KISPLYX 10mg capsules medication leaflet

Kisplyx 4 mg hard capsules

Kisplyx 10 mg hard capsules

Kisplyx 4 mg hard capsules

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

Kisplyx 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.

Kisplyx 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.

Kisplyx 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.

Kisplyx is indicated for the treatment of adults with advanced renal cell carcinoma (RCC):

- in combination with pembrolizumab, as first-line treatment (see section 5.1).

- in combination with everolimus, following one prior vascular endothelial growth factor(VEGF)-targeted therapy (see section 5.1).

Treatment should be initiated and supervised by a healthcare professional experienced in the use ofanticancer therapies.

Kisplyx in combination with pembrolizumab as first-line treatment

The recommended dose of lenvatinib is 20 mg (two 10-mg capsules) orally once daily in combinationwith pembrolizumab either 200 mg every 3 weeks or 400 mg every 6 weeks administered as anintravenous infusion over 30 minutes. The daily dose of lenvatinib is to be modified as neededaccording to the dose/toxicity management plan. Lenvatinib treatment should continue until diseaseprogression or unacceptable toxicity. Pembrolizumab should be continued until disease progression,unacceptable toxicity or the maximum duration of therapy as specified for pembrolizumab.

See the Summary of Product Characteristics (SmPC) for pembrolizumab for full pembrolizumabdosing information.

Kisplyx in combination with everolimus as second-line treatment

The recommended daily dose of lenvatinib is 18 mg (one 10-mg capsule and two 4-mg capsules)orally once daily in combination with 5 mg of everolimus once daily. The daily dose of lenvatinib and,if necessary, everolimus is to be modified as needed according to the dose/toxicity management plan.

See the SmPC for everolimus for full everolimus dosing information.

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

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

Dose adjustment and discontinuation for lenvatinib

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.

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 renalfailure (see section 4.4).

For toxicities thought to be related to lenvatinib (see Table 2), upon resolution/improvement of anadverse reaction to Grade 0 to 1 or baseline, treatment should be resumed at a reduced dose oflenvatinib as suggested in Table 1.

Table 1 Dose modifications from recommended lenvatinib daily dosea

Lenvatinib dose in combination with Lenvatinib dose in combination withpembrolizumab everolimus

Recommended 20 mg orally once daily 18 mg orally once dailydaily dose (two 10-mg capsules) (one 10-mg capsule + two 4-mg capsules)

First dose reduction 14 mg orally once daily 14 mg orally once daily(one 10-mg capsule + one 4-mg capsule) (one 10-mg capsule + one 4-mg capsule)

Second dose 10 mg orally once daily 10 mg orally once dailyreduction (one 10-mg capsule) (one 10-mg capsule)

Third dose 8 mg orally once daily 8 mg orally once dailyreduction (two 4-mg capsules) (two 4-mg capsules)a Limited data are available for doses below 8 mg

When used in combination with pembrolizumab, one or both medicines should be interrupted asappropriate. Lenvatinib should be withheld, dose reduced, or discontinued as appropriate. Withhold ordiscontinue pembrolizumab in accordance with the instructions in the SmPC for pembrolizumab. Nodose reductions are recommended for pembrolizumab.

For toxicities thought to be related to everolimus, treatment should be interrupted, reduced to alternateday dosing, or discontinued (see the SmPC for everolimus for dose adjustment recommendationsregarding specific adverse reactions).

For toxicities thought to be related to both lenvatinib and everolimus, lenvatinib should be reduced(see Table 1) prior to reducing everolimus.

All treatments 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).

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

Events (CTCAE).

Table 2 Adverse reactions requiring dose modification of lenvatinib

Adverse reaction Severity Action Dose reduce andresume lenvatinib

Hypertension Grade 3 Interrupt Resolves to Grade 0, 1 or 2.

(despite optimal See detailed guidanceantihypertensive therapy) in Table 3 in section 4.4.

Grade 4 Discontinue Do not resume

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

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

Renal impairment or failure Grade 3 Interrupt Resolves to Grade 0-1 orbaseline.

Grade 4* Discontinue Do not resume

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

Grade 4 Discontinue Do not resume

PRES/RPLS Any grade Interrupt Consider resuming at reduceddose if resolves to Grade 0-1.

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

Grade 4* Discontinue Do not resume

Arterial thromboembolisms Any grade Discontinue Do not resume

Haemorrhage Grade 3 Interrupt Resolves to Grade 0-1.

Grade 4 Discontinue Do not resume

GI perforation or fistula Grade 3 Interrupt Resolves to Grade 0-1 orbaseline.

Grade 4 Discontinue Do not resume

Non-GI fistula Grade 4 Discontinue Do not resume

QT interval prolongation >500 ms Interrupt Resolves to <480 ms orbaseline

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

Grade 4 (despite medical Discontinue Do not resumemanagement)

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

For information about clinical experience with the combination treatment of lenvatinib andpembrolizumab, see section 4.8.

Patients of age ≥65 years, with baseline hypertension or those with renal impairment appear to havereduced tolerability to lenvatinib (see section 4.8).

No data for the combination of lenvatinib and everolimus are available for most of the specialpopulations. The following information is derived from clinical experience of single agent lenvatinibin patients with differentiated thyroid cancer (DTC; see SmPC for Lenvima).

All patients other than those with severe hepatic or renal impairment (see below) should initiatetreatment at the recommended dose of 20 mg of lenvatinib daily with pembrolizumab or 18 mg oflenvatinib with 5 mg of everolimus taken once daily as indicated, following which the dose should befurther 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).

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. The combination should be used in patients with severe hepatic impairmentonly if the anticipated benefit exceeds the risk (see section 4.8).

No data for the combination of lenvatinib with everolimus are available in patients with hepaticimpairment. No adjustment of starting dose of the combination is required on the basis of hepaticfunction in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Inpatients with severe (Child-Pugh C) hepatic impairment, the recommended starting dose of lenvatinibis 10 mg taken once daily in combination with the dose of everolimus recommended for patients withsevere hepatic impairment in the SmPC for everolimus. Further dose adjustments may be necessary onthe basis of individual tolerability. The combination should be used in patients with severe hepaticimpairment only if the anticipated benefit exceeds the risk (see section 4.8).

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 or everolimus fordosing in patients with renal impairment. Further dose adjustments may be necessary based onindividual tolerability. Patients with end-stage renal disease have not been studied, therefore the use oflenvatinib in these patients is not recommended (see section 4.8).

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).

Ethnic Origin

No adjustment of starting dose is required on the basis of race (see section 5.2). Currently availabledata are described in section 4.8.

Body weight below 60 kg

No adjustment of starting dose is required on the basis of body weight. Limited data are available ontreatment with lenvatinib in combination with everolimus in patients with a body weight below 60 kgwith RCC (see section 4.8).

Performance status

Patients with an ECOG (Eastern Cooperative Oncology Group) performance status of 2 or higher wereexcluded from RCC Study 205 (see section 5.1). Patients with a KPS (Karnofsky Performance Status)<70 were excluded from Study 307 (CLEAR). Benefit-risk in these patients has not been evaluated.

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 within24 hours, the suspension should be discarded.

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 patients, monotherapy with one of the classes of antihypertensive 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 3.

Table 3 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 the currentantihypertensive therapy or initiate additionalantihypertensive therapy

Systolic BP ≥160 mmHg or 1. Withhold lenvatinibdiastolic BP ≥100 mmHg 2. When systolic BP ≤150 mmHg, diastolic BPdespite optimal antihypertensive therapy ≤95 mmHg, and patient has been on a stable doseof antihypertensive therapy for at least 48 hours,resume lenvatinib at a reduced dose (seesection 4.2)

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

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.

