recommended inthese patients (see sections 4.4 and 5.2). Lenvatinib has not been studied in patients with severehepatic impairment (Child-Pugh C) and is not recommended for use in these patients.

EC

Limited data are available for the combination of lenvatinib with pembrolizumab in patients withhepatic impairment. No adjustment of starting dose of the combination is required on the basis ofhepatic function in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

In patients with severe (Child-Pugh C) hepatic impairment, the recommended starting dose oflenvatinib is 10 mg taken once daily. Please refer to the SmPC for pembrolizumab for dosing inpatients with hepatic impairment. Further dose adjustments may be necessary on the basis ofindividual tolerability.

DTC

No adjustment of starting dose is required on the basis of renal function in patients with mild ormoderate renal impairment. In patients with severe renal impairment, the recommended starting doseis 14 mg taken once daily. Further dose adjustments may be necessary based on individual tolerability.

Patients with end-stage renal disease were not studied, therefore the use of lenvatinib in these patientsis not recommended (see section 4.8).

HCC

No dose adjustments are required on the basis of renal function in patients with mild or moderate renalimpairment. The available data do not allow for a dosing recommendation for patients with HCC andsevere renal impairment.

EC

No adjustment of starting dose is required on the basis of renal function in patients with mild ormoderate renal impairment. In patients with severe renal impairment, the recommended starting doseis 10 mg of lenvatinib taken once daily. Please refer to the SmPC for pembrolizumab for dosing inpatients with renal impairment. Further dose adjustments may be necessary based on individualtolerability. Patients with end-stage renal disease have not been studied, therefore the use of lenvatinibin these patients is not recommended.

No adjustment of starting dose is required on the basis of age. Limited data are available on use inpatients aged ≥75 years (see section 4.8).

The safety and efficacy of lenvatinib in children aged 2 to <18 years have not been established.

Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on aposology can be made.

Lenvatinib should not be used in children younger than 2 years of age because of safety concernsidentified in animal studies (see section 5.3).

No adjustment of starting dose is required on the basis of race (see section 5.2). Limited data areavailable on use in patients from ethnic origins other than Caucasian or Asian (see section 4.8).

Lenvatinib is for oral use. The capsules should be taken at about the same time each day, with orwithout food (see section 5.2). Caregivers should not open the capsule, in order to avoid repeatedexposure to the contents of the capsule.

Lenvatinib capsules can be swallowed whole with water or administered as a suspension prepared bydispersing the whole capsule(s) in water, apple juice, or milk. The suspension may be administeredorally or via a feeding tube. If administered via a feeding tube, then the suspension should be preparedusing water (see section 6.6 for preparation and administration of suspension).

If not used at the time of preparation, lenvatinib suspension may be stored in a covered container andmust be refrigerated at 2ºC to 8ºC for a maximum of 24 hours. After removal from the refrigerator thesuspension should be shaken for approximately 30 seconds before use. If not administered within 24hours, the suspension should be discarded.

For use in combination with pembrolizumab, refer to the SmPC for pembrolizumab.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6).

Hypertension has been reported in patients treated with lenvatinib, usually occurring early in thecourse of treatment (see section 4.8). Blood pressure (BP) should be well controlled prior to treatmentwith lenvatinib and, if patients are known to be hypertensive, they should be on a stable dose ofantihypertensive therapy for at least 1 week prior to treatment with lenvatinib. Serious complicationsof poorly controlled hypertension, including aortic dissection, have been reported. The early detectionand effective management of hypertension are important to minimise the need for lenvatinib doseinterruptions and reductions. Antihypertensive agents should be started as soon as elevated BP isconfirmed. BP should be monitored after 1 week of treatment with lenvatinib, then every 2 weeks forthe first 2 months, and monthly thereafter. The choice of antihypertensive treatment should beindividualised to the patient’s clinical circumstances and follow standard medical practice. Forpreviously normotensive subjects, monotherapy with one of the classes of antihypertensives should bestarted when elevated BP is observed. For those patients already on an antihypertensive medicinalproduct, the dose of the current agent may be increased, if appropriate, or one or more agents of adifferent class of antihypertensive should be added. When necessary, manage hypertension asrecommended in Table 5.

Table 5 Recommended management of hypertension

Blood Pressure (BP) level Recommended action

Systolic BP ≥140 mmHg up to <160 mmHg or Continue lenvatinib and initiate antihypertensivediastolic BP ≥90 mmHg up to <100 mmHg therapy, if not already receiving

OR

Continue lenvatinib and increase the dose of thecurrent antihypertensive therapy or initiateadditional antihypertensive therapy

Systolic BP ≥160 mmHg or 1. Withhold lenvatinibdiastolic BP ≥100 mmHg 2. When systolic BP ≤150 mmHg, diastolicdespite optimal antihypertensive therapy BP ≤95 mmHg, and patient has been on astable dose of antihypertensive therapy forat least 48 hours, resume lenvatinib at areduced dose (see section 4.2)

Life-threatening consequences Urgent intervention is indicated. Discontinue(malignant hypertension, neurological deficit, lenvatinib and institute appropriate medicalor hypertensive crisis) management.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote theformation of aneurysms and/or artery dissections. Before initiating lenvatinib, this risk should becarefully 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 courseof treatment (see section 4.8). Urine protein should be monitored regularly. If urine dipstickproteinuria ≥2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary (seesection 4.2). Cases of nephrotic syndrome have been reported in patients using lenvatinib. Lenvatinibshould be discontinued in the event of nephrotic syndrome.

In DTC, liver-related adverse reactions most commonly reported in patients treated with lenvatinibincluded increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bloodbilirubin. Hepatic failure and acute hepatitis (<1%; see section 4.8) have been reported in patients with

DTC treated with lenvatinib. The hepatic failure cases were generally reported in patients withprogressive metastatic liver metastases disease.

In HCC patients treated with lenvatinib in the REFLECT trial, liver-related adverse reactionsincluding hepatic encephalopathy and hepatic failure (including fatal reactions) were reported at ahigher frequency (see section 4.8) compared to patients treated with sorafenib . Patients with worsehepatic impairment and/or greater liver tumour burden at baseline had a higher risk of developinghepatic encephalopathy and hepatic failure. Hepatic encephalopathy also occurred more frequently inpatients aged 75 years and older. Approximately half of the events of hepatic failure and one third ofthe 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 arecurrently no data available in HCC patients with severe hepatic impairment (Child-Pugh C). Sincelenvatinib is mainly eliminated by hepatic metabolism, an increase in exposure in patients withmoderate to severe hepatic impairment is expected.

In EC, liver-related adverse reactions most commonly reported in patients treated with lenvatinib andpembrolizumab included increases in alanine aminotransferase (ALT) and aspartate aminotransferase(AST). Hepatic failure and hepatitis (<1%; see section 4.8) have been reported in patients with ECtreated with lenvatinib and pembrolizumab.

Close monitoring of the overall safety is recommended in patients with mild or moderate hepaticimpairment (see sections 4.2 and 5.2). Liver function tests should be monitored before initiation oftreatment, then every 2 weeks for the first 2 months and monthly thereafter during treatment. Patientswith HCC should be monitored for worsening liver function including hepatic encephalopathy. In thecase of hepatotoxicity, dose interruptions, adjustments, or discontinuation may be necessary (seesection 4.2).

Renal failure and impairment

Renal impairment and renal failure have been reported in patients treated with lenvatinib (seesection 4.8). The primary risk factor identified was dehydration and/or hypovolemia due togastrointestinal toxicity. Gastrointestinal toxicity should be actively managed in order to reduce therisk of development of renal impairment or renal failure. Dose interruptions, adjustments, ordiscontinuation may be necessary (see section 4.2).

If patients have severe renal impairment, the initial dose of lenvatinib should be adjusted (see sections4.2 and 5.2).

Diarrhoea has been reported frequently in patients treated with lenvatinib, usually occurring early inthe course of treatment (see section 4.8). Prompt medical management of diarrhoea should beinstituted in order to prevent dehydration. Lenvatinib should be discontinued in the event ofpersistence of Grade 4 diarrhoea despite medical management.

Cardiac dysfunction

Cardiac failure (<1%) and decreased left ventricular ejection fraction have been reported in patientstreated with lenvatinib (see section 4.8). Patients should be monitored for clinical symptoms or signsof cardiac decompensation, as dose interruptions, adjustments, or discontinuation may be necessary(see section 4.2).

Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior leucoencephalopathysyndrome (RPLS)

PRES, also known as RPLS, has been reported in patients treated with lenvatinib (<1%; seesection 4.8). PRES is a neurological disorder which can present with headache, seizure, lethargy,confusion, altered mental function, blindness, and other visual or neurological disturbances. Mild tosevere hypertension may be present. Magnetic resonance imaging is necessary to confirm thediagnosis of PRES. Appropriate measures should be taken to control blood pressure (see section 4.4).

In patients with signs or symptoms of PRES, dose interruptions, adjustments, or discontinuation maybe necessary (see section 4.2).

Arterial thromboembolisms

Arterial thromboembolisms (cerebrovascular accident, transient ischaemic attack, and myocardialinfarction) have been reported in patients treated with lenvatinib (see section 4.8). Lenvatinib has notbeen studied in patients who have had an arterial thromboembolism within the previous 6 months, andtherefore should be used with caution in such patients. A treatment decision should be made basedupon an assessment of the individual patient's benefit/risk. Lenvatinib should be discontinuedfollowing an arterial thrombotic event.

Women of childbearing potential must use highly effective contraception while taking lenvatinib andfor one month after stopping treatment (see section 4.6). It is currently unknown if lenvatinib increasesthe risk of thromboembolic events when combined with oral contraceptives.

Serious tumour related bleeds, including fatal haemorrhagic events have occurred in clinical trials andhave been reported in post-marketing experience (see section 4.8). In post-marketing surveillance,serious and fatal carotid artery haemorrhages were seen more frequently in patients with anaplasticthyroid carcinoma (ATC) than in DTC or other tumour types. The degree of tumourinvasion/infiltration of major blood vessels (e.g., carotid artery) should be considered because of thepotential risk of severe haemorrhage associated with tumour shrinkage/necrosis following lenvatinibtherapy. Some cases of bleeding have occurred secondarily to tumour shrinkage and fistula formation,e.g., tracheo-oesophageal fistulae. Cases of fatal intracranial haemorrhage have been reported in somepatients 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 apatient with HCC has been reported.

