4.1. Therapeutic indications

Differentiated Thyroid Carcinoma (DTC)

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

Hepatocellular Carcinoma (HCC)

Lenvatinib Eisai as monotherapy is indicated for the treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have received no prior systemic therapy (see section 5.1).

Endometrial Carcinoma (EC)

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

Renal cell carcinoma (RCC)

Lenvatinib Eisai 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).

4.2. Posology and method of administration

Lenvatinib Eisai treatment should be initiated and supervised by a healthcare professional experienced in the use of anticancer therapies.

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

Posology

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

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

Differentiated thyroid cancer (DTC)

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

Dose adjustments and discontinuations for DTC

Management of adverse reactions may require dose interruption, adjustment, or discontinuation of lenvatinib therapy (see section 4.4). Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not warrant interruption of lenvatinib, unless intolerable to the patient despite optimal management. Severe (e.g., Grade 3) or intolerable adverse reactions require interruption of lenvatinib until improvement of the reaction to Grade 0 to 1 or baseline.

For lenvatinib-related toxicities (see Table 5), 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 daily dose

24 mg orally once daily

Two 10‑mg capsules plus one 4‑mg capsule

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 capsule

a: Further dose reductions should be considered on an individual patient basis as limited data are available for doses below 10 mg.

Treatment should be discontinued in case of life-threatening reactions (e.g., Grade 4) with the exception of laboratory abnormalities judged to be non-life-threatening, in which case they should be managed 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 a body weight of < 60 kg and 12 mg (three 4-mg capsules) once daily for patients with a body weight of ≥ 60 kg. Dose adjustments are based only on toxicities observed and not on body weight changes during treatment. The daily dose is to be modified, as needed, according to the dose/toxicity management plan.

Dose adjustments and Discontinuation for HCC

Management of some adverse reactions may require dose interruption, adjustment, or discontinuation of lenvatinib therapy. Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not warrant interruption of lenvatinib, unless intolerable to the patient despite optimal management. For lenvatinib-related toxicities, see Table 5. Details for monitoring, dose adjustment and discontinuation are provided in Table 2.

Table 2 Dose modifications from recommended lenvatinib daily dose in HCC patients

Starting Dose

≥60 kg BW

12 mg (three 4‑mg capsules orally once daily)

<60 kg BW

8 mg (two 4‑mg capsules orally once daily)

Persistent and Intolerable Grade 2 or Grade 3 Toxicitiesa

Adverse Reaction

Modification

Adjusted Doseb

(≥60 kg BW)

Adjusted Doseb

(<60 kg BW)

First occurrence c

Interrupt until resolved to Grade 0-1 or baselined

8 mg

(two 4‑mg capsules)

orally once daily

4 mg

(one 4‑mg capsule)

orally once daily

Second occurrence

(same reaction or new reaction)

Interrupt until resolved to Grade 0-1 or baselined

4 mg

(one 4‑mg capsule) orally once daily

4 mg

(one 4‑mg capsule)

orally every other day

Third occurrence

(same reaction or new reaction)

Interrupt until resolved to Grade 0-1 or baselined

4 mg

(one 4‑mg capsule) orally every other day

Discontinue

Life-threatening toxicities (Grade 4): Discontinuee

a. 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 resolves to 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 lenvatinib is 20 mg orally once daily, in combination with pembrolizumab either 200 mg every 3 weeks or 400 mg every 6 weeks, administered as an intravenous infusion over 30 minutes, until unacceptable toxicity or disease progression (see section 5.1).

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

Dose adjustments and Discontinuation for EC

For lenvatinib-related toxicities see Table 5. When administering lenvatinib in combination with pembrolizumab, interrupt, dose reduce, or discontinue lenvatinib as appropriate (see Table 3). Withhold or discontinue pembrolizumab in accordance with the instructions in the SmPC for pembrolizumab. No dose reductions are recommended for pembrolizumab.

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

Starting Dose in combination with pembrolizumab

20 mg orally once daily

(two 10-mg capsules)

Persistent and Intolerable Grade 2 or Grade 3 Toxicities

Adverse Reaction

Modification

Adjusted Dose

First occurrence

Interrupt until resolved to Grade 0-1 or baseline

14 mg orally once daily

(one 10-mg capsule + one 4-mg capsule)

Second occurrence

(same reaction or new reaction)

Interrupt until resolved to Grade 0-1 or baseline

10 mg orally once daily

(one 10-mg capsule)

Third occurrence

(same reaction or new reaction)

Interrupt until resolved to Grade 0-1 or baseline

8 mg orally once daily

(two 4-mg capsules)

Life-threatening toxicities (Grade 4): Discontinueb

a. 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 of laboratory abnormalities judged to be non-life-threatening, in which case they should be managed as severe reactions (e.g., Grade 3).