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.

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.

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. Caution should be taken in patients receivingagents acting on the renin-angiotensin aldosterone system given a potentially higher risk for acuterenal failure with the combination treatment. Dose interruptions, adjustments, or discontinuation maybe necessary (see section 4.2).

If patients have severe renal impairment, the initial dose of lenvatinib should be adjusted (seesections 4.2 and 5.2).

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,

Hypertension). In patients with signs or symptoms of PRES, dose interruptions, adjustments, ordiscontinuation may be necessary (see section 4.2).

Liver-related adverse reactions most commonly reported in patients treated with lenvatinib includedincreases in alanine aminotransferase, increases in aspartate aminotransferase, and increases in bloodbilirubin. Hepatic failure and acute hepatitis (<1%; see section 4.8) have been reported in patientstreated with lenvatinib. The hepatic failure cases were generally reported in patients with progressiveliver metastases. Liver function tests should be monitored before initiation of treatment, then every2 weeks for the first 2 months and monthly thereafter during treatment. In the case of hepatotoxicity,dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).

If patients have severe hepatic impairment, the initial dose of lenvatinib should be adjusted (seesections 4.2 and 5.2).

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.

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.

In the case of bleeding, dose interruptions, adjustments, or discontinuation may be required (seesection 4.2, Table 2).

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 other areas of the body 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 fistulae 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 do 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 in all patients with a special attention for those with congenital long QT syndrome,congestive heart failure, bradyarrhythmics, and those taking medicinal products known to prolong the

QT interval, including Class Ia and III antiarrhythmics. Lenvatinib should be withheld in the event ofdevelopment of QT interval prolongation greater than 500 ms. Lenvatinib should be resumed at areduced dose when QTc prolongation is resolved to < 480 ms or baseline.

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. Periodic monitoring of ECG and electrolytes (magnesium,potassium and calcium) should be considered during treatment. Blood calcium levels should bemonitored at least monthly and calcium should be replaced as necessary during lenvatinib treatment.

Lenvatinib dose should be interrupted or dose adjusted as necessary depending on severity, presenceof ECG changes, and persistence 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.

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.

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 of 4 weeks.

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. Additionally, in patients with RCC thepharmacokinetics of lenvatinib was not significantly affected by concomitant everolimus.

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.

Additionally, in patients with RCC the pharmacokinetics of everolimus was not significantly affectedby concomitant lenvatinib. No significant drug-drug interaction is therefore expected betweenlenvatinib and other CYP3A4/Pgp substrates.

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 (seesection 4.6).

Women of childbearing potential/ Contraception in females

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 duringbreast-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.

The safety profile of lenvatinib is based on pooled data from 497 RCC patients treated with lenvatinibin combination with pembrolizumab, including Study 307 (CLEAR); pooled data from 623 RCCpatients treated with lenvatinib in combination with everolimus: 458 DTC patients and 496 HCCpatients treated with lenvatinib as monotherapy.

Lenvatinib in combination with pembrolizumab in RCC

The safety profile of lenvatinib in combination with pembrolizumab is based on data from 497 RCCpatients. The most frequently reported adverse reactions (occurring in ≥30% of patients) werediarrhoea (61.8%), hypertension (51.5%) fatigue (47.1%), hypothyroidism (45.1%), decreased appetite(42.1%), nausea (39.6%), stomatitis (36.6%), proteinuria (33.0%), dysphonia (32.8%), and arthralgia(32.4%).

The most common severe (Grade ≥3) adverse reactions (≥5%) were hypertension (26.2%), lipaseincreased (12.9%), diarrhoea (9.5%), proteinuria (8.0%), amylase increased (7.6%), weight decreased(7.2%), and fatigue (5.2%).

Discontinuation of lenvatinib, pembrolizumab, or both due to an adverse reaction occurred in 33.4%of patients; 23.7% lenvatinib, and 12.9 % both drugs. The most common adverse reactions (≥1%)leading to discontinuation of lenvatinib, pembrolizumab, or both were myocardial infarction (2.4%),diarrhoea (2.0%), proteinuria (1.8%), and rash (1.4%). Adverse reactions that most commonly led todiscontinuation of lenvatinib (≥1%) were myocardial infarction (2.2%), proteinuria (1.8%), anddiarrhoea (1.0%).

Dose interruptions of lenvatinib, pembrolizumab, or both due to an adverse reaction occurred in 80.1%of patients; lenvatinib was interrupted in 75.3%, and both drugs in 38.6% of patients. Lenvatinib wasdose reduced in 68.4% of patients. The most common adverse reactions (≥5%) resulting in dosereduction or interruption of lenvatinib were diarrhoea (25.6%), hypertension (16.1%), proteinuria(13.7%), fatigue (13.1%), appetite decreased (10.9%), palmar-plantar erythrodysaesthesia syndrome(PPE) (10.7%), nausea (9.7%), asthenia (6.6%), stomatitis (6.2%), lipase increased (5.6%), and vomiting(5.6%).

Lenvatinib in combination with everolimus in RCC

The safety profile of lenvatinib in combination with everolimus is based on data from 623 patients.

The most frequently reported adverse reactions(occurring in ≥30% of patients) were diarrhoea(69.0%), fatigue (41.9%), hypertension (41.7%), decreased appetite (41.6%), stomatitis (40.6%),nausea (38.8%), proteinuria (34.2%), vomiting (32.7%) and weight decreased (31.3%).

The most common severe (Grade ≥3) adverse reactions (≥5%) were hypertension (19.3%), diarrhoea(13.8%), proteinuria (8.8%), fatigue (7.1%), decreased appetite (6.3%) and weight decreased (5.8%).

Discontinuation of lenvatinib, everolimus, or both due to an adverse reaction occurred in 27.0% ofpatients; 21.7% lenvatinib, and 18.7% both drugs. The most common adverse reactions (≥1%) leadingto discontinuation of lenvatinib, everolimus, or both were proteinuria (2.7%), diarrhoea (1.0%) anddecreased appetite (1.0%). Adverse reaction that most commonly led to discontinuation of lenvatinib(≥1%) was proteinuria (2.1%).

Dose interruptions of lenvatinib, everolimus, or both due to an adverse reaction occurred in 82.2% ofpatients; in patients where data on individual drug modifications were collected, lenvatinib wasinterrupted in 74.3%, and both drugs in 71.9% of patients. The most common adverse reactions (≥5%)resulting in dose reduction or interruption of lenvatinib were diarrhoea (30.4%), fatigue (15.3%),proteinuria (14.7%), appetite decreased (13.4%), stomatitis (13.2%), nausea (10.9%), vomiting(10.2%), hypertension (9.2%), asthenia (7.9%), platelet count decreased (5.7%), and weight decreased(5.1%).

Adverse reactions observed in clinical trials and reported from post-marketing use of lenvatinib arelisted in Table 4. Adverse reactions known to occur with lenvatinib or combination therapycomponents given alone may occur during treatment with these medicinal products in combination,even if these reactions were not reported in clinical studies with combination therapy.

For additional safety information when lenvatinib is administered in combination, refer to the SmPCfor the respective combination therapy components.

Frequencies are defined as:

- Very common (≥1/10)

- Common (≥1/100 to <1/10)

- Uncommon (≥1/1,000 to <1/100)

- Rare (≥1/10,000 to <1/1,000)

- Very rare (˂1/10,000)

- Not known (cannot be estimated from the available data)

Within each frequency category, adverse reactions are presented in order of decreasing seriousness.