Screening for and subsequent treatment of oesophageal varices in patients with liver cirrhosis shouldbe performed as per standard of care before starting treatment with lenvatinib

In the case of bleeding, dose interruptions, adjustments, or discontinuation may be required (seesection 4.2, Table 3).

Gastrointestinal perforation and fistula formation

Gastrointestinal perforation or fistulae have been reported in patients treated with lenvatinib (seesection 4.8). In most cases, gastrointestinal perforation and fistulae occurred in patients with riskfactors such as prior surgery or radiotherapy. In the case of a gastrointestinal perforation or fistula,dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).

Non-gastrointestinal fistula

Patients may be at increased risk for the development of fistulae when treated with lenvatinib. Casesof fistula formation or enlargement that involve areas of the body other than stomach or intestineswere 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 reportedwith and without clear evidence of a bronchopleural fistula. Some reports of fistula and pneumothoraxoccurred in association with tumour regression or necrosis. Prior surgery and radiotherapy may becontributing risk factors. Lung metastases may also increase the risk of pneumothorax. Lenvatinibshould not be started in patients with fistula to avoid worsening and lenvatinib should be permanentlydiscontinued in patients with oesophageal or tracheobronchial tract involvement and any Grade 4fistula (see section 4.2); limited information is available on the use of dose interruption or reduction inmanagement of other events, but worsening was observed in some cases and caution should be taken.

Lenvatinib may adversely affect the wound healing process as for other agents of the same class.

QT interval prolongation

QT/QTc interval prolongation has been reported at a higher incidence in patients treated withlenvatinib than in patients treated with placebo (see section 4.8). Electrocardiograms should bemonitored at baseline and periodically during treatment in all patients with particular attention to thosewith congenital long QT syndrome, congestive heart failure, bradyarrhythmias, and those takingmedicinal 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 >500 ms.

Lenvatinib should be resumed at a reduced dose when QTc prolongation is resolved to <480 ms orbaseline.

Electrolyte disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia increase the riskof QT prolongation; therefore, electrolyte abnormalities should be monitored and corrected in allpatients before starting treatment. Electrolytes (magnesium, potassium and calcium) should bemonitored periodically during treatment. Blood calcium levels should be monitored at least monthlyand calcium should be replaced as necessary during lenvatinib treatment. Lenvatinib dose should beinterrupted or dose adjusted as necessary depending on severity, presence of ECG changes, andpersistence of hypocalcaemia.

Impairment of thyroid stimulating hormone suppression/ Thyroid dysfunction

Hypothyroidism has been reported in patients treated with lenvatinib (see section 4.8). Thyroidfunction should be monitored before initiation of, and periodically throughout, treatment withlenvatinib. Hypothyroidism should be treated according to standard medical practice to maintaineuthyroid state.

Lenvatinib impairs exogenous thyroid suppression (see section 4.8). Thyroid stimulating hormone(TSH) levels should be monitored on a regular basis and thyroid hormone administration should beadjusted to reach appropriate TSH levels, according to the patient’s therapeutic target.

No formal studies of the effect of lenvatinib on wound healing have been conducted. Impaired woundhealing has been reported in patients receiving lenvatinib. Temporary interruption of lenvatinib shouldbe considered in patients undergoing major surgical procedures. There is limited clinical experienceregarding the timing of reinitiation of lenvatinib following a major surgical procedure. Therefore, thedecision to resume lenvatinib following a major surgical procedure should be based on clinicaljudgment of adequate wound healing.

Cases of ONJ have been reported in patients treated with lenvatinib. Some cases were reported inpatients who had received prior or concomitant treatment with antiresorptive bone therapy, and/orother angiogenesis inhibitors, e.g. bevacizumab, TKI, mTOR inhibitors. Caution should therefore beexercised when lenvatinib is used either simultaneously or sequentially with antiresorptive therapyand/or other angiogenesis inhibitors.

Invasive dental procedures are an identified risk factor. Prior to treatment with lenvatinib, a dentalexamination and appropriate preventive dentistry should be considered. In patients who havepreviously received or are receiving intravenous bisphosphonates, invasive dental procedures shouldbe avoided if possible (see section 4.8).

Lenvatinib can cause TLS which can be fatal. Risk factors for TLS include but are not limited to hightumour burden, pre-existing renal impairment and dehydration. These patients should be monitoredclosely and treated as clinically indicated, and prophylactic hydration should be considered.

Limited data are available for patients of ethnic origin other than Caucasian or Asian, and in patientsaged ≥75 years. Lenvatinib should be used with caution in such patients, given the reduced tolerabilityof lenvatinib in Asian and elderly patients (see section 4.8).

There are no data on the use of lenvatinib immediately following sorafenib or other anticancertreatments and there may be a potential risk for additive toxicities unless there is an adequate washoutperiod between treatments. The minimal washout period in clinical trials was 4 weeks.

Patients with ECOG PS ≥ 2 were excluded from clinical studies (except for thyroid carcinoma).

Effect of other medicinal products on lenvatinib

Chemotherapeutic agents

Concomitant administration of lenvatinib, carboplatin, and paclitaxel has no significant impact on thepharmacokinetics 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 ofmidazolam (a sensitive CYP3A and Pgp substrate) were not altered in the presence of lenvatinib. Nosignificant drug-drug interaction is therefore expected between lenvatinib and other CYP3A4/Pgpsubstrates.

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 section4.6).

Women of childbearing potential should avoid becoming pregnant and use highly effectivecontraception while on treatment with lenvatinib and for at least one month after finishing treatment. Itis currently unknown whether lenvatinib may reduce the effectiveness of hormonal contraceptives, andtherefore women using oral hormonal contraceptives should add a barrier method.

There are no data on the use of lenvatinib in pregnant women. Lenvatinib was embryotoxic andteratogenic when administered to rats and rabbits (see section 5.3).

Lenvatinib should not be used during pregnancy unless clearly necessary and after a carefulconsideration of the needs of the mother and the risk to the foetus.

It is not known whether lenvatinib is excreted in human milk. Lenvatinib and its metabolites areexcreted in rat milk (see section 5.3). A risk to newborns or infants cannot be excluded and, therefore,lenvatinib is contraindicated during breast-feeding (see section 4.3).

Effects in humans are unknown. However, testicular and ovarian toxicity has been observed in rats,dogs, and monkeys (see section 5.3).

Lenvatinib has minor influence on the ability to drive and use machines, due to undesirable effectssuch as fatigue and dizziness. Patients who experience these symptoms should use caution whendriving or operating machines.

DTC

The most frequently reported adverse reactions (occurring in ≥30% of patients) are hypertension(68.6%), diarrhoea (62.8%), decreased appetite (51.5%), decreased weight (49.1%), fatigue (45.8%),nausea (44.5%), proteinuria 36.9%), stomatitis (35.8%), vomiting (34.5%), dysphonia (34.1%),headache (34.1%), and palmar-plantar erythrodysaesthesia syndrome (PPE) (32.7%). Hypertensionand proteinuria tend to occur early during lenvatinib treatment (see sections 4.4 and 4.8). The majorityof 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 were renal failure and impairment (2.4%),arterial thromboembolisms (3.9%), cardiac failure (0.7%), intracranial tumour haemorrhage (0.7%),

PRES/RPLS (0.2%), hepatic failure (0.2%), and arterial thromboembolisms (cerebrovascularaccident (1.1%), transient ischaemic attack (0.7%), and myocardial infarction (0.9%).

In 452 patients with RAI-refractory DTC, dose reduction and discontinuation were the actions takenfor an adverse reaction in 63.1% and 19.5% of patients, respectively. Adverse reactions that mostcommonly led to dose reductions (in ≥5% of patients) were hypertension, proteinuria, diarrhoea,fatigue, PPE, decreased weight, and decreased appetite. Adverse reactions that most commonly led todiscontinuation of lenvatinib were proteinuria, asthenia, hypertension, cerebrovascular accident,diarrhoea, and pulmonary embolism.

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%), arterialthromboembolic events (2.0%) including myocardial infarction (0.8%), cerebral infarction (0.4%) andcerebrovascular accident (0.4%) and renal failure/impairment events (1.4%). There was a higherincidence 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 theactions taken for an adverse reaction in 62.3% and 20.2% of patients, respectively. Adverse reactionsthat 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 mostcommonly led to discontinuation of lenvatinib were hepatic encephalopathy, fatigue, increased bloodbilirubin, proteinuria and hepatic failure.

EC

The safety of lenvatinib in combination with pembrolizumab has been evaluated in 530 patients withadvanced EC receiving 20 mg lenvatinib once daily and 200 mg pembrolizumab every 3 weeks. Themost 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%), andhypomagnesaemia (20%).

The most common (occurring in ≥5% of patients) severe (Grade ≥3) adverse reactions werehypertension (37.2%), decreased weight (9.1%), diarrhoea (8.1%), increased lipase (7.7%), decreasedappetite (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 andpembrolizumab 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 werehypertension (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. Doseinterruption of lenvatinib and pembrolizumab due to an adverse reaction occurred in 34.3% ofpatients. The most common (occurring in ≥5% of patients) adverse reactions leading to interruption oflenvatinib 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 mostcommon (occurring in ≥5% of patients) adverse reactions resulting in dose reduction of lenvatinibwere 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%), anddecreased weight (5.1%).

The safety profile of lenvatinib as monotherapy is based on data from 452 DTC patients and 496 HCCpatients; allowing characterisation only of common adverse drug reactions in DTC and HCC patients.

The adverse reactions presented in this section are based on safety data of both DTC and HCC patients(see section 5.1).

The safety profile of lenvatinib as combination therapy is based on data from 530 EC patients treatedwith lenvatinib in combination with pembrolizumab (see section 5.1).