Renal cell carcinoma (RCC)

Lenvatinib Eisai in combination with pembrolizumab as first-line treatment

The recommended dose of lenvatinib is 20 mg (two 10-mg capsules) orally once daily in combination with pembrolizumab either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The daily dose of lenvatinib is to be modified as needed according to the dose/toxicity management plan. Lenvatinib treatment should continue until disease progression 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 pembrolizumab dosing information.

Lenvatinib Eisai 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.

Dose adjustment and discontinuation for RCC

Management of adverse reactions may require dose interruption, adjustment, or discontinuation of lenvatinib therapy (see section 4.4). Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not warrant interruption of lenvatinib, unless intolerable to the patient despite optimal management.Severe (e.g., Grade 3) or intolerable adverse reactions require interruption of lenvatinib until improvement of the reaction to Grade 0 to 1 or baseline.

For toxicities thought to be related to lenvatinib (see Table 5), 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 4.

Table 4 Dose modifications from recommended lenvatinib daily dosea

Lenvatinib dose in combination with pembrolizumab

Lenvatinib dose in combination with everolimus

Recommended daily dose

20 mg orally once daily

(two 10-mg capsules)

18 mg orally once daily

(one 10-mg capsule + two 4-mg capsules)

First dose reduction

14 mg orally once daily

(one 10-mg capsule + one 4-mg capsule)

14 mg orally once daily

(one 10-mg capsule + one 4-mg capsule)

Second dose reduction

10 mg orally once daily

(one 10-mg capsule)

10 mg orally once daily

(one 10-mg capsule)

Third dose reduction

8 mg orally once daily

(two 4-mg capsules)

8 mg orally once daily

(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 as appropriate. Lenvatinib should be withheld, dose reduced, or discontinued as appropriate. Withhold or discontinue pembrolizumab in accordance with the instructions in the SmPC for pembrolizumab. No dose reductions are recommended for pembrolizumab.

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

For toxicities thought to be related to both lenvatinib and everolimus, lenvatinib should be reduced (see Table 4) prior to reducing everolimus.

All treatments should be discontinued in case of life-threatening reactions (e.g., Grade 4) with the exception of laboratory abnormalities judged to be non-life-threatening, in which case they should be managed as severe reactions (e.g., Grade 3).

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

Table 5 Adverse reactions requiring dose modification of lenvatinib

Adverse reaction

Severity

Action

Dose reduce and resume lenvatinib

Hypertension

Grade 3

(despite optimal antihypertensive therapy)

Interrupt

Resolves to Grade 0, 1 or 2.

See detailed guidance in Table 6 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 or baseline.

Grade 4*

Discontinue

Do not resume

Cardiac dysfunction

Grade 3

Interrupt

Resolves to Grade 0-1 or baseline.

Grade 4

Discontinue

Do not resume

Posterior reversible encephalopathy syndrome (PRES)/reversible posterior leukoencephalopathy syndrome (RPLS)

Any grade

Interrupt

Consider resuming at reduced dose if resolves to Grade 0-1.

Hepatotoxicity

Grade 3

Interrupt

Resolves to Grade 0-1 or baseline.

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

Gastrointestinal perforation or fistula

Grade 3

Interrupt

Resolves to Grade 0-1 or baseline.

Grade 4

Discontinue

Do not resume

Non-Gastrointestinal fistula

Grade 4

Discontinue

Do not resume

QT interval prolongation

>500 ms

Interrupt

Resolves to <480 ms or baseline.

Diarrhoea

Grade 3

Interrupt

Resolves to Grade 0-1 or baseline.

Grade 4 (despite medical management)

Discontinue

Do not resume

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

Special populations

DTC

Patients of age ≥75 years, of Asian race, with comorbidities (such as hypertension, and hepatic or renal impairment), or body weight below 60 kg appear to have reduced tolerability to lenvatinib (see section 4.8). All patients other than those with severe hepatic or renal impairment (see below) should initiate treatment at the recommended 24 mg dose, following which the dose should be further adjusted on the basis of individual tolerability.