Table 4 Adverse reactions reported in patients treated with lenvatinib§

System Organ Class Lenvatinib Combination with Combination with(MedDRA monotherapy everolimus pembrolizumabterminology)

Very common Urinary tract infection

Common Urinary tract infection Urinary tract infection

Uncommon Perineal abscess Perineal abscess Perineal abscess

Blood and lymphatic disorders

Very common Thrombocytopenia‡ Thrombocytopenia‡ Thrombocytopenia‡

Lymphopenia‡ Lymphopenia‡ Lymphopenia‡

Leukopenia‡ Leukopenia‡ Leukopenia‡

Neutropenia‡ Neutropenia‡ Neutropenia‡

Uncommon Splenic infarction

Very common Hypothyroidism* Hypothyroidism* Hypothyroidism*

Increased blood thyroid Increased blood thyroid Increased blood thyroidstimulating hormone*,‡ stimulating hormone*, ‡ stimulating hormone*, ‡

Common Adrenal insufficiency

Uncommon Adrenal insufficiency Adrenal insufficiency

Very common Hypocalcaemia*, ‡ Hypocalcaemia‡ Hypocalcaemia‡

Hypokalaemia‡ Hypokalaemia‡ Hypokalaemia‡

Hypomagnesaemia‡ Hypomagnesaemia‡ Hypomagnesaemia‡

Hypercholesterolaemia‡ Hypercholesterolaemia *, ‡ Hypercholesterolaemia *, ‡

Decreased weight Decreased weight Decreased weight

Decreased appetite Decreased appetite Decreased appetite

Common Dehydration Dehydration Dehydration

Rare Tumour lysis Tumour lysis syndrome † Tumour lysis syndrome †syndrome †

Very common Insomnia Insomnia Insomnia

Very common Dizziness Headache Dizziness

Headache Dysgeusia Headache

Dysgeusia Dysgeusia

Common Cerebrovascular Dizzinessaccident†

Uncommon Posterior reversible Cerebrovascular accident† Cerebrovascular accidentencephalopathy Transient ischaemic attack Posterior reversiblesyndrome encephalopathy syndrome

Monoparesis Transient ischaemic attack

Transient ischaemicattack

System Organ Class Lenvatinib Combination with Combination with(MedDRA monotherapy everolimus pembrolizumabterminology)

Common Myocardial infarctiona,† Myocardial infarctiona,† Myocardial infarctiona

Cardiac failure Cardiac failure† Prolonged electrocardiogram

Prolonged Prolonged QTelectrocardiogram QT electrocardiogram QT

Decreased ejectionfraction

Uncommon Decreased ejection fraction Cardiac failure†

Decreased ejection fraction

Very common Haemorrhageb, *, † Haemorrhageb, *, † Haemorrhageb, *, †

Hypertensionc,* Hypertensionc,* Hypertensionc,*

Common Hypotension Hypotension

Not known Aneurysms and artery Aneurysms and artery Aneurysms and arterydissections dissections dissections

Very common Dysphonia Dysphonia Dysphonia

Common Pulmonary embolism† Pulmonary embolism Pulmonary embolism

Pneumothorax

Uncommon Pneumothorax Pneumothorax

Very common Diarrhoea* Diarrhoea* Diarrhoea*

Gastrointestinal and Gastrointestinal and Gastrointestinal andabdominal painsd abdominal painsd abdominal painsd

Vomiting Vomiting Vomiting

Nausea Nausea Nausea

Oral inflammatione Oral inflammatione Oral inflammatione

Oral painf Oral painf Oral painf

Constipation Constipation Constipation

Dyspepsia Dyspepsia Dyspepsia

Dry mouth Increased lipase‡ Dry mouth

Increased lipase‡ Increased amylase‡ Increased lipase‡

Increased amylase‡ Increased amylase‡

Common Anal fistula Dry mouth Pancreatitisg

Flatulence Flatulence Colitis

Gastrointestinal Gastrointestinal perforation Flatulenceperforation Gastrointestinal perforation

Uncommon Pancreatitisg Pancreatitisg Anal fistula

Colitis Anal fistula

System Organ Class Lenvatinib Combination with Combination with(MedDRA monotherapy everolimus pembrolizumabterminology)

Very common Increased blood Hypoalbuminaemia*, ‡ Increased blood bilirubin ‡bilirubin*, ‡ Increased alanine Hypoalbuminaemia‡

Hypoalbuminaemia*, ‡ aminotransferase‡ Increased alanine

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

Increased aspartate Increased blood alkaline aminotransferase‡aminotransferase*, ‡ phosphatase‡ Increased blood alkaline

Increased blood alkaline phosphatase‡phosphatase‡

Increased gamma-glutamyltransferase‡

Common Hepatic failureh, † Cholecystitis Cholecystitis

Hepatic Abnormal hepatic function Abnormal hepatic functionencephalopathyi, † Increased gamma- Increased gamma-

Cholecystitis glutamyltransferase glutamyltransferase

Abnormal hepatic Increased blood bilirubin*, ‡function

Uncommon Hepatocellular Hepatic failureh, † Hepatic failureh, †damage/hepatitisj Hepatic encephalopathyi Hepatic encephalopathyi

Hepatocellulardamage/hepatitisj

Very common Palmar-plantar Palmar-plantar Palmar-plantarerythrodysaesthesia erythrodysaesthesia erythrodysaesthesiasyndrome syndrome syndrome

Rash Rash Rash

Alopecia

Common Hyperkeratosis Alopecia Hyperkeratosis

Alopecia

Uncommon Hyperkeratosis

Very common Back pain Back pain Back pain

Arthralgia Arthralgia Arthralgia

Myalgia Myalgia

Pain in extremity Pain in extremity

Musculoskeletal pain Musculoskeletal pain

Common Myalgia

Pain in extremity

Musculoskeletal pain

Uncommon Osteonecrosis of the jaw Osteonecrosis of the jaw

Very common Proteinuria* Proteinuria* Proteinuria*

Increased blood Increased blood creatinine‡ Increased blood creatinine‡creatinine‡

Common Renal failurek, *, † Renal failurek, *, † Renal failurek, *

Renal impairment* Renal impairment* Increased blood urea

Increased blood urea Increased blood urea

Uncommon Nephrotic syndrome Nephrotic syndrome

Renal impairment*

System Organ Class Lenvatinib Combination with Combination with(MedDRA monotherapy everolimus pembrolizumabterminology)

Very common Fatigue Fatigue Fatigue

Asthenia Asthenia Asthenia

Oedema peripheral Oedema peripheral Oedema peripheral

Common Malaise Malaise Malaise

Uncommon Impaired healing Impaired healing Impaired healing

Non-gastrointestinal fistulal Non-gastrointestinal fistulal

Not known Non-gastrointestinalfistulal§: Adverse reaction frequencies presented in Table 4 may not be fully attributable to lenvatinib alone but may containcontributions 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: Myocardial infarction includes myocardial infarction and acute myocardial infarction.b: Includes all haemorrhage terms:

Haemorrhage terms that occurred in 5 or more patients with RCC in lenvatinib plus pembrolizumab were: epistaxis,haematuria, contusion, gingival bleeding, rectal haemorrhage, haemoptysis, ecchymosis, and haematochezia.

c: Hypertension includes: hypertension, hypertensive crisis, increased blood pressure diastolic, orthostatic hypertensionand increased blood pressure.