Adverse reactions observed in clinical trials in DTC, HCC, and EC, and reported from post-marketinguse of lenvatinib are listed in Table 6. The adverse reaction frequency category represents the mostconservative estimate of frequency from the individual populations. Adverse reactions known to occurwith lenvatinib or combination therapy components given alone may occur during treatment withthese medicinal products in combination, even if these reactions were not reported in clinical studieswith combination therapy.

For additional safety information when lenvatinib is administered in combination, refer to the SmPCfor the respective combination therapy component (pembrolizumab).

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.

Table 6 Adverse reactions reported in patients treated with lenvatinib§

System Organ Class Lenvatinib monotherapy Combination with pembrolizumab(MedDRA terminology)

Very common Urinary tract infection Urinary tract infection

Uncommon Perineal abscess Perineal abscess

Blood and lymphatic disorders

Very common Thrombocytopeniaa,‡ Thrombocytopeniaa,‡

Lymphopeniaa,‡ Lymphopeniaa,‡

Leukopeniaa,‡ Leukopeniaa,‡

Neutropeniaa,‡ Neutropeniaa,‡

Uncommon Splenic infarction

Very common Hypothyroidism Hypothyroidism

Increased blood thyroid Increased blood thyroid stimulatingstimulating hormone*,‡ hormone*

Common Adrenal insufficiency

Uncommon Adrenal insufficiency

Very common Hypocalcaemia*,‡ Hypocalcaemia*,‡

Hypokalaemia‡ Hypokalaemia‡

Hypercholesterolaemiab,‡ Hypercholesterolaemiab,‡

Hypomagnesaemiab, ‡ Hypomagnesaemiab,‡

Decreased weight Decreased weight

Decreased appetite Decreased appetite

Common Dehydration Dehydration

Rare Tumour lysis syndrome† Tumour lysis syndrome†

Very common Insomnia

Common Insomnia

Very common Dizziness Dizziness

Headache Headache

Dysgeusia Dysgeusia

Common Cerebrovascular accident†

Uncommon Posterior reversible Posterior reversible encephalopathyencephalopathy syndrome syndrome

Monoparesis Cerebrovascular accident†

Transient ischaemic attack Monoparesis

Transient ischaemic attack

Table 6 Adverse reactions reported in patients treated with lenvatinib§

System Organ Class Lenvatinib monotherapy Combination with pembrolizumab(MedDRA terminology)

Common Myocardial infarctionc,† Prolonged electrocardiogram QT

Cardiac failure

Prolonged electrocardiogram

Decreased ejection fraction

Uncommon Myocardial infarctionc,†

Cardiac failure

Decreased ejection fraction

Very common Haemorrhaged, *,† Haemorrhaged, *,†

Hypertensione,* Hypertensione,*

Common Hypotension

Unknown Aneurysms and arterydissections

Very common Dysphonia Dysphonia

Common Pulmonary embolism† Pulmonary embolism†

Uncommon Pneumothorax Pneumothorax

Very common Diarrhoea Diarrhoea

Gastrointestinal and Gastrointestinal and abdominal painsfabdominal painsf Vomiting

Vomiting Nausea

Nausea Oral inflammationg

Oral inflammationg Oral painh

Oral painh Constipation

Constipation Dry mouth

Dyspepsia Increased lipase

Dry mouth Increased amylase‡

Increased lipase‡

Increased amylase‡

Common Anal fistula Pancreatitisi

Flatulence Flatulence

Gastrointestinal perforation Dyspepsia

Gastrointestinal perforation

Uncommon Pancreatitisi Anal fistula

Table 6 Adverse reactions reported in patients treated with lenvatinib§

System Organ Class Lenvatinib monotherapy Combination with pembrolizumab(MedDRA terminology)

Very common Increased blood bilirubinj,* ,‡ Increased blood bilirubinj,*,‡

Hypoalbuminaemiaj,* ,‡ Hypoalbuminaemiaj,*,‡

Increased alanine Increased alanine aminotransferase*, ‡aminotransferase*,‡ Increased aspartate aminotransferase*, ‡

Increased aspartate Increased blood alkaline phosphatase‡aminotransferase*,‡

Increased blood alkalinephosphatase‡

Increased gamma-glutamyltransferase‡

Common Hepatic failurek,*,† Cholecystitis

Hepatic encephalopathyl,*,† Abnormal hepatic function

Abnormal hepatic function Increased gamma-glutamyltransferase

Cholecystitis

Uncommon Hepatocellular Hepatic failurek,*†damage/hepatitism Hepatic encephalopathyl,†

Hepatocellular damage/hepatitism

Very common Palmar-plantar Palmar-plantarerythrodysaesthesia erythrodysaesthesia syndromesyndrome Rash

Alopecia

Common Hyperkeratosis Alopecia

Uncommon Hyperkeratosis

Very common Back pain Back pain

Arthralgia Arthralgia

Myalgia Myalgia

Pain in extremity Pain in extremity

Musculoskeletal pain

Common Musculoskeletal pain

Uncommon Osteonecrosis of the jaw

Very common Proteinuria* Proteinuria*

Increased blood creatinine‡ Increased blood creatinine‡

Common Renal failure n, *,† Renal failure n, *,†

Renal impairment*

Increased blood urea

Uncommon Nephrotic syndrome Renal impairment*

Increased blood urea

Table 6 Adverse reactions reported in patients treated with lenvatinib§

System Organ Class Lenvatinib monotherapy Combination with pembrolizumab(MedDRA terminology)

Very common Fatigue Fatigue

Asthenia Asthenia

Oedema peripheral Oedema peripheral

Common Malaise Malaise

Uncommon Impaired healing Impaired healing

Not known Non-gastrointestinal fistulao§: Adverse reaction frequencies presented in Table 6 may not be fully attributable to lenvatinib alone, but maycontain contributions from the underlying disease or from other medicinal products used in a combination.

*: See section 4.8 Description of selected adverse reactions for further characterisation.†: Includes cases with a fatal outcome.‡: Frequency based on laboratory data.

The following terms have been combined:a: Thrombocytopenia includes thrombocytopenia and decreased platelet count. Neutropenia includesneutropenia and decreased neutrophil count. Leukopenia includes leukopenia and decreased white blood cellcount. Lymphopenia includes lymphopenia and lymphocyte count decreased.

b: Hypomagnesaemia includes hypomagnesaemia and decreased blood magnesium. Hypercholesterolaemiaincludes hypercholesterolaemia and increased blood cholesterol.

c: Myocardial infarction includes myocardial infarction and acute myocardial infarction.d: Includes all haemorrhage terms.

Haemorrhage terms that occurred in 5 or more subjects with DTC were: epistaxis, haemoptysis, haematuria,contusion, haematochezia, gingival bleeding, petechial, pulmonary haemorrhage, rectal haemorrhage, bloodurine present, haematoma and vaginal haemorrhage.

Haemorrhage terms that occurred in 5 or more subjects with HCC were: epistaxis, haematuria, gingivalbleeding, haemoptysis, oesophageal varices haemorrhage, haemorrhoidal haemorrhage, mouth haemorrhage,rectal haemorrhage and upper gastrointestinal haemorrhage.

Haemorrhage term that occurred in 5 or more subjects with EC was: vaginal haemorrhage.

e: Hypertension includes: hypertension, hypertensive crisis, increased diastolic blood pressure, orthostatichypertension, and increased blood pressure.

f: Gastrointestinal and abdominal pains includes: abdominal discomfort, abdominal pain, abdominal pain lower,abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain.

g: Oral inflammation includes: aphthous stomatitis, aphthous ulcer, gingival erosion, gingival ulceration, oralmucosal blistering, stomatitis, glossitis, mouth ulceration, and mucosal inflammation.

h: Oral pain includes: oral pain, glossodynia, gingival pain, oropharyngeal discomfort, oropharyngeal pain andtongue discomfort.

i: Pancreatitis includes: pancreatitis and acute pancreatitis.j: Increased blood bilirubin includes: hyperbilirubinaemia, increased blood bilirubin, jaundice and increasedbilirubin conjugated. Hypoalbuminaemia includes hypoalbuminaemia and decreased blood albumin.k: Hepatic failure includes: hepatic failure, acute hepatic failure and chronic hepatic failure.l: Hepatic encephalopathy includes: hepatic encephalopathy, coma hepatic, metabolic encephalopathy andencephalopathy.m: Hepatocellular damage and hepatitis includes: drug-induced liver injury, hepatic steatosis, and cholestaticliver injury.n: Renal failure cases includes: acute prerenal failure, renal failure, renal failure acute, acute kidney injury andrenal tubular necrosis.o: Non-gastrointestinal fistula includes cases of fistula occurring outside of the stomach and intestines such astracheal, tracheo-oesophageal, oesophageal, female genital tract fistula, and cutaneous fistula.

Hypertension (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), hypertension (including hypertension,hypertensive crisis, increased diastolic blood pressure, and increased blood pressure) was reported in72.8% of lenvatinib-treated patients and 16.0% of patients in the placebo-treated group. The mediantime to onset in lenvatinib-treated patients was 16 days. Reactions of Grade 3 or higher (including1 reaction of Grade 4) occurred in 44.4% of lenvatinib-treated patients compared with 3.8% ofplacebo-treated patients. The majority of cases recovered or resolved following dose interruption orreduction, which occurred in 13.0% and 13.4% of patients, respectively. In 1.1% of patients,hypertension led to permanent treatment discontinuation.

HCC

In the Phase 3 REFLECT trial (see section 5.1), hypertension (including hypertension, increased bloodpressure, increased diastolic blood pressure and orthostatic hypertension) was reported in 44.5% oflenvatinib-treated patients and Grade 3 hypertension occurred in 23.5%. The median time to onset was26 days. The majority of cases recovered following dose interruption or reduction, which occurred in3.6% and 3.4% of patients, respectively. One subject (0.2%) discontinued lenvatinib due tohypertension.