HCC

Patients ≥75 years, of white race or female sex or those with worse baseline hepatic impairment (Child‑Pugh A score of 6 compared to score of 5) appear to have reduced tolerability to lenvatinib.

HCC patients other than those with moderate and severe hepatic impairment or severe renal impairment should initiate treatment at the recommended starting dose of 8 mg (two 4‑mg capsules) for body weight < 60 kg and 12 mg (three 4‑mg capsules) for body weight ≥ 60 kg, following which the dose should be further adjusted on the basis of individual tolerability.

RCC

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

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

No data for the combination of lenvatinib and everolimus are available for most of the special populations. The following information is derived from clinical experience of single agent lenvatinib in patients with DTC.

All patients other than those with severe hepatic or renal impairment (see below) should initiate treatment at the recommended dose of 20 mg of lenvatinib daily with pembrolizumab or 18 mg of lenvatinib with 5 mg of everolimus taken once daily as indicated, following which the dose should be further adjusted on the basis of individual tolerability.

Patients with hypertension

Blood pressure should be well controlled prior to treatment with lenvatinib, and should be regularly monitored during treatment (see sections 4.4 and 4.8).

Patients with hepatic impairment

DTC

No adjustment of starting dose is required on the basis of hepatic function in patients with mild (Child‑Pugh A) or moderate (Child-Pugh B) hepatic impairment. In patients with severe (Child-Pugh C) hepatic impairment, the recommended starting dose is 14 mg taken once daily. Further dose adjustments may be necessary on the basis of individual tolerability. Refer also to section 4.8.

HCC

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

EC

Limited data are available for the combination of lenvatinib with pembrolizumab in patients with hepatic impairment. No adjustment of starting dose of the combination is required on the basis of hepatic function in patients with mild (Child‑Pugh A) or moderate (Child‑Pugh B) hepatic impairment. In patients with severe (Child‑Pugh C) hepatic impairment, the recommended starting dose of lenvatinib is 10 mg taken once daily. Please refer to the SmPC for pembrolizumab for dosing in patients with hepatic impairment. Further dose adjustments may be necessary on the basis of individual tolerability.

RCC

Limited data are available for the combination of lenvatinib with pembrolizumab in patients with hepatic impairment. No adjustment of starting dose of the combination is required on the basis of hepatic function in patients with mild (Child‑Pugh A) or moderate (Child‑Pugh B) hepatic impairment. In patients with severe (Child‑Pugh C) hepatic impairment, the recommended starting dose of lenvatinib is 10 mg taken once daily. Please refer to the SmPC for pembrolizumab for dosing in patients with hepatic impairment. Further dose adjustments may be necessary on the basis of individual tolerability. The combination should be used in patients with severe hepatic impairment only 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 hepatic impairment. No adjustment of starting dose of the combination is required on the basis of hepatic function in patients with mild (Child‑Pugh A) or moderate (Child‑Pugh B) hepatic impairment. In patients with severe (Child‑Pugh C) hepatic impairment, the recommended starting dose of lenvatinib is 10 mg taken once daily in combination with the dose of everolimus recommended for patients with severe hepatic impairment in the SmPC for everolimus. Further dose adjustments may be necessary on the basis of individual tolerability. The combination should be used in patients with severe hepatic impairment only if the anticipated benefit exceeds the risk (see section 4.8).

Patients with renal impairment

DTC

No adjustment of starting dose is required on the basis of renal function in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended starting dose is 14 mg taken once daily. Further dose adjustments may be necessary based on individual tolerability. Patients with end‑stage renal disease were not studied, therefore the use of lenvatinib in these patients is not recommended (see section 4.8).

HCC

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

EC

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

RCC

No adjustment of starting dose is required on the basis of renal function in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended starting dose is 10 mg of lenvatinib taken once daily. Please refer to the SmPC for pembrolizumab or everolimus for dosing in patients with renal impairment. Further dose adjustments may be necessary based on individual tolerability. Patients with end‑stage renal disease have not been studied, therefore the use of lenvatinib in these patients is not recommended (see section 4.8).

Elderly population

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

Paediatric population

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 a posology can be made.

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

Race/Ethnic Origin

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

Body weight below 60 kg

RCC

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

Performance status

RCC

Patients with an ECOG (Eastern Cooperative Oncology Group) performance status of 2 or higher were excluded 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.

Method of administration

Lenvatinib is for oral use. The capsules should be taken at about the same time each day, with or without food (see section 5.2). Caregivers should not open the capsule, in order to avoid repeated exposure to the contents of the capsule.