d: Gastrointestinal and abdominal pain includes: abdominal discomfort, abdominal pain, lower abdominal pain, upperabdominal pain, abdominal tenderness, epigastric discomfort, and gastrointestinal pain.

e: Oral inflammation includes: aphthous stomatitis, aphthous ulcer, gingival erosion, gingival ulceration, oral mucosalblistering, stomatitis, glossitis, mouth ulceration, and mucosal inflammation.

f: Oral pain includes: oral pain, glossodynia, gingival pain, oropharyngeal discomfort, oropharyngeal pain and tonguediscomfort.

g: Pancreatitis includes: pancreatitis and acute pancreatitis.h: Hepatic failure includes: hepatic failure, acute hepatic failure and chronic hepatic failure.i: Hepatic encephalopathy includes: hepatic encephalopathy, coma hepatic, metabolic encephalopathy and encephalopathy.j: Hepatocellular damage and hepatitis includes: drug-induced liver injury, hepatic steatosis, and cholestatic liver injury.k: Renal failure includes: acute prerenal failure, renal failure, renal failure acute, acute kidney injury, and renal tubularnecrosis.l: Non-gastrointestinal fistula includes cases of fistula occurring outside of the stomach and intestines such as tracheal,tracheo-oesophageal, oesophageal, cutaneous fistula and female genital tract fistula.

Hypertension (see section 4.4)

In CLEAR (see section 5.1), hypertension was reported in 56.3% of patients in the lenvatinib pluspembrolizumab-treated group and 42.6% of patients in the sunitinib-treated group. The exposure-adjusted frequency of hypertension was 0.65 episodes per patient year in the lenvatinib pluspembrolizumab-treated group and 0.73 episodes per patient year in the sunitinib-treated group. Themedian time to onset in lenvatinib plus pembrolizumab-treated patients was 0.7 months. Reactions of

Grade 3 or higher occurred in 28.7% of lenvatinib plus pembrolizumab-treated group compared with19.4% of the sunitinib-treated group. 16.8% of patients with hypertension had dose modifications oflenvatinib (9.1% dose interruption and 11.9% dose reduction). In 0.9% of patients, hypertension led topermanent treatment discontinuation of lenvatinib.

In the pooled RCC population treated with lenvatinib and everolimus, hypertension was reported in42.5% of patients (the incidence of Grade 3 or Grade 4 hypertension was 19.7%). In patients wheredata on individual drug modifications were collected, 9.8% of patients with hypertension had dosemodifications of lenvatinib (5.3% dose reduction and 6.2% dose interruption) and led to permanenttreatment discontinuation in 0.9% of patients. The median time to onset of hypertension events inlenvatinib plus everolimus treated patients was 0.5 months.

Proteinuria (see section 4.4)

In the pooled RCC population treated with lenvatinib and everolimus, proteinuria was reported in34.8% of patients (9.0% were Grade ≥3). In patients where data on individual drug modifications werecollected, 15.1% of patients with proteinuria had dose modifications of lenvatinib (9.6% reduction and9.8% interruption) and led to permanent treatment discontinuation in 2.1% of patients. The mediantime to onset of proteinuria events in lenvatinib plus everolimus treated patients was 1.4 months.

Renal failure and impairment (see section 4.4)

In the pooled RCC population treated with lenvatinib and everolimus, 1.3% of patients developedrenal failure (0.6% were Grade ≥3) and 5.3% developed acute kidney injury (2.7% were Grade ≥3).

Renal events were reported in 17.2% of patients (4.3% were Grade ≥3). In patients where data onindividual drug modifications were collected, 5.5% of patients with renal events had dosemodifications of lenvatinib (2.3% reduction and 4.0% interruption) and led to permanent treatmentdiscontinuation in 1.9% of patients. The median time to onset of renal events in lenvatinib pluseverolimus treated patients was 3.5 months.

Cardiac dysfunction (see section 4.4)

In the pooled RCC population treated with lenvatinib and everolimus, cardiac dysfunction events werereported in 3.5% of patients (1.8% were Grade ≥3). In patients where data on individual drugmodifications were collected, 0.9% of patients with cardiac dysfunction events had dose modificationsof lenvatinib (0.4% reduction and 0.8% interruption) and led to permanent treatment discontinuationin 0.6% of patients. The median time to onset of cardiac dysfunction events in lenvatinib pluseverolimus treated patients was 3.6 months.

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

In the pooled RCC population treated with lenvatinib and everolimus, there was 1 event of PRESreported (Grade 2), occurring after 1.3 months of treatment for which no dose modifications ordiscontinuation were required.

Hepatotoxicity (see section 4.4)

In CLEAR (see section 5.1), the most commonly reported liver-related adverse reactions in thelenvatinib plus pembrolizumab-treated group were elevations of liver enzyme levels, includingincreases in alanine aminotransferase (11.9%), aspartate aminotransferase (11.1%) and blood bilirubin(4.0%). Similar events occurred in the sunitinib-treated group at rates of 10.3%, 10.9% and 4.4%respectively. The median time to onset of liver events was 3.0 months (any grade) in the lenvatinibplus pembrolizumab-treated group and 0.7 months in the sunitinib-treated group. The exposure-adjusted frequency of hepatoxicity events was 0.39 episodes per patient year in the lenvatinib pluspembrolizumab-treated group and 0.46 episodes per patient year in the sunitinib-treated group.

Grade 3 liver-related reactions occurred in 9.9% of lenvatinib plus pembrolizumab-treated patients and5.3% of sunitinib-treated patients. Liver-related reactions led to dose interruptions and reductions oflenvatinib in 8.5% and 4.3% of patients, respectively, and to permanent discontinuation of lenvatinibin 1.1% of patients.

In the pooled RCC population treated with lenvatinib and everolimus, the most commonly reportedliver-related adverse reactions were elevations of liver enzyme levels, including increases in alanineaminotransferase (11.9%), aspartate aminotransferase (11.4%) and gamma-glutamyltransferaseincreased (2.7%). Grade 3 liver related reactions occurred in 6.1% of lenvatinib plus everolimustreated patients. In patients where data on individual drug modifications were collected, 6.0% ofpatients with hepatotoxicity events had dose modifications of lenvatinib (2.8% reduction and 4.2%interruption) and led to permanent treatment discontinuation in 0.9% of patients. The median time toonset of liver-related reactions in lenvatinib plus everolimus treated patients was 1.8 months.

Arterial thromboembolisms (see section 4.4)

In CLEAR (see section 5.1), 5.4% of patients in the lenvatinib plus pembrolizumab-treated groupreported arterial thromboembolic events (of which 3.7% were Grade ≥ 3) compared with 2.1% ofpatients in the sunitinib-treated group (of which 0.6% were Grade ≥ 3). No events were fatal. Theexposure-adjusted frequency of arterial thromboembolic event episodes was 0.04 episodes per patientyear in the lenvatinib plus pembrolizumab-treated group and 0.02 episodes per patient year in thesunitinib-treated group. The most commonly reported arterial thromboembolic event in the lenvatinibplus pembrolizumab-treated group was myocardial infarction (3.4%). One event of myocardialinfarction (0.3%) occurred in the sunitinib-treated group. The median time to onset of arterialthromboembolic events was 10.4 months in the lenvatinib plus pembrolizumab-treated group.

In the pooled RCC population treated with lenvatinib and everolimus, arterial thromboembolic eventswere reported in 2.7% of patients (2.2% were Grade ≥3). In patients where data on individual drugmodifications were collected, 0.6% of patients with arterial thromboembolic events had dosemodifications of lenvatinib (0.6% interruption) and led to permanent treatment discontinuation in1.5% of patients. The most commonly reported arterial thromboembolic event in the lenvatinib pluseverolimus-treated group was myocardial infarction (1.3%). The median time to onset of arterialthromboembolic events in lenvatinib plus everolimus treated patients was 6.8 months.