EC

In the Phase 3 Study 309 (see section 5.1), hypertension was reported in 65% of patients in thelenvatinib plus pembrolizumab group. Reactions of Grade 3 or higher occurred in 38.4% of patients inthe lenvatinib plus pembrolizumab group. The median time to onset in the lenvatinib pluspembrolizumab group was 15 days. Dose interruption, reduction and discontinuation of lenvatiniboccurred in 11.6%, 17.7% and 2.0% of patients, respectively.

Proteinuria (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), 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 was6.7 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 doseinterruption or reduction, which occurred in 16.9% and 10.7% of patients, respectively. Proteinuria ledto permanent treatment discontinuation in 0.8% of patients.

HCC

In the Phase 3 REFLECT trial (see section 5.1), 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. Themajority of cases recovered following dose interruption or reduction, which occurred in 6.9% and2.5% of patients, respectively. Proteinuria led to permanent treatment discontinuation in 0.6% ofpatients.

EC

In the Phase 3 Study 309 (see section 5.1), proteinuria was reported in 29.6% of lenvatinib pluspembrolizumab-treated patients and Grade ≥3 reactions occurred in 5.4% of patients. The median timeto onset was 34.5 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in6.2%, 7.9% and 1.2% of patients, respectively.

Renal failure and impairment (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), 5.0% of patients developed renal failure and1.9% developed renal impairment (3.1% of patients had a Grade ≥ 3 event of renal failure orimpairment). In the placebo group 0.8% of patients developed renal failure or impairment (0.8% were

Grade ≥ 3).

HCC

In the Phase 3 REFLECT trial (see section 5.1), 7.1% of lenvatinib-treated patients developed a renalfailure/impairment event. Grade 3 or greater reactions occurred in 1.9% of lenvatinib-treated patients.

EC

In the Phase 3 Study 309 (see section 5.1), 18.2% of lenvatinib plus pembrolizumab-treated patientsdeveloped a renal failure/impairment event. Grade ≥ 3 reactions occurred in 4.2% of patients. Themedian time to onset was 86.0 days. Dose interruption, reduction and discontinuation of lenvatiniboccurred in 3.0%, 1.7% and 1.2% of patients, respectively.

Cardiac dysfunction (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), decreased ejection fraction/cardiac failure wasreported in 6.5% of patients (1.5% were Grade ≥ 3) in the lenvatinib-treated group, and 2.3% in theplacebo group (none were Grade ≥ 3).

HCC

In the Phase 3 REFLECT trial (see section 5.1), cardiac dysfunction (including congestive cardiacfailure, cardiogenic shock, and cardiopulmonary failure) was reported in 0.6% of patients (0.4% were

Grade ≥ 3) in the lenvatinib-treated group.

EC

In the Phase 3 Study 309 (see section 5.1), cardiac dysfunction was reported in 1.0% of lenvatinib pluspembrolizumab-treated patients and Grade ≥3 reactions occurred in 0.5% of patients. The median timeto onset was 112.0 days. Dose reduction and discontinuation of lenvatinib both occurred in 0.2% ofpatients.

Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior leucoencephalopathysyndrome (RPLS) (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), there was 1 event of PRES (Grade 2) in thelenvatinib-treated group and no reports in the placebo group.

HCC

In the Phase 3 REFLECT trial (see section 5.1), there was 1 event of PRES (Grade 2) in thelenvatinib-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 doseinterruption, or permanent discontinuation.

EC

In the Phase 3 Study 309 (see section 5.1), there was one event of PRES (Grade 1) in the lenvatinibplus pembrolizumab-treated group for which lenvatinib was interrupted.

Hepatotoxicity (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), the most commonly reported liver-relatedadverse reactions were hypoalbuminaemia (9.6% lenvatinib vs. 1.5% placebo) and elevations of liverenzyme 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% lenvatinibvs. 0 placebo). The median time to onset of liver reactions in lenvatinib-treated patients was12.1 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%.

Amongst 1,166 patients treated with lenvatinib, there were 3 cases (0.3%) of hepatic failure, all with afatal outcome. One occurred in a patient with no liver metastases. There was also a case of acutehepatitis in a patient without liver metastases.

HCC

In the Phase 3 REFLECT trial (see section 5.1), the most commonly reported hepatotoxicity adversereactions 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. Hepatotoxicityreactions of ≥ Grade 3 occurred in 26.1% of lenvatinib-treated patients. Hepatic failure (including fatalevents 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 were17 (3.6%) deaths due to hepatotoxicity events in the lenvatinib arm and 4 (0.8%) deaths in thesorafenib arm. Hepatotoxicity adverse reactions led to dose interruptions and reductions in 12.2% and7.4% of lenvatinib-treated patients respectively, and to permanent discontinuation in 5.5%.

Across clinical trials 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 in2 patients (0.2%), acute hepatitis in 2 patients (0.2%), and hepatocellular injury in 1 patient (0.1%).

EC

In the Phase 3 Study 309 (see section 5.1), hepatotoxicity was reported in 33.7% of lenvatinib pluspembrolizumab-treated patients and Grade ≥3 reactions occurred in 12.1% of patients. The mediantime to onset was 56.0 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in5.2%, 3.0% and 1.2% of patients, respectively.

Arterial thromboembolisms (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), arterial thromboembolic events were reported in5.4% of lenvatinib-treated patients and 2.3% of patients in the placebo group.

HCC

In the Phase 3 REFLECT trial (see section 5.1), arterial thromboembolic events were reported in 2.3%of patients treated with lenvatinib.

Amongst 1,823 patients treated with lenvatinib monotherapy in clinical trials, there were 10 cases(0.5%) of arterial thromboembolisms (5 cases of myocardial infarction and 5 cases of cerebrovascularaccident) with a fatal outcome.

EC

In the Phase 3 Study 309 (see section 5.1), arterial thromboembolisms were reported in 3.7% oflenvatinib 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 occurredin 0.2% and 2.0% of patients, respectively.

Haemorrhage (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), 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-treatedpatients. 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%), rectalhaemorrhage (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 caseof fatal intracranial haemorrhage among 16 patients who received lenvatinib and had CNS metastasesat baseline.

The median time to first onset in lenvatinib-treated patients was 10.1 weeks. No differences betweenlenvatinib- and placebo-treated patients were observed in the incidences of serious reactions (3.4% vs.3.8%), reactions leading to premature discontinuation (1.1% vs. 1.5%), or reactions leading to doseinterruption (3.4% vs. 3.8%) or reduction (0.4% vs. 0).

HCC

In the Phase 3 REFLECT trial (see section 5.1), haemorrhage was reported in 24.6% of patients and5.0% 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. Ahaemorrhage event led to dose interruption or reduction in 3.2% and 0.8% patients respectively and totreatment discontinuation in 1.7% of patients.

Across clinical trials 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.

EC

In the Phase 3 Study 309 (see section 5.1), haemorrhage was reported in 24.4% of lenvatinib pluspembrolizumab-treated patients and Grade ≥3 reactions occurred in 3.0% of patients. The median timeto onset was 65.0 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in1.7%, 1.2% and 1.7% of patients, respectively.

Hypocalcaemia (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), hypocalcaemia was reported in 12.6% oflenvatinib-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, withoutdose interruption or reduction, which occurred in 1.5% and 1.1% of patients, respectively; 1 patientwith Grade 4 hypocalcaemia discontinued treatment permanently.

HCC

In the Phase 3 REFLECT trial (see section 5.1), hypocalcaemia was reported in 1.1% of patients, withgrade 3 reactions occurring in 0.4%. Lenvatinib dose interruption due to hypocalcaemia occurred inone subject (0.2%) and there were no dose reductions or discontinuations.

EC

In the Phase 3 Study 309 (see section 5.1), hypocalcaemia was reported in 3.9% of lenvatinib pluspembrolizumab-treated patients and Grade ≥3 reactions occurred in 1.0% of patients. The median timeto onset was 148.0 days. No lenvatinib dose modifications were reported.

Gastrointestinal perforation and fistula formation (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), events of gastrointestinal perforation or fistulawere reported in 1.9% of lenvatinib-treated patients and 0.8% of patients in the placebo group.

HCC

In the Phase 3 REFLECT trial (see section 5.1), events of gastrointestinal perforation or fistula werereported in 1.9% of lenvatinib-treated patients.

EC

In the Phase 3 Study 309 (see section 5.1), events of fistula formation were reported in 2.5% oflenvatinib 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-treatedpatients 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 fistulae (see section 4.4)

Lenvatinib use has been associated with cases of fistulae including reactions resulting in death.

Reports of fistulae that involve areas of the body other than stomach or intestines were observedacross various indications. Reactions were reported at various time points during treatment rangingfrom two weeks to greater than 1 year from initiation of lenvatinib, with median latency of about3 months.

QT interval prolongation (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), QT/QTc interval prolongation was reported in8.8% of lenvatinib-treated patients and 1.5% of patients in the placebo group. The incidence of QTinterval prolongation of greater than 500 ms was 2% in the lenvatinib-treated patients compared to noreports in the placebo group.

HCC

In the Phase 3 REFLECT trial (see section 5.1), QT/QTc interval prolongation was reported in 6.9%of lenvatinib-treated patients. The incidence of QTcF interval prolongation of greater than 500ms was2.4%.

EC

In the Phase 3 Study 309 (see section 5.1), QT interval prolongation was reported in 3.9% oflenvatinib 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 in0.2% and 0.5% of patients, respectively.

Increased blood thyroid stimulating hormone (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), 88% of all patients had a baseline TSH levelless than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH levelabove 0.5 mU/L was observed post baseline in 57% of lenvatinib-treated patients as compared with14% of placebo-treated patients.

HCC

In the Phase 3 REFLECT trial (see section 5.1), 89.6% of patients had a baseline TSH level of lessthan the upper limit of normal. Elevation of TSH above the upper limit of normal was observed postbaseline in 69.6% of lenvatinib-treated patients.

EC

In the Phase 3 Study 309 (see section 5.1), hypothyroidism was reported in 68.2% of lenvatinib pluspembrolizumab-treated patients and Grade ≥3 reactions occurred in 1.2% of patients. The median timeto onset was 62.0 days. Dose interruption and reduction of lenvatinib occurred in 2.2% and 0.7% ofpatients, respectively.