Lenvatinib capsules can be swallowed whole with water or administered as a suspension prepared by dispersing the whole capsule(s) in water, apple juice, or milk. The suspension may be administered orally or via a feeding tube. If administered via a feeding tube, then the suspension should be prepared using 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 and must be refrigerated at 2°C to 8°C for a maximum of 24 hours. After removal from the refrigerator the suspension should be shaken for approximately 30 seconds before use. If not administered within 24 hours, the suspension should be discarded.

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

4.3. Contraindications

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

Breast‑feeding (see section 4.6).

4.4. Special warnings and precautions for use

Hypertension

Hypertension has been reported in patients treated with lenvatinib, usually occurring early in the course of treatment (see section 4.8). Blood pressure (BP) should be well controlled prior to treatment with lenvatinib and, if patients are known to be hypertensive, they should be on a stable dose of antihypertensive therapy for at least 1 week prior to treatment with lenvatinib. Serious complications of poorly controlled hypertension, including aortic dissection, have been reported. The early detection and effective management of hypertension are important to minimise the need for lenvatinib dose interruptions and reductions. Antihypertensive agents should be started as soon as elevated BP is confirmed. BP should be monitored after 1 week of treatment with lenvatinib, then every 2 weeks for the first 2 months, and monthly thereafter. The choice of antihypertensive treatment should be individualised to the patient's clinical circumstances and follow standard medical practice. For previously normotensive patients, monotherapy with one of the classes of antihypertensive should be started when elevated BP is observed. For those patients already on an antihypertensive medicinal product, the dose of the current agent may be increased, if appropriate, or one or more agents of a different class of antihypertensive should be added. When necessary, manage hypertension as recommended in Table 6.

Table 6 Recommended management of hypertension

Blood Pressure (BP) level

Recommended action

Systolic BP ≥140 mmHg up to <160 mmHg or diastolic BP ≥90 mmHg up to <100 mmHg

Continue lenvatinib and initiate antihypertensive therapy, if not already receiving

OR

Continue lenvatinib and increase the dose of the current antihypertensive therapy or initiate additional antihypertensive therapy

Systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg despite optimal antihypertensive therapy

1. Withhold lenvatinib

2. When systolic BP ≤150 mmHg, diastolic BP ≤95 mmHg, and patient has been on a stable dose of antihypertensive therapy for at least 48 hours, resume lenvatinib at a reduced dose (see section 4.2)

Life‑threatening consequences(malignant hypertension, neurological deficit, or hypertensive crisis)

Urgent intervention is indicated. Discontinue lenvatinib and institute appropriate medical management.

Aneurysms and artery dissections

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating lenvatinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Women of childbearing potential

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

Proteinuria

Proteinuria has been reported in patients treated with lenvatinib, usually occurring early in the course of treatment (see section 4.8). Urine protein should be monitored regularly. If urine dipstick proteinuria ≥2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2). Cases of nephrotic syndrome have been reported in patients using lenvatinib. Lenvatinib should be discontinued in the event of nephrotic syndrome.

Renal failure and impairment

Renal impairment and renal failure have been reported in patients treated with lenvatinib (see section 4.8). The primary risk factor identified was dehydration and/or hypovolemia due to gastrointestinal toxicity. Gastrointestinal toxicity should be actively managed in order to reduce the risk of development of renal impairment or renal failure. Caution should be taken in patients receiving agents acting on the renin-angiotensin aldosterone system given a potentially higher risk for acute renal failure with the combination treatment. Dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).

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

Cardiac dysfunction

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

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

PRES, also known as RPLS, has been reported in patients treated with lenvatinib (<1%; see section 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 to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES. Appropriate measures should be taken to control blood pressure (see section 4.4, Hypertension). In patients with signs or symptoms of PRES, dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).

Hepatotoxicity

DTC

In DTC, liver-related adverse reactions most commonly reported in patients treated with lenvatinib included increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood bilirubin. Hepatic failure and acute hepatitis (<1%; see section 4.8) have been reported in patients with DTC treated with lenvatinib. The hepatic failure cases were generally reported in patients with progressive metastatic liver metastases disease.