Haemorrhage (see section 4.4)

In the pooled RCC population treated with lenvatinib and everolimus, haemorrhage events werereported in 28.6% of patients (3.2% were Grade ≥3). In patients where data on individual drugmodifications were collected, 4.9% of patients with haemorrhage events had dose modifications oflenvatinib (4.2% interruption and 0.8% reduction) and led to permanent treatment discontinuation in0.6% of patients. The most commonly reported haemorrhage events in the lenvatinib pluseverolimus-treated group were epistaxis (19.4%) and haematuria (4.2%). The median time to onset ofhaemorrhage events in lenvatinib plus everolimus treated patients was 1.9 months.

Hypocalcaemia (see section 4.4, QT interval prolongation)

In the pooled RCC population treated with lenvatinib and everolimus, hypocalcaemia was reported in4.8% of patients (1.1% were Grade ≥3). In patients where data on individual drug modifications werecollected, 0.8% of patients with hypocalcaemia had dose modifications of lenvatinib (0.6% doseinterruption and 0.4% dose reduction) and led to permanent treatment discontinuation in no patients.

The median time to onset of hypocalcaemia events in lenvatinib plus everolimus-treated patients was2.9 months.

Gastrointestinal perforation and fistula formation (see section 4.4)

In the pooled RCC population treated with lenvatinib and everolimus, GI perforation events werereported in 3.7% of patients (2.9% were Grade ≥3). In patients where data on individual drugmodifications were collected, 2.1% of patients with GI perforations had dose modifications oflenvatinib (1.5% interruption and 0.6% reduction) and led to permanent treatment discontinuation in1.1% of patients. The median time to onset of GI perforation events in lenvatinib plus everolimus-treated patients was 3.6 months.

In the pooled RCC population treated with lenvatinib and everolimus, fistula formation events werereported in 1.0% of patients (0.5% were Grade ≥3). In patients where data on individual drugmodifications were collected, 0.8% of patients with GI perforations had dose modifications oflenvatinib (0.8% interruption) and led to permanent treatment discontinuation in 0.4% of patients. Themedian time to onset of fistula formation events in lenvatinib plus everolimus-treated patients was 3.7months.

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 a median latency of about3 months.

QT interval prolongation (see section 4.4)

In the pooled RCC population treated with lenvatinib and everolimus, QTcF interval increases greaterthan 60 ms were reported in 9.8% of patients in the lenvatinib plus everolimus-treated group. Theincidence of QTc interval greater than 500 ms was 3.3% in the lenvatinib plus everolimus-treatedgroup. The median time to onset of QT prolongation events in lenvatinib plus everolimus-treatedpatients was 3.0 months.

Blood thyroid stimulating hormone increased/hypothyroidism (see section 4.4)

In CLEAR (see section 5.1), hypothyroidism occurred in 47.2% of patients in the lenvatinib pluspembrolizumab-treated group and 26.5% of patients in the sunitinib-treated group. The exposure-adjusted frequency of hypothyroidism was 0.39 episodes per patient year in the lenvatinib pluspembrolizumab-treated group and 0.33 episodes per patient year in the sunitinib-treated group. Ingeneral, the majority of hypothyroidism events in the lenvatinib plus pembrolizumab-treated groupwere of Grade 1 or 2. Grade 3 hypothyroidism was reported in 1.4% of patients in the lenvatinib pluspembrolizumab-treated group versus none in the sunitinib-treated group. At baseline, 90.0% ofpatients in the lenvatinib plus pembrolizumab-treated group and 93.1% of patients in the sunitinib-treated group had baseline TSH levels ≤ upper limit of normal. Elevations of TSH > upper limit ofnormal were observed post baseline in 85.0% of lenvatinib plus pembrolizumab-treated patients versus65.6% of sunitinib-treated patients. In lenvatinib plus pembrolizumab-treated patients, hypothyroidismevents resulted in dose modification of lenvatinib (reduction or interruption) in 2.6% patients anddiscontinuation of lenvatinib in 1 patient.

In the pooled RCC population treated with lenvatinib and everolimus, hypothyroidism occurred in24.1% of patients. In general, the majority of hypothyroidism events were of Grade 1 or 2. Grade 3hypothyroidism was reported in 0.3% of patients in the lenvatinib plus everolimus-treated patients.

The median time to onset of hypothyroidism events in lenvatinib plus everolimus-treated patients was2.7 months. At baseline, 83.0% of patients in the lenvatinib plus everolimus-treated group had TSHlevels ≤ upper limit of normal. Elevations of TSH > upper limit of normal were observed post-baselinein 71.3% of lenvatinib plus everolimus-treated patients. In patients where data on individual drugmodifications were collected, hypothyroidism events resulted in dose modification of lenvatinib (0.4%dose reduction or 0.9% dose interruption) in 1.3% of patients. No discontinuations were reported.

Diarrhoea (see section 4.4)

In the pooled RCC population treated with lenvatinib and everolimus, diarrhoea was reported in 69.0%of patients (13.8% were Grade ≥3). In patients where data on individual drug modifications werecollected, 30.4% of patients had dose modifications of lenvatinib (17.7% interruptions and 19.6%reductions) and led to permanent treatment discontinuation in 0.6% of patients.

In the paediatric Studies 216 and 231 (see section 5.1), the overall safety profile of lenvatinib as asingle agent or in combination with everolimus was consistent with that observed in adults treatedwith lenvatinib.

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 and 231, no patient discontinued studytreatment due to pneumothorax (for additional paediatric information see also Lenvima SmPCsection 4.8).

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

In CLEAR, elderly patients (≥75 years) had a higher (≥ 10% difference) incidence of proteinuria thanyounger patients (<65 years).

In the pooled RCC population treated with lenvatinib and everolimus, elderly patients (≥75 years) hada higher (≥10% difference) incidence of platelet count decreased, weight decreased, proteinuria andhypertension than younger patients (<65 years).

In CLEAR, males had a higher (≥ 10% difference) incidence than females of diarrhoea.

In the pooled RCC population treated with lenvatinib and everolimus, females had a higher (≥10%difference) incidence than males of nausea, vomiting, asthenia and hypertension.

In CLEAR, Asian patients had a higher (≥ 10% difference) incidence than Caucasian patients ofpalmar-plantar erythrodysaesthesia syndrome, proteinuria and hypothyroidism (including bloodthyroid hormone increased) while Caucasian patients had a higher incidence of fatigue, nausea,arthralgia, vomiting, and asthenia.

In the pooled RCC population treated with lenvatinib and everolimus, Asian patients had a higher(≥10% difference) incidence than Caucasian patients of hypothyroidism, stomatitis, platelet countdecreased, proteinuria, dysphonia, PPE and hypertension while Caucasian patients had a higherincidence of nausea, asthenia, fatigue and hypercholesterolaemia.

Baseline hypertension

In CLEAR, patients with baseline hypertension had a higher incidence of proteinuria than patientswithout baseline hypertension.

Baseline diabetes

In the pooled RCC population treated with lenvatinib and everolimus, patients with baseline diabeteshad a higher incidence (≥10% difference) of proteinuria than those without baseline diabetes.

There are limited data on patients with hepatic impairment in RCC.

In RCC patients treated with lenvatinib and everolimus, patients with baseline renal impairment hadhigher incidence of thrombocytopenia or platelet count decreased compared with patients with normalrenal function.