Blood TSH increased was reported in 12.8% of lenvatinib plus pembrolizumab-treated patients withno patients reporting Grade ≥3 reactions. Dose interruption occurred in 0.2% of patients.

Diarrhoea (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), diarrhoea was reported in 67.4% of patients inthe lenvatinib-treated group (9.2% were Grade ≥ 3) and in 16.8% of patients in the placebo group(none were Grade ≥ 3).

HCC

In the Phase 3 REFLECT trial (see section 5.1), diarrhoea was reported in 38.7% of patients treatedwith lenvatinib (4.2% were Grade ≥ 3).

EC

In the Phase 3 Study 309 (see section 5.1), diarrhoea was reported in 54.2% of lenvatinib pluspembrolizumab-treated patients (7.6% were Grade ≥ 3). Dose interruption, reduction anddiscontinuation of lenvatinib occurred in 10.6%, 11.1% and 1.2% of patients, respectively.

In the paediatric Studies 207, 216, 230, and 231 (see section 5.1), the overall safety profile oflenvatinib as a single agent or in combination with either ifosfamide and etoposide or everolimus wasconsistent with that observed in adults treated with lenvatinib.

In patients with relapsed/refractory osteosarcoma, pneumothorax was reported at a frequency higherthan that observed in adults with DTC, HCC, RCC and EC. In Study 207, pneumothorax occurred in 6patients (10.9%) treated with single -agent lenvatinib and 7 patients (16.7%) treated with lenvatinib incombination with ifosfamide and etoposide. Overall, 2 patients discontinued study treatment due topneumothorax. In Study 230, pneumothorax was reported in a total of 14 patients (11 patients [28.2%]treated with lenvatinib plus ifosfamide and etoposide, and 3 patients [7.7%] treated with ifosfamideand etoposide). In Study 216, pneumothorax was reported in 3 patients (4.7%) with Ewing sarcoma,rhabdomyosarcoma (RMS) and Wilms tumour; all 3 patients had lung metastases at baseline. In

Study 231, pneumothorax was reported in 7 patients (5.5%) with spindle cell sarcoma, undifferentiatedsarcoma, RMS, malignant peripheral nerve sheath tumour, synovial sarcoma, spindle cell carcinoma,and malignant fibromyxoid ossifying tumour; all 7 patients had lung metastases or primary disease inthe chest wall or pleural cavity at baseline. For Studies 216, 230, and 231, no patient discontinuedstudy treatment due to pneumothorax. Pneumothorax occurrence appeared to be mainly associatedwith pulmonary metastases and underlying disease.

In the single-agent dose-finding cohort of Study 207, the most frequently (≥40%) reported adversedrug reactions were decreased appetite, diarrhoea, hypothyroidism, vomiting, abdominal pain, pyrexia,hypertension, and weight decreased; and in the single-agent expansion cohort of patients with relapsedor refractory osteosarcoma, the most frequently (≥40%) reported adverse drug reactions weredecreased appetite, headache, vomiting, hypothyroidism, and proteinuria.

In the combination dose-finding cohort of Study 207, the most frequently (≥50%) reported adversedrug reactions were vomiting, anaemia, nausea, diarrhoea, hypothyroidism, abdominal pain, arthralgia,epistaxis, neutropenia, constipation, headache, and pain in extremity; and in the combinationexpansion cohort, the most frequently (≥50%) reported adverse drug reactions were anaemia, nausea,white blood cell count decreased, diarrhoea, vomiting, and platelet count decreased.

In Phase 1 (combination dose-finding cohort) of Study 216, the most frequently (≥40%) reportedadverse drug reactions were hypertension, hypothyroidism, hypertriglyceridemia, abdominal pain, anddiarrhoea; and in Phase 2 (combination expansion cohort), the most frequently reported (≥35%)adverse drug reactions were hypertriglyceridemia, proteinuria, diarrhoea, lymphocyte count decreased,white blood cell count decreased, blood cholesterol increased, fatigue, and platelet count decreased.

In the OLIE study (Study 230), the most frequently (≥35%) reported adverse drug reactions werehypothyroidism, anaemia, nausea, platelet count decreased, proteinuria, vomiting, back pain, febrileneutropenia, hypertension, constipation, diarrhoea, neutrophil count decreased, and pyrexia.

In Study 231, the most frequently reported (≥15%) adverse drug reactions were hypothyroidism,hypertension, proteinuria, decreased appetite, diarrhoea, and platelet count decreased.

DTC

Patients of age ≥75 years were more likely to experience Grade 3 or 4 hypertension, proteinuria,decreased appetite, and dehydration.

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 diseasecharacteristics at baseline or with the use of concomitant medicinal products. Arterial thromboembolicevents also occurred at an increased incidence in this age group.

EC

Patients of age ≥75 years were more likely to experience urinary tract infections and Grade ≥3hypertension (≥ 10% increase compared to patients of age <65 years).

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 gastrointestinalperforation and fistula formation.

HCC

Females had a higher incidence of hypertension, fatigue, ECG QT prolongation and alopecia. Men hada higher incidence (26.5%) of dysphonia than women (12.3%), decreased weight and decreasedplatelet count. Hepatic failure events were observed in male patients only.

DTC

Asian patients had a higher (≥ 10% difference) incidence than Caucasian patients of peripheraloedema, 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 Asianpatients had a lenvatinib dose reduction compared to Caucasian patients. the median time to first dosereduction and the average daily dose taken were lower in Asian than in Caucasian patients.

HCC

Asian patients had a higher incidence than Caucasian patients of proteinuria, decreased neutrophilcount, decreased platelet count, decreased white blood count and PPE, while Caucasian patients had ahigher incidence of fatigue, hepatic encephalopathy, acute kidney injury, anxiety, asthenia, nausea,thrombocytopenia and vomiting.

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 Caucasianpatients had a higher incidence of mucosal inflammation, abdominal pain, diarrhoea, urinary tractinfection, weight decreased, hypomagnesaemia, dizziness, asthenia and fatigue.

Baseline hypertension

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 (abdominalpain, diarrhoea, vomiting).

DTC

Patients with baseline hepatic impairment had a higher incidence of hypertension and PPE, and ahigher incidence of Grade 3 or 4 hypertension, asthenia, fatigue, and hypocalcaemia compared withpatients with normal hepatic function.

HCC

Patients with a baseline Child-Pugh (CP) score of 6 (about 20% patients in the REFLECT study) had ahigher incidence of decreased appetite, fatigue, proteinuria, hepatic encephalopathy and hepatic failurecompared to patients with a baseline CP score of 5. Hepatotoxicity events and haemorrhage eventsalso occurred at a higher incidence in CP score 6 patients compared to CP score 5 patients.

DTC

Patients with baseline renal impairment had a higher incidence of Grade 3 or 4 hypertension,proteinuria, fatigue, stomatitis, oedema peripheral, thrombocytopenia, dehydration, prolonged QT,hypothyroidism, hyponatraemia, increased blood thyroid stimulating hormone, pneumonia comparedwith subjects with normal renal function. These patients also had a higher incidence of renal reactionsand a trend towards a higher incidence of liver reactions.

HCC

Patients with baseline renal impairment had a higher incidence of fatigue, hypothyroidism,dehydration, diarrhoea, decreased appetite, proteinuria and hepatic encephalopathy. These patientsalso had a higher incidence of renal reactions and arterial thromboembolic events.

Patients with body weight <60 kg

DTC

Patients with low body weight (<60 kg) had a higher incidence of PPE, proteinuria, of Grade 3 or 4hypocalcaemia and hyponatraemia, and a trend towards a higher incidence of Grade 3 or 4 decreasedappetite.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The highest doses of lenvatinib studied clinically were 32 mg and 40 mg per day. Accidentalmedication errors resulting in single doses of 40 to 48 mg have occurred in clinical trials. The mostfrequently observed adverse drug reactions at these doses were hypertension, nausea, diarrhoea,fatigue, stomatitis, proteinuria, headache, and aggravation of PPE. There have also been reports ofoverdose with lenvatinib involving single administrations of 6 to 10 times the recommended dailydose. These cases were associated with adverse reactions consistent with the known safety profile oflenvatinib (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, lenvatinibshould be withheld and appropriate supportive care given as required.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EX08

Lenvatinib is a multikinase inhibitor which has shown mainly antiangiogenic properties in vitro and invivo, and direct inhibition of tumour growth was also observed in in vitro models.

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities ofvascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and

VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs includingfibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor(PDGF) receptor PDGFRα, KIT, and RET.

In addition, lenvatinib had selective, direct antiproliferative activity in hepatocellular cell linesdependent on activated FGFR signalling, which is attributed to the inhibition of FGFR signalling bylenvatinib.

In syngeneic mouse tumour models, lenvatinib decreased tumour-associated macrophages, increasedactivated cytotoxic T cells, and demonstrated greater antitumour activity in combination with an anti-

PD-1 monoclonal antibody compared to either treatment alone.

Although not studied directly with lenvatinib, the mechanism of action (MOA) for hypertension ispostulated 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 downregulationof VEGFR1 and VEGFR2 in the podocytes of the glomerulus.

The mechanism of action for hypothyroidism is not fully elucidated.

Radioiodine-refractory differentiated thyroid cancer

The SELECT study was a multicentre, randomised, double-blind, placebo-controlled trial that wasconducted in 392 patients with radioiodine-refractory differentiated thyroid cancer with independent,centrally reviewed, radiographic evidence of disease progression within 12 months (+1 monthwindow) prior to enrolment. Radioiodine-refractory was defined as one or more measurable lesionseither with a lack of iodine uptake or with progression in spite of radioactive-iodine (RAI) therapy, orhaving a cumulative activity of RAI of >600 mCi or 22 GBq with the last dose at least 6 months priorto 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 outcomemeasure was progression-free survival (PFS) as determined by blinded independent radiologic reviewusing Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Secondary efficacy outcomemeasures included overall response rate and overall survival. Patients in the placebo arm could opt toreceive lenvatinib treatment at the time of confirmed disease progression.

Eligible patients with measurable disease according to RECIST 1.1 were randomised 2:1 to receivelenvatinib 24 mg once daily (n=261) or placebo (n=131). Baseline demographics and diseasecharacteristics 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, andthe median age was 63 years. Histologically, 66.1% had a confirmed diagnosis of papillary thyroidcancer 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 in38.8%, liver in 18.1%, pleura in 16.3%, and brain in 4.1%. The majority of patients had an ECOGperformance 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 patientscompared with those receiving placebo (p<0.0001) (see figure 1). The positive effect on PFS was seenacross the subgroups of age (above or below 65 years), sex, race, histological subtype, geographicregion, and those who received 0 or 1 prior VEGF/VEGFR-targeted therapies. Following independentreview confirmation of disease progression, 109 (83.2%) patients randomised to placebo had crossedover to open-label lenvatinib at the time of the primary efficacy analysis.

The objective response rate (complete response [CR] plus partial response [PR]) per independentradiological review was significantly (p<0.0001) higher in the lenvatinib-treated group (64.8%) than inthe placebo-treated group (1.5%). Four (1.5%) subjects treated with lenvatinib attained a CR and 165subjects (63.2%) had a PR, while no subjects treated with placebo had a CR and 2 (1.5%) subjects hada PR.

The median time to first dose reduction was 2.8 months. The median time to objective responsive was2.0 (95% CI: 1.9, 3.5) months; however, of the patients who experienced a complete or partialresponse to lenvatinib, 70.4% were observed to develop the response on or within 30 days of being onthe 24-mg dose.

The overall survival analysis was confounded by the fact that placebo-treated subjects with confirmeddisease progression had the option to cross over to open-label lenvatinib. There was no statisticallysignificant difference in overall survival between the treatment groups at the time of the primaryefficacy analysis (HR=0.73; 95% CI: 0.50, 1.07, p=0.1032). The median Overall Survival (OS) hadnot been reached for either the lenvatinib group or the placebo crossover group.

Table 7 Efficacy results in DTC patients

Lenvatinib Placebo

N=261 N=131

Progression-Free Survival (PFS)a

Number of progressions or deaths (%) 107 (41.0) 113 (86.3)

Median PFS in months (95% CI) 18.3 (15.1, NE) 3.6 (2.2, 3.7)

Hazard ratio (99% CI)b,c 0.21 (0.14, 0.31)

P valueb <0.0001

Patients who had received 0 prior195 (74.7) 104 (79.4)

VEGF/VEGFR-targeted therapy (%)

Number of progressions or deaths 76 88

Median PFS in months (95% CI) 18.7 (16.4, NE) 3.6 (2.1, 5.3)

Hazard ratio (95% CI)b,c 0.20 (0.14, 0.27)

Patients who had received 1 prior66 (25.3) 27 (20.6)

VEGF/VEGFR-targeted therapy (%)

Number of progressions or deaths 31 25

Median PFS in months (95% CI) 15.1 (8.8, NE) 3.6 (1.9, 3.7)

Hazard ratio (95% CI)b,c 0.22 (0.12, 0.41)

Objective Response Ratea

Number of objective responders (%) 169 (64.8) 2 (1.5)(95% CI) (59.0, 70.5) (0.0, 3.6)

P valueb <0.0001

Number of complete responses 4 0

Number of partial responses 165 2

Median time to objective response,d months (95% CI) 2.0 (1.9, 3.5) 5.6 (1.8, 9.4)

Duration of response,d months, median (95% CI) NE (16.8, NE) NE (NE, NE)

Overall Survival

Number of deaths (%) 71 (27.2) 47 (35.9)

Median OS in months (95% CI) NE (22.0, NE) NE (20.3,

NE)

Hazard ratio (95% CI)b, e 0.73 (0.50, 1.07)

P value b, e 0.1032

CI, confidence interval; NE, not estimable; OS, overall survival; PFS, progression-free survival; RPSFT, rankpreserving structural failure time model; VEGF/VEGFR, vascular endothelial growth factor/vascularendothelial growth factor receptor.a: Independent radiologic review.b: Stratified by region (Europe vs. North America vs. Other), age group (≤65 years vs >65 years), andprevious VEGF/VEGFR-targeted therapy (0 vs. 1).c: Estimated with Cox proportional hazard model.d: Estimated using the Kaplan-Meier method; the 95% CI was constructed with a generalised Brookmeyerand Crowley method in patients with a best overall response of complete response or partial response.e: Not adjusted for crossover effect.

Figure 1 Kaplan-Meier Curve of Progression-Free Survival - DTC

CI, confidence interval; NE, not estimable.

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 hepatocellularcarcinoma (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 givenorally 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 excludedwho had prior systemic anticancer therapy for advanced/unresectable HCC or any prior anti-VEGFtherapy. Target lesions previously treated with radiotherapy or locoregional therapy had to showradiographic evidence of disease progression. Patients with ≥50% liver occupation, clear invasion intothe 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 thesorafenib groups and are shown below 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 of1: 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 includingtransarterial (chemo)embolisation (52%), radiofrequency ablation (21%) and percutaneousethanol injection (4%)

The primary efficacy endpoint was Overall Survival (OS). Lenvatinib was non-inferior for OS tosorafenib 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 8 and Figure 2). The results for surrogate endpoints (PFS and ORR) are presented in Table8 below.

Table 8 Efficacy Results from the REFLECT study in HCCa, b Median (95% CI)e

Hazard ratio

Efficacy parameter P valued(95% CI) Lenvatinib Sorafenib(N= 478) (N=476)

OS 0.92 (0.79,1.06) NA 13.6 (12.1, 14.9) 12.3 (10.4, 13.9)

PFSg (mRECIST) 0.64 (0.55, 0.75) <0.00001 7.3 (5.6, 7.5) 3.6 (3.6, 3.7)

Percentages (95% CI)

ORRc, f, g (mRECIST) NA <0.00001 41% (36%, 45%) 12% (9%, 15%)

Data cut-off date: 13 Nov 2016.a: Hazard ratio (HR) is for lenvatinib vs. sorafenib, based on a Cox model including treatment group as afactor.b: Stratified by region (Region 1: Asia-Pacific; Region 2: Western), macroscopic portal vein invasion orextrahepatic spread or both (yes, no), ECOG PS (0, 1) and body weight (<60 kg, ≥60 kg).c: Results are based on confirmed and unconfirmed responses.d: P- value is for the superiority test of lenvatinib versus sorafenib.e: Quartiles are estimated by the Kaplan-Meier method, and the 95% CIs are estimated with a generalised

Brookmeyer and Crowley methodf: Response rate (complete or partial response)g: Per independent radiology review retrospective analysis. The median duration of objective response was7.3 (95% CI 5.6, 7.4) months in the lenvatinib arm and 6.2 (95% CI 3.7, 11.2) months in the sorafenibarm.

Figure 2 Kaplan-Meier Curve of Overall Survival - HCC1. Data cut-off date = 13 Nov 2016.2. Noninferiority margin for hazard ratio (HR: lenvatinib vs sorafenib = 1.08).3. Median was estimated with the Kaplan-Meier method and the 95% confidence interval was constructedwith a generalised Brookmeyer and Crowley method.

4. HR was estimated from the Cox proportional hazard model with treatment as independent variable andstratified by IxRS stratification factors. The Efron method was used for ties.

5. + = censored observations.

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 of1.01 (95% CI 0.78, 1.30)] and patients without MPVI, EHS or both [HR of 1.05 (0.79, 1.40)]. Theresults 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 and3.7 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 insubjects who received post-treatment anticancer therapy than in those who did not. In the lenvatinibarm, median OS was 19.5 months (95% CI: 15.7, 23.0) for subjects who received post-treatmentanticancer therapy (43%) and 10.5 months (95% CI: 8.6, 12.2) for those who did not. In the sorafenibarm, median OS was 17.0 months (95% CI: 14.2, 18.8) for subjects who received posttreatmentanticancer therapy (51%) and 7.9 months (95% CI: 6.6, 9.7) for those who did not. Median OS waslonger by approximately 2.5 months in the lenvatinib compared with the sorafenib arm in both subsetsof subjects (with or without post-treatment anticancer therapy).

The efficacy of lenvatinib in combination with pembrolizumab was investigated in Study 309, arandomised, multicentre, open-label, active-controlled study conducted in patients with advanced ECwho had been previously treated with at least one prior platinum-based chemotherapy regimen in anysetting, including in the neoadjuvant and adjuvant settings. Participants may have received up to 2platinum-containing therapies in total, as long as one was given in the neoadjuvant or adjuvanttreatment setting. The study excluded patients with endometrial sarcoma (including carcinosarcoma),or patients who had active autoimmune disease or a medical condition that requiredimmunosuppression. Randomisation was stratified by mismatch repair (MMR) status (dMMR orpMMR [not dMMR]) using a validated IHC test. The pMMR stratum was further stratified by ECOGperformance 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 intravenouslyevery 3 weeks.

- investigator’s choice consisting of either doxorubicin 60 mg/m2 every 3 weeks, or paclitaxel80 mg/m2 given weekly, 3 weeks on/1 week off.

Treatment with lenvatinib and pembrolizumab continued until RECIST v1.1-defined progression ofdisease as verified by Blinded Independent Central Review (BICR), unacceptable toxicity, or forpembrolizumab, 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 derivingclinical benefit and the treatment was tolerated. A total of 121/411 (29%) of the lenvatinib andpembrolizumab-treated patients received continued study therapy beyond RECIST-defined diseaseprogression. The median duration of post-progression therapy was 2.8 months. Assessment of tumourstatus was performed every 8 weeks.