Patients with body weight <60 kg

In RCC patients treated with lenvatinib and everolimus, those with low body weight (<60 kg) had ahigher incidence (≥10% difference) of platelet count decreased and hypertension.

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 also occurred in clinical trials. Themost frequently observed adverse drug reactions at these doses were hypertension, nausea, diarrhoea,fatigue, stomatitis, proteinuria, headache, and aggravation of PPE. There have also been reports 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.

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 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 syngeneic mouse tumour models, lenvatinib decreasedtumour-associated macrophages, increased activated cytotoxic T cells, and demonstrated greaterantitumour activity in combination with an anti-PD-1 monoclonal antibody compared to eithertreatment alone.

The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumouractivity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGFsignalling in vitro and tumour volume in mouse xenograft models of human renal cell cancer greaterthan each substance 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.

The mechanism of action for the worsening of hypercholesterolaemia with the combination oflenvatinib and everolimus has not been studied directly and is not fully elucidated.

Although not studied directly, the MOA for the worsening of diarrhoea with the combination oflenvatinib and everolimus is postulated to be mediated by the impairment of intestinal function relatedto the MOAs for the individual agents - VEGF/VEGFR and c-KIT inhibition by lenvatinib coupledwith mTOR/NHE3 inhibition by everolimus.

First-line treatment of patients with RCC (in combination with pembrolizumab)

The efficacy of lenvatinib in combination with pembrolizumab was investigated in Study 307(CLEAR), a multicentre, open-label, randomized trial that enrolled 1069 patients with advanced RCCwith clear cell component including other histological features such as sarcomatoid and papillary inthe first-line setting. Patients were enrolled regardless of PD-L1 tumour expression status. Patientswith active autoimmune disease or a medical condition that required immunosuppression wereineligible. Randomisation was stratified by geographic region. (North America and Western Europeversus “Rest of the World”) and Memorial Sloan Kettering Cancer Center (MSKCC) prognosticgroups (favourable, intermediate and poor risk).

Patients were randomized to lenvatinib 20 mg orally once daily in combination with pembrolizumab200 mg intravenously every 3 weeks (n=355), or lenvatinib 18 mg orally once daily in combinationwith everolimus 5 mg orally once daily (n=357), or sunitinib 50 mg orally once daily for 4 weeks thenoff treatment for 2 weeks (n=357). All patients on the lenvatinib plus pembrolizumab arm were startedon lenvatinib 20 mg orally once daily. The median time to first dose reduction for lenvatinib was 1.9months. The median average daily dose for lenvatinib was 14 mg. Treatment continued untilunacceptable toxicity or disease progression as determined by the investigator and confirmed byindependent radiologic review committee (IRC) using Response Evaluation Criteria in Solid Tumours

Version 1.1 (RECIST 1.1). Administration of lenvatinib with pembrolizumab was permitted beyond

RECIST-defined disease progression if the patient was clinically stable and considered by theinvestigator to be deriving clinical benefit. Pembrolizumab was continued for a maximum of 24months; however, treatment with lenvatinib could be continued beyond 24 months. Assessment oftumour status was performed at baseline and then every 8 weeks.

The study population (355 patients in the lenvatinib with pembrolizumab arm and 357 in the sunitinibarm) characteristics were: median age of 62 years (range: 29 to 88 years); 41% age 65 or older, 74%male; 75% White, 21% Asian, 1% Black, and 2% other races; 17% and 83% of patients had a baseline

KPS of 70 to 80 and 90 to 100, respectively; patient distribution by IMDC (International Metastatic

RCC Database Consortium) risk categories was 33% favourable, 56% intermediate and 10% poor, and

MSKCC prognostic groups was 27% favourable, 64% intermediate and 9% poor. Metastatic diseasewas present in 99% of the patients and locally advanced disease was present in 1%. Common sites ofmetastases in patients were lung (69%), lymph node (46%), and bone (26%).

The primary efficacy outcome measure was progression free survival (PFS) based on RECIST 1.1 per

IRC. Key secondary efficacy outcome measures included overall survival (OS) and objective responserate (ORR). Lenvatinib in combination with pembrolizumab demonstrated statistically significantimprovements in PFS, OS and ORR compared with sunitinib at the prespecified interim analysis (finalanalysis for PFS). The median PFS for lenvatinib in combination with pembrolizumab was 23.9months (95% CI: 20.8, 27.7) compared with 9.2 months (95% CI: 6.0, 11.0) for sunitinib, with HR0.39 (95% CI: 0.32, 0.49; P value <0.0001). For OS, HR was 0.66 (95% CI: 0.49, 0.88; P value0.0049) with the median OS follow-up time of 26.5 months and the median duration of treatment forlenvatinib plus pembrolizumab of 17.0 months. The ORR for lenvatinib in combination withpembrolizumab was 71% (95% CI: 66, 76) vs 36% (95% CI: 31, 41) P value <0.0001 for sunitinib.

Efficacy results for PFS, OS and ORR at the protocol-specified final analysis (median follow-up timeof 49.4 months) are summarised in Table 5, Figure 1 and Figure 2. PFS results were consistent acrosspre-specified subgroups, MSKCC prognostic groups and PD-L1 tumour expression status. Efficacyresults by MSKCC prognostic group are summarised in Table 6.

The final OS analysis was not adjusted to account for subsequent therapies, with 195/357 (54.6%)patients in the sunitinib arm and 56/355 (15.8%) patients in the lenvatinib plus pembrolizumab armreceiving subsequent anti-PD-1/PD-L1 therapy.

Table 5 Efficacy Results in Renal Cell Carcinoma Per IRC in CLEAR

Lenvatinib 20 mg with Sunitinib 50mg

Pembrolizumab 200mg N=357

N=355

Progression-Free Survival (PFS)*

Number of events, n (%) 207 (58%) 214 (60%)

Median PFS in months (95% CI)a 23.9 (20.8, 27.7) 9.2 (6.0, 11.0)

Hazard Ratio (95% CI)b, c 0.47 (0.38, 0.57)

P valuec <0.0001

Overall Survival (OS)

Number of deaths, n (%) 149 (42%) 159 (45%)

Median OS in months (95% CI)a 53.7 (48.7, NE) 54.3 (40.9, NE)

Hazard Ratio (95% CI)b, c 0.79 (0.63, 0.99)

P valuec 0.0424

Objective Response Rate (Confirmed)

Objective response rate, n (%) 253 (71.3%) 131 (36.7%)(95% CI) (66.6, 76.0) (31.7, 41.7)

Number of complete responses (CR), n (%) 65 (18.3%) 17 (4.8%)

Number of partial responses (PR), n (%) 188 (53.0%) 114 (32%)

P valued <0.0001

Duration of Responsea

Median in months (range) 26.7 (1.64+, 55.92+) 14.7 (1.64+, 54.08+)

Tumour assessments were based on RECIST 1.1; only confirmed responses are included for ORR.

Data cutoff date (DCO) = 31 July 2022

CI = confidence interval; NE= Not estimable

* The primary analysis of PFS included censoring for new anti-cancer treatment. Results for PFS with andwithout censoring for new anti-cancer treatment were consistent.a Quartiles are estimated by Kaplan-Meier method.b Hazard ratio is based on a Cox Proportional Hazards Model including treatment group as a factor; Efronmethod is used for ties.c Stratified by geographic region (Region 1: Western Europe and North America, Region 2: Rest of the World)and MSKCC prognostic groups (favourable, intermediate and poor risk) in IxRS. Nominal two-sided P valuebased on stratified log-rank test.

d Nominal two-sided P value based on the stratified Cochran-Mantel-Haenszel (CMH) test. At the earlier pre-specified final analysis of ORR (median follow-up time of 17.3 months), statistically significant superioritywas achieved for ORR comparing lenvatinib plus pembrolizumab with sunitinib, (odds ratio: 3.84 (95% CI:2.81, pct. 5.26), P value <0.0001).