A total of 827 patients were enrolled and randomised to lenvatinib in combination withpembrolizumab (n=411) or investigator’s choice of doxorubicin (n=306) or paclitaxel (n=110). Thebaseline characteristics of these patients were: median age of 65 years (range 30 to 86), 50% age 65 orolder; 61% White, 21% Asian, and 4% Black; ECOG PS of 0 (59%) or 1 (41%), and 84% with pMMRtumour status, and 16% with dMMR tumour status. The histologic subtypes were endometrioidcarcinoma (60%), serous (26%), clear cell carcinoma (6%), mixed (5%), and other (3%). All 827 ofthese patients received prior systemic therapy for EC: 69% had one, 28% had two, and 3% had threeor more prior systemic therapies. Thirty-seven percent of patients received only prior neoadjuvant oradjuvant therapy.

The median duration of study treatment was 7.6 months (range 1 day to 26.8 months). The medianduration 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 thepre-specified interim analysis, with a median follow-up time of 11.4 months (range: 0.3 to 26.9months), 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 durationfrom 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 aresummarised in Table 9. Kaplan-Meier curves for final OS and interim PFS analyses are shown in

Figures 3 and 4, respectively.

Table 9 Efficacy Results in Endometrial Carcinoma in Study 309

Endpoint LENVIMA with Doxorubicin orpembrolizumab Paclitaxel

N=411 N=416

OS

Number (%) of patients with event 276 (67%) 329 (79%)

Median in months (95% CI) 18.7 (15.6, 21.3) 11.9 (10.7, 13.3)

Hazard ratioa (95% CI) 0.65 (0.55, 0.77)

P valueb <0.0001

PFSd

Number (%) of patients with event 281 (68%) 286 (69%)

Median in months (95% CI) 7.2 (5.7, 7.6) 3.8 (3.6, 4.2)

Hazard ratioa (95% CI) 0.56 (0.47, 0.66)

P valuec <0.0001

ORRd

ORRe (95% CI) 32% (27, 37) 15% (11,18)

Complete response 7% 3%

Partial response 25% 12%

P valuef <0.0001

Duration of Responsed

Median in monthsg (range) 14.4 (1.6+, 23.7+) 5.7 (0.0+, 24.2+)a: Based on the stratified Cox regression modelb: One-sided nominal p-Value based on stratified log-rank test (final analysis). At the pre-specified interimanalysis of OS with a median follow-up time of 11.4 months (range:0.3 to 26.9 months), statisticallysignificant superiority was achieved for OS comparing the combination of lenvatinib and pembrolizumabwith doxorubicin or paclitaxel (HR: 0.62 [95%CI: 0.51, 0.75] p-Value <0.0001).

c: One-sided p-Value based on stratified log-rank testd: At pre-specified interim analysise: Response: Best objective response as confirmed complete response or partial responsef: Based on Miettinen and Nurminen method stratified by ECOG performance status, geographic region, andhistory of pelvic radiation.g: Based on Kaplan-Meier estimation

Figure 3 Kaplan-Meier Curves for Overall Survival in Study 309*

*Based on the protocol-specified final analysis

Figure 4 Kaplan-Meier Curves for Progression-Free Survival in Study 309

QT interval prolongation

A single 32-mg dose of lenvatinib did not prolong the QT/QTc interval based on results from athorough QT study in healthy volunteers; however, QT/QTc interval prolongation has been reported ata higher incidence in patients treated with lenvatinib than in patients treated with placebo (see sections4.4 and 4.8).

The European Medicines Agency has deferred the obligation to submit the results of studies withlenvatinib in one or more subsets of the paediatric population in the treatment of hepatocellularcarcinoma (HCC) and endometrial carcinoma (EC) (see section 4.2 for information on paediatric use).

Paediatric studies

The efficacy of lenvatinib was assessed but not established in four open-label studies:

Study 207 was a Phase 1/2, open-label, multi-centre, dose-finding and activity-estimating study oflenvatinib as a single agent and in combination with ifosfamide and etoposide in paediatric patients(aged 2 to <18 years; 2 to ≤25 years for osteosarcoma), with relapsed or refractory solid tumours. Atotal of 97 patients were enrolled. In the lenvatinib single agent dose-finding cohort, 23 patients wereenrolled and received lenvatinib orally, once daily, across 3 dose levels (11, 14, or 17 mg/m2). In thelenvatinib in combination with ifosfamide and etoposide dose-finding cohort, a total of 22 patientswere enrolled and received lenvatinib across 2 dose levels (11 or 14 mg/m2). The recommended dose(RD) of lenvatinib as a single agent, and in combination with ifosfamide and etoposide wasdetermined as 14 mg/m2 orally, once daily.

In the lenvatinib single agent expansion cohort of relapsed or refractory DTC, the primary efficacyoutcome measure was objective response rate (ORR; complete response [CR] + partial response [PR]).

One patient was enrolled, and this patient achieved a PR. In both the lenvatinib single agent, andcombination with ifosfamide and etoposide expansion cohorts of relapsed or refractory osteosarcoma,the primary efficacy outcome measure was progression-free survival rate at 4 months (PFS-4); the

PFS-4 by binomial estimate including all 31 patients treated with lenvatinib as a single agent was 29%(95%CI: 14.2, 48.0); the PFS-4 by binomial estimate in all 20 patients treated in the lenvatinib incombination with ifosfamide and etoposide expansion cohort was 50% (95%CI: 27.2, 72.8).

Study 216 was a multicentre, open-label, single-arm, Phase 1/2 study to determine the safety,tolerability, and antitumour activity of lenvatinib administered in combination with everolimus inpaediatric patients (and young adults aged ≤21 years) with relapsed or refractory solid malignancies,including CNS tumours. A total of 64 patients were enrolled and treated. In Phase 1 (combinationdose-finding), 23 patients were enrolled and treated: 5 at Dose Level -1 (lenvatinib 8 mg/m2 andeverolimus 3 mg/m2) and 18 at Dose Level 1 (lenvatinib 11 mg/m2 and everolimus 3 mg/m2). Therecommended dose (RD) of the combination was lenvatinib 11 mg/m2 and everolimus 3 mg/m2, takenonce daily. In Phase 2 (combination expansion), 41 patients were enrolled and treated at the RD in thefollowing cohorts: Ewing Sarcoma (EWS, n=10), Rhabdomyosarcoma (RMS, n=20), and High-gradeglioma (HGG, n=11). The primary efficacy outcome measure was objective response rate (ORR) at

Week 16 in evaluable patients based on investigator assessment using RECIST v1.1 or RANO (forpatients with HGG). There were no objective responses observed in the EWS and HGG cohorts;2 partial responses (PRs) were observed in the RMS cohort for an ORR at Week 16 of 10%(95% CI: 1.2, 31.7).

The OLIE study (Study 230) was a Phase 2, open-label, multicentre, randomized, controlled trial inpatients (aged 2 to ≤25 years) with relapsed or refractory osteosarcoma. A total of 81 patients wererandomized in a 1:1 ratio (78 treated; 39 in each arm) to lenvatinib 14 mg/m2 in combination withifosfamide 3000 mg/m2 and etoposide 100 mg/m2 (Arm A) or ifosfamide 3000 mg/m2 and etoposide100 mg/m2 (Arm B). Ifosfamide and etoposide were administered intravenously on Days 1 to 3 of each21-day cycle for a maximum of 5 cycles. Treatment with lenvatinib was permitted until RECIST v1.1-defined disease progression as verified by Blinded Independent Central Review (BICR) orunacceptable toxicity. The primary efficacy outcome measure was progression-free survival (PFS) per

RECIST 1.1 by BICR. The trial did not demonstrate a statistically significant difference in median

PFS: 6.5 months (95%CI: 5.7, 8.2) for lenvatinib in combination with ifosfamide and etoposide versus5.5 months (95%CI: 2.9, 6.5) for ifosfamide and etoposide (HR=0.54 [95%CI: 0.27, 1.08]). Study 230was not powered to detect a statistically significant difference in OS. At the end of study analysis, the

HR was 0.93 (95% CI: 0.53, 1.62) for the comparison of lenvatinib in combination with ifosfamideand etoposide versus ifosfamide and etoposide, with median OS 12.4 months (95% CI 10.4, 19.8)versus 17.2 months (95% CI 11.1, 22.3), respectively, and median follow-up time 24.1 months and29.5 months, respectively.

Study 231 is a multicentre, open-label, Phase 2 basket study to evaluate the antitumour activity andsafety of lenvatinib in children, adolescents, and young adults between 2 to ≤21 years of age withrelapsed or refractory solid malignancies, including EWS, RMS, and HGG. A total of 127 patientswere enrolled and treated at the lenvatinib RD (14 mg/m2) in the following cohorts: EWS (n=9),

RMS (n=17), HGG (n=8), and other solid tumours (n=9 each for diffuse midline glioma,medulloblastoma, and ependymoma; all other solid tumours n=66). The primary efficacy outcomemeasure was ORR at Week 16 in evaluable patients based on investigator assessment using

RECIST v1.1 or RANO (for patients with HGG). There were no objective responses observed inpatients with HGG, diffuse midline glioma, medulloblastoma, or ependymoma. Two PRs wereobserved in both the EWS and RMS cohorts for an ORR at Week 16 of 22.2% (95% CI: 2.8, 60.0) and11.8% (95% CI: 1.5, 36.4), respectively. Five PRs (in patients with synovial sarcoma [n=2],kaposiform hemangioendothelioma [n=1], Wilms tumour nephroblastoma [n=1], and clear cellcarcinoma [n=1]) were observed among all other solid tumours for an ORR at Week 16 of 7.7%(95% CI: 2.5, 17.0).

Pharmacokinetic parameters of lenvatinib have been studied in healthy adult subjects, adult subjectswith hepatic impairment, renal impairment, and solid tumours.

Lenvatinib is rapidly absorbed after oral administration with tmax typically observed from 1 to 4 hourspostdose. Food does not affect the extent of absorption, but slows the rate of absorption. Whenadministered with food to healthy subjects, peak plasma concentrations are delayed by 2 hours. Absolutebioavailability has not been determined in humans; however, data from a mass-balance study suggestthat it is in the order of 85%. Lenvatinib exhibited good oral bioavailability in dogs (70.4%) andmonkeys (78.4%).

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-acidglycoprotein and γ-globulin.

In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608(0.1 - 10 μg/mL, mesilate).