Figure 1 Kaplan-Meier Curves for Progression-Free Survival in CLEAR*1.00.90.80.70.60.50.40.30.20.1

Median (Months) PFS Rate PFS Rate HR0 (95% CI) at 24 Months at 36 Months (95% CI)

Lenvatinib+Pembrolizumab 23.9 (20.8 , 27.7 ) 49% 37% 0.47

Sunitinib 9.2 ( 6.0 , 11.0 ) 23% 18% ( 0.38, 0.57)0 6 12 18 24 30 36 42 48 54 60

Time (months)

Number of subjects at risk:

Lenvatinib+ 355 276 213 161 128 99 81 49 25 4 0

Pembrolizumab

Sunitinib 357 145 85 59 41 30 23 12 7 1 0

DCO: 31 July 2022

*Based on updated PFS analysis conducted at the time of the protocol-specified final OS analysis.

Figure 2 Kaplan-Meier Curves for Overall Survival in CLEAR*

NE = Not estimable.

DCO: 31 July 2022

*Based on the protocol-specified final OS analysis

The CLEAR study was not powered to evaluate efficacy of individual subgroups. Table 6 summarisesthe efficacy measures by MSKCC prognostic group based on the final OS analysis at a median follow-up of 49.4 months.

Table 6 Efficacy Results in CLEAR by MSKCC Prognostic Group

Lenvatinib +

Sunitinib Lenvatinib +

Pembrolizumab(N=357) Pembrolizumab(N=355) vs. Sunitinib

Number of Number of Number of Number of

Patients Events Patients Events

Progression-Free Survival (PFS) by IRCa

PFS HR (95% CI)

Favourable 96 56 97 65 0.46 (0.32, 0.67)

Intermediate 227 129 228 130 0.51 (0.40, 0.65)

Poor 32 22 32 19 0.18 (0.08, 0.42)

Overall Survival (OS)a

OS HR (95% CI)

Favourable 96 27 97 31 0.89 (0.53, 1.50)

Intermediate 227 104 228 108 0.81 (0.62, 1.06)

Poor 32 18 32 20 0.59 (0.31, 1.12)a Median follow up 49.4 months (DCO - 31 July 2022)

Open-label, single arm Phase 2 study

Additional data are available from the open-label, single-arm, Phase 2 study KEYNOTE-B61 oflenvatinib (20 mg OD) in combination with pembrolizumab (400 mg every 6 weeks) for the first-linetreatment of patients with advanced or metastatic RCC with non-clear cell histology (n=158),including 59% papillary, 18% chromophobe, 4% translocation, 1% medullary, 13% unclassified, and6% other. The ORR was 50.6% (95% CI (42.6, 58.7)), and the median duration of response was19.5 months (95% CI 15.3, NR).

Second-line treatment of patients with RCC (in combination with everolimus)

Study 205, a multicentre, randomised, open-label, trial was conducted to determine the safety andefficacy of lenvatinib administered alone or in combination with everolimus in patients withunresectable advanced or metastatic RCC. The study consisted of a Phase 1b dose finding and a

Phase 2 portion. The Phase 1b portion included 11 patients who received the combination of 18 mg oflenvatinib plus 5 mg of everolimus. The Phase 2 portion enrolled a total of 153 patients withunresectable advanced or metastatic RCC following 1 prior VEGF-targeted treatment. A total of62 patients received the combination of lenvatinib and everolimus at the recommended dose. Patientswere required, among others, to have histological confirmation of predominant clear cell RCC,radiographic evidence of disease progression according to RECIST 1.1, one prior VEGF-targetedtherapy and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.

Patients were randomly allocated to one of 3 arms: 18 mg of lenvatinib plus 5 mg of everolimus,24 mg of lenvatinib or 10 mg of everolimus using a 1:1:1 ratio. Patients were stratified byhaemoglobin level (≤13 g/dL vs. >13 g/dL for males and ≤11.5 g/dL vs >11.5 g/dL for females) andcorrected serum calcium (≥10 mg/dL vs. <10 mg/dL). The median of average daily dose in thecombination arm per patient was 13.5 mg of lenvatinib (75.0% of the intended dose of 18 mg) and4.7 mg of everolimus (93.6% of the intended dose of 5 mg). The final dose level in the combinationarm was 18 mg for 29% of patients, 14 mg for 31% of patients, 10 mg for 23% of patients, 8 mg for16% of patients and 4 mg for 2% of patients.

Of the 153 patients randomly allocated, 73% were male, the median age was 61 years, 37% were65 years or older, 7% were 75 years or older, and 97% were Caucasian. Metastases were present in95% of the patients and unresectable advanced disease was present in 5%. All patients had a baseline

ECOG PS of either 0 (55%) or 1 (45%) with similar distribution across the 3 treatment arms.

Memorial Sloan Kettering Cancer Centre (MSKCC) poor risk was observed in 39% of patients in thelenvatinib plus everolimus arm, 44% in the lenvatinib arm and 38% in the everolimus arm.

International mRCC Database Consortium (IMDC) poor risk was observed in 20% of patients in thelenvatinib plus everolimus arm, 23% in the lenvatinib arm, and 24% in the everolimus arm. Themedian time from diagnosis to first dose was 32 months in the lenvatinib plus everolimus-treatmentarm, 33 months in the lenvatinib arm and 26 months in the everolimus arm. All patients had beentreated with 1 prior VEGF-inhibitor; 65% with sunitinib, 23% with pazopanib, 4% with tivozanib, 3%with bevacizumab, and 2% each with sorafenib or axitinib.

The primary efficacy outcome measure, based on investigator assessed tumour response, was PFS ofthe lenvatinib plus everolimus arm vs the everolimus arm and of the lenvatinib arm vs the everolimusarm. Other efficacy outcome measures included OS and investigator-assessed ORR. Tumourassessments were evaluated according to RECIST 1.1.

The lenvatinib plus everolimus arm showed a statistically significant and clinically meaningfulimprovement in PFS compared with the everolimus arm (see Table 7 and Figure 3). Based on theresults of a post-hoc exploratory analysis in a limited number of patients per subgroup, the positiveeffect on PFS was seen regardless of which prior VEGF-targeted therapy was used: sunitinib (Hazardratio [HR] = 0.356 [95% CI: 0.188, 0.674] or other therapies (HR = 0.350 [95% CI: 0.148, 0.828]).

The lenvatinib arm also showed an improvement in PFS compared with the everolimus arm. Overallsurvival was longer in the lenvatinib plus everolimus arm (see Table 7 and Figure 4). The study wasnot powered for the OS analysis.

The treatment effect of the combination on PFS and ORR was also supported by a post-hocretrospective independent blinded review of scans. The lenvatinib plus everolimus arm showed astatistically significant and clinically meaningful improvement in PFS compared with the everolimusarm. Results for ORR were consistent with that of the investigators’ assessments, 35.3% in thelenvatinib plus everolimus arm, with one complete response and 17 partial responses; no patient hadan objective response in the everolimus arm (P < 0.0001) in favour of the lenvatinib plus everolimusarm.

Table 7 Efficacy results following one prior VEGF targeted therapy in RCC Study 205lenvatinib 18 mg + lenvatinib everolimus 10 mgeverolimus 5 mg 24 mg(N=51) (N=52) (N=50)

Progression-free survival (PFS)a by investigator assessment

Median PFS in months (95% CI) 14.6 (5.9, 20.1) 7.4 (5.6, 10.2) 5.5 (3.5, 7.1)

Hazard Ratio (95% CI)b 0.40 (0.24, 0.67) - -lenvatinib + everolimus vs everolimus

P value 0.0005 - -lenvatinib + everolimus vs everolimus

Progression-free survival (PFS)a by post-hoc retrospective independent review

Median PFS in months (95% CI) 12.8 (7.4, 17.5) 9.0 (5.6, 10.2) 5.6 (3.6, 9.3)

Hazard Ratio (95% CI)b 0.45 (0.26, 0.79) - -lenvatinib + everolimus vs everolimus

P value 0.003 - -lenvatinib + everolimus vs everolimus

Overall Survivalc

Number of deaths, n (%) 32 (63) 34 (65) 37 (74)

Median OS in months (95% CI) 25.5 (16.4, 32.1) 19.1 (13.6, 26.2) 15.4 (11.8, 20.6)

Hazard Ratio (95% CI) b 0.59 (0.36, 0.97) - -lenvatinib + everolimus vs everolimuslenvatinib 18 mg + lenvatinib everolimus 10 mgeverolimus 5 mg 24 mg(N=51) (N=52) (N=50)

Objective Response Rate n (%) by investigator assessment

Complete responses 1 (2) 0 0

Partial responses 21 (41) 14 (27) 3 (6)

Objective Response Rate 22 (43) 14 (27) 3 (6)

Stable disease 21 (41) 27 (52) 31 (62)

Duration of response, months, median 13.0 (3.7, NE) 7.5 (3.8, NE) 8.5 (7.5, 9.4)(95% CI)

Tumour assessment was based on RECIST 1.1 criteria. Data cut-off date = 13 Jun 2014

Percentages are based on the total number of patients in the Full Analysis Set within relevant treatment group.

CI = confidence interval, NE = not estimableaPoint estimates are based on Kaplan-Meier method and 95% CIs are based on the Greenwood formula using log-logtransformation.bStratified hazard ratio is based on a stratified Cox regression model including treatment as a covariate factor andhaemoglobin and corrected serum calcium as strata. The Efron method was used for correction for tied events.cData cut-off date = 31 Jul 2015

Figure 3 Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment)1.0

Median (months) (95% CI)

Lenvatinib (18mg) + Everolimus (5mg) 14.6 (5.9, 20.1)

Lenvatinib (24mg) 7.4 (5.6, 10.2)0.8

Everolimus (10mg) 5.5 (3.5, 7.1)0.60.40.2 Lenvatinib(18mg) + Everolimus(5mg) vs Everolimus(10mg):

HR (95% CI): 0.40 (0.24, 0.67)

Logrank Text: P = 0.0005

Median0 .(0months) (95% CI)

L+P0NE (41.5, NE) 3 6 9 12 15 18 21 24

S NE (38.4, NE)

Time (months)

Number of subjects at risk:

L(18mg + E (5mg) 51 41 27 23 16 10 5 1 0

L(24mg) 52 41 29 20 11 6 4 1 0

E(10mg) 50 29 15 11 7 3 1 0

L(18mg) + E(5mg)=Lenvatinib 18mg + Everolimus 5mg; L(24mg)=Lenvatinib 24; E(10mg)=Everolimus 10mg

Data Cutoff Date: 13JUN2014

Progression-Free Survival

Figure 4 Kaplan-Meier Plot of Overall Survival1.0

Median (months) (95% CI)

Lenvatinib (18mg) + Everolimus (5mg) 25.5 (16.4, 32.1)

Lenvatinib (24mg) 19.1 (13.6, 26.2)0.8

Everolimus (10mg) 15.4 (11.8, 20.6)0.60.40.2

Lenvatinib(18mg) + Everolimus(5mg) vs Everolimus(10mg):

HR (95% CI): 0.59 (0.36, 0.97)0.00 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Time (months)

Number of subjects at risk:

L(18mg + E (5mg) 51 48 46 44 37 35 32 30 26 17 11 7 2 0 0

L(24mg) 52 50 45 42 37 31 28 23 19 12 7 3 2 1 0

E(10mg) 50 46 42 38 30 27 20 17 13 10 9 5 1 0 0

L(18mg) + E(5mg)=Lenvatinib 18mg + Everolimus 5mg; L(24mg)=Lenvatinib 24; E(10mg)=Everolimus 10mg

Data Cutoff Date: 31JUL2015

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 renal cell carcinoma(RCC) (see section 4.2 for information on paediatric use).

Paediatric studies

The efficacy of lenvatinib was assessed but not established in two open-label studies (for additionalpaediatric information see also Lenvima SmPC section 5.1):

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).

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 outcome measure was ORR at

Week 16 in evaluable patients based on investigator assessment using RECIST v1.1 or RANO (for

Survival Probabilitypatients with HGG). There were no objective responses observed in patients with HGG, diffusemidline glioma, medulloblastoma, or ependymoma. Two PRs were observed in both the EWS and

RMS cohorts for an ORR at Week 16 of 22.2% (95% CI: 2.8, 60.0) and 11.8% (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 cell carcinoma [n=1]) were observed among allother 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.

Absolute bioavailability has not been determined in humans; however, data from a mass-balance studysuggests that it is in the order of 85%.

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. A similar plasma protein binding (97% to 99%) with no dependencies onlenvatinib concentrations (0.2 to 1.2 μg/mL) was observed in plasma from hepatically impaired,renally impaired, and matching healthy subjects.

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

In vitro studies indicate that lenvatinib is a substrate for P-gp and BCRP. Lenvatinib shows minimal orno inhibitory activities toward P-gp mediated and BCRP mediated transport activities. Similarly, noinduction of P-gp mRNA expression was observed. Lenvatinib is not a substrate for OAT1, OAT3,

OATP1B1, OATP1B3, OCT1, OCT2, or the BSEP. In human liver cytosol, lenvatinib did not inhibitaldehyde oxidase activity.

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

Please see distribution section.

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

Following administration of radiolabelled lenvatinib to 6 patients with solid tumours, approximatelytwo-thirds and one-fourth of the radiolabel were eliminated in the faeces and urine, respectively. The

M3 metabolite was the predominant analyte in excreta (~17% of the dose), followed by M2’ (~11% 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 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. The median half-lifewas comparable in subjects with mild, moderate, and severe hepatic impairment as well as those withnormal hepatic function and ranged from 26 hours to 31 hours. The percentage of the dose oflenvatinib excreted in urine was low in all cohorts (<2.16% across treatment cohorts).

Lenvatinib exposure, based on dose-adjusted AUC(0-t) and AUC(0-inf) data, was 119%, 107%, and 180%of normal for subjects with mild, moderate, and severe hepatic impairment, respectively. It has beendetermined that plasma protein binding in plasma from hepatically impaired subjects was similar tothe respective matched healthy subjects and no concentration dependency was observed. Seesection 4.2 for dosing recommendation.

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 AUC(0-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, ethnic origin

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 significant effects onclearance (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.

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Do not store above 25°C.

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Polyamide/Aluminium/PVC/Aluminium blisters containing 10 capsules. Each carton contains30, 60, or 90 hard capsules. Not all pack sizes may be marketed.

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Kisplyx 4 mg hard capsules

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Date of first authorisation: 25 August 2016

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