Lenvatinib is a substrate for P-gp and BCRP. Lenvatinib is not a substrate for OAT1, OAT3,

OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K or the bile salt export pump BSEP.

In patients, the median apparent volume of distribution (Vz/F) of the first dose ranged from 50.5 L to92 L and was generally consistent across the dose groups from 3.2 mg to 32 mg. The analogousmedian apparent volume of distribution at steady-state (Vz/Fss) was also generally consistent andranged from 43.2 L to 121 L.

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-mediatedpathways contributed to a significant portion of the overall metabolism of lenvatinib. Consequently, invivo, inducers and inhibitors of CYP 3A4 had a minimal effect on lenvatinib exposure (seesection 4.5).

In human liver microsomes, the demethylated form of lenvatinib (M2) was identified as the mainmetabolite. M2’ and M3’, the major metabolites in human faeces, were formed from M2 andlenvatinib, respectively, by aldehyde oxidase.

In plasma samples collected up to 24 hours after administration, lenvatinib constituted 97% of theradioactivity in plasma radiochromatograms while the M2 metabolite accounted for an additional2.5%. Based on AUC(0 - inf), lenvatinib accounted for 60% and 64% of the total radioactivity in plasmaand blood, respectively.

Data from a human mass balance/excretion study indicate lenvatinib is extensively metabolised inhumans. 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, andintramolecular rearrangement of the cysteinylglycine and cysteine conjugates with subsequentdimerisation). These in vivo metabolic routes align with the data provided in the in vitro studies usinghuman biomaterials.

In vitro transporter studies

For the following transporters, OAT1, OAT3, OATP1B1, OCT1, OCT2, and BSEP, clinically relevantinhibition was excluded based on a cutoff of IC50> 50 × Cmax,unbound.

Lenvatinib showed minimal or no inhibitory activities toward P-gp-mediated and breast cancerresistance protein (BCRP)-mediated transport activities. Similarly, no induction of P-gp mRNAexpression was observed .

Lenvatinib showed minimal or no inhibitory effect on OATP1B3 and MATE2-K. Lenvatinib weaklyinhibits MATE1. In human liver cytosol, lenvatinib did not inhibit aldehyde oxidase activity.

Plasma concentrations decline bi-exponentially following Cmax. The mean terminal exponential half-life of lenvatinib is approximately 28 hours.

Following administration of radiolabelled lenvatinib to 6 patients with solid tumours, approximatelytwo-thirds and one-quarter 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% ofthe dose) and M2 (~4.4 of the dose).

Dose proportionality and accumulation

In patients with solid tumours administered single and multiple doses of lenvatinib once daily,exposure to lenvatinib (Cmax and AUC) increased in direct proportion to the administered dose over therange of 3.2 to 32 mg once-daily.

Lenvatinib displays minimimal accumulation at steady state. Over this range, the median accumulationindex (Rac) ranged from 0.96 (20 mg) to 1.54 (6.4 mg). The Rac in HCC subjects with mild andmoderate liver impairment was similar to that reported for other solid tumours.

The pharmacokinetics of lenvatinib following a single 10-mg dose were evaluated in 6 subjects eachwith mild and moderate hepatic impairment (Child-Pugh A and Child-Pugh B, respectively). A 5-mgdose 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 AUC0-t and AUC0-inf data, was 119%, 107%, and 180% of normal for subjectswith mild, moderate, and severe hepatic impairment, respectively. It has been determined that plasmaprotein binding in plasma from hepatically impaired subjects was similar to the respective matchedhealthy subjects and no concentration dependency was observed. See section 4.2 for dosingrecommendation.

There are not sufficient data for HCC patients with Child-Pugh B (moderate hepatic impairment, 3patients treated with lenvatinib in the pivotal trial) and no data available in Child-Pugh C HCCpatients (severe hepatic impairment). Lenvatinib is mainly eliminated via the liver and exposure mightbe increased in these patient populations.

The median half-life was comparable in subjects with mild, moderate, and severe hepatic impairmentas well as those with normal hepatic function and ranged from 26 hours to 31 hours. The percentage ofthe dose of lenvatinib excreted in urine was low in all cohorts (<2.16% across treatment cohorts).

The pharmacokinetics of lenvatinib following a single 24-mg dose were evaluated in 6 subjects eachwith mild, moderate, and severe renal impairment, and compared with 8 healthy, demographicallymatched subjects. Subjects with end-stage renal disease were not studied.

Lenvatinib exposure, based on AUC0-inf data, was 101%, 90%, and 122% of normal for subjects withmild, moderate, and severe renal impairment, respectively. It has been determined that plasma proteinbinding in plasma from renally impaired subjects was similar to the respective matched healthysubjects and no concentration dependency was observed. See section 4.2 for dosing recommendation.

Age, sex, weight, race

Based on a population pharmacokinetic analysis of patients receiving up to 24 mg lenvatinib oncedaily, age, sex, weight, and race (Japanese vs. other, Caucasian vs. other) had no clinically relevanteffects on clearance (see section 4.2).

Based on a population pharmacokinetics analysis in paediatric patients of 2 to 12 years old, whichincluded data from 3 paediatric patients aged 2 to <3 years, 28 paediatric patients aged ≥3 to <6 yearsand 89 paediatric patients aged 6 to ≤12 years across the lenvatinib paediatric program, lenvatinib oralclearance (CL/F) was affected by body weight but not age. Predicted exposure levels in terms of areaunder the curve at steady-state (AUCss) in paediatric patients receiving 14 mg/m2 were comparable tothose in adult patients receiving a fixed dose of 24 mg. In these studies, there were no apparentdifferences in the pharmacokinetics of active substance lenvatinib among children (2 - 12 years),adolescents, and young adult patients with studied tumour types, but data in children are relativelylimited to draw definite conclusions (see section 4.2).

In the repeated-dose toxicity studies (up to 39 weeks), lenvatinib caused toxicologic changes invarious organs and tissues related to the expected pharmacologic effects of lenvatinib includingglomerulopathy, testicular hypocellularity, ovarian follicular atresia, gastrointestinal changes, bonechanges, changes to the adrenals (rats and dogs), and arterial (arterial fibrinoid necrosis, medialdegeneration, or haemorrhage) lesions in rats, dogs, and cynomolgus monkeys. Elevated transaminaselevels asociated 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 allanimal species investigated.

Lenvatinib was not genotoxic.

Carcinogenicity studies have not been conducted with lenvatinib.

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 (follicularatresia) were observed in repeated-dose toxicity studies in animals at exposures 11 to 15 times (rat) or0.6 to 7 times (monkey) the anticipated clinical exposure (based on AUC) at the maximum toleratedhuman dose. These findings were reversible at the end of a 4-week recovery period.

Administration of lenvatinib during organogenesis resulted in embryolethality and teratogenicity inrats (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 thatlenvatinib has a teratogenic potential, likely related to the pharmacologic activity of lenvatinib as anantiangiogenic 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 lowercompared with the exposure at which mortality was observed in adult rats, suggesting an increasingsensitivity to toxicity with decreasing age. Therefore, mortality may be attributed to complicationsrelated to primary duodenal lesions with possible contribution from additional toxicities in immaturetarget organs.

The toxicity of lenvatinib was more prominent in younger rats (dosing initiated on PND7) comparedwith those with dosing initiated on PND21 and mortality and some toxicities were observed earlier inthe juvenile rats at 10 mg/kg compared with adult rats administered the same dose level. Growthretardation, secondary delay of physical development, and lesions attributable to pharmacologiceffects (incisors, femur [epiphyseal growth plate], kidneys, adrenals, and duodenum) were alsoobserved in juvenile rats.

Calcium carbonate

Mannitol

Microcrystalline cellulose

Hydroxypropylcellulose

Low-substituted hydroxypropylcellulose

Talc

Hypromellose

Titanium dioxide (E171)

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Red iron oxide (E172)

Shellac

Black iron oxide (E172)

Potassium hydroxide

Not applicable.

4 years.

Do not store above 25°C. Store in the original blister in order to protect from moisture.

Polyamide/Aluminium/PVC/Aluminium blisters containing 10 capsules. Each carton contains 30, 60,or 90 hard capsules.

Not all pack sizes may be marketed.

Caregivers should not open the capsule, in order to avoid repeated exposure to the contents of thecapsule.

Preparation and administration of suspension:

- The suspension may be prepared using water, apple juice, or milk. If administered via a feedingtube, then the suspension should be prepared using water.

- Place the capsule(s) corresponding to the prescribed dose (up to 5 capsules) in a small container(approximately 20 mL (4 tsp) capacity) or oral syringe (20 mL); do not break or crush thecapsules.

- Add 3 mL of liquid to the container or oral syringe Wait 10 minutes for the capsule shell (outersurface) to disintegrate, then stir or shake the mixture for 3 minutes until the capsules are fullydisintegrated.o If using an oral syringe, cap the syringe, remove plunger and use a second syringe orcalibrated dropper to add the liquid to the first syringe, then replace plunger prior tomixing.

- Administer the entire contents of the container or oral syringe. The suspension may beadministered from the container directly into the mouth, or from the oral syringe directly intothe mouth or via feeding tube.

- Next, add an additional 2 mL of liquid to the container, or oral syringe using a second syringe ordropper, swirl or shake and administer. Repeat this step at least twice and until there is novisible residue to ensure all of the medication is taken.

Note: Compatibility has been confirmed for polypropylene syringes and for feeding tubes of at least 5

French diameter (polyvinyl chloride or polyurethane tube),at least 6 French diameter (silicone tube)and up to 16 French diameter for polyvinyl chloride, polyurethane, or silicone tubing.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Eisai GmbH

Edmund-Rumpler-Straße 360549 Frankfurt am Main

Germany

E-mail: medinfo_de@eisai.net

Lenvima 4mg hard capsules

EU/1/15/1002/001

EU/1/15/1002/003

EU/1/15/1002/004

Lenvima 10 mg hard capsules

EU/1/15/1002/002

EU/1/15/1002/005

EU/1/15/1002/006

Date of first authorisation: 28 May 2015

Date of latest renewal: 20 May 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.