HCC

In HCC patients treated with lenvatinib in the REFLECT trial, liver-related adverse reactions including hepatic encephalopathy and hepatic failure (including fatal reactions) were reported at a higher frequency (see Section 4.8) compared to patients treated with sorafenib . Patients with worse hepatic impairment and/or greater liver tumour burden at baseline had a higher risk of developing hepatic encephalopathy and hepatic failure. Hepatic encephalopathy also occurred more frequently in patients aged 75 years and older. Approximately half of the events of hepatic failure and one third of the events of the hepatic encephalopathy were reported in patients with disease progression.

Data in HCC patients with moderate hepatic impairment (Child-Pugh B) are very limited and there are currently no data available in HCC patients with severe hepatic impairment (Child-Pugh C). Since lenvatinib is mainly eliminated by hepatic metabolism, an increase in exposure in patients with moderate to severe hepatic impairment is expected. Patients with HCC should be monitored for worsening liver function including hepatic encephalopathy.

EC

In EC, liver-related adverse reactions most commonly reported in patients treated with lenvatinib and pembrolizumab 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 EC treated with lenvatinib and pembrolizumab.

RCC

Liver‑related adverse reactions most commonly reported in patients treated with lenvatinib included increases in alanine aminotransferase, increases in aspartate aminotransferase, and increases in blood bilirubin. Hepatic failure and acute hepatitis (<1%; see section 4.8) have been reported in patients treated with lenvatinib. The hepatic failure cases were generally reported in patients with progressive liver metastases. Liver function tests should be monitored before initiation of treatment, then every 2 weeks for the first 2 months and monthly thereafter during treatment. If patients have severe hepatic impairment, the initial dose of lenvatinib should be adjusted (see sections 4.2 and 5.2).

In the case of hepatotoxicity, dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).

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

Arterial thromboembolisms

Arterial thromboembolisms (cerebrovascular accident, transient ischaemic attack, and myocardial infarction) have been reported in patients treated with lenvatinib (see section 4.8). Lenvatinib has not been studied in patients who have had an arterial thromboembolism within the previous 6 months, and therefore should be used with caution in such patients. A treatment decision should be made based upon an assessment of the individual patient's benefit/risk. Lenvatinib should be discontinued following an arterial thrombotic event.

Haemorrhage

Serious tumour related bleeds, including fatal haemorrhagic events have occurred in clinical trials and have been reported in post‑marketing experience (see section 4.8). In post‑marketing surveillance, serious and fatal carotid artery haemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than in DTC or other tumour types. The degree of tumour invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe haemorrhage associated with tumour shrinkage/necrosis following lenvatinib therapy. Some cases of bleeding have occurred secondarily to tumour shrinkage and fistula formation, e.g., tracheo-oesophageal fistulae. Cases of fatal intracranial haemorrhage have been reported in some patients with or without brain metastases. Bleeding in sites other than the brain (e.g. trachea, intra‑abdominal, lung) has also been reported. One fatal case of hepatic tumour haemorrhage in a patient with HCC has been reported.

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

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

Gastrointestinal perforation and fistula formation

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

Non-gastrointestinal fistula

Patients may be at increased risk for the development of fistulae when treated with lenvatinib. Cases of fistula formation or enlargement that involve other areas of the body than stomach or intestines were observed in clinical trials and in post-marketing experience (e.g. tracheal, tracheo-oesophageal, oesophageal, cutaneous, female genital tract fistulae). In addition, pneumothorax has been reported with and without clear evidence of a bronchopleural fistula. Some reports of fistula and pneumothorax occurred in association with tumour regression or necrosis. Prior surgery and radiotherapy may be contributing risk factors. Lung metastases may also increase the risk of pneumothorax. Lenvatinib should not be started in patients with fistulae to avoid worsening and lenvatinib should be permanently discontinued in patients with oesophageal or tracheobronchial tract involvement and any Grade 4 fistula (see section 4.2); limited information is available on the use of dose interruption or reduction in management of other events, but worsening was observed in some cases and caution should be taken. Lenvatinib may adversely affect the wound healing process as do other agents of the same class.

QT interval prolongation

QT/QTc interval prolongation has been reported at a higher incidence in patients treated with lenvatinib than in patients treated with placebo (see section 4.8). Electrocardiograms should be monitored at baseline and periodically during treatment in all patients with a special attention for those with congenital long QT syndrome, congestive heart failure, 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 of development of QT interval prolongation greater than 500 ms. Lenvatinib should be resumed at a reduced dose when QTc prolongation is resolved to < 480 ms or baseline.

Electrolyte disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia increase the risk of QT prolongation; therefore electrolyte abnormalities should be monitored and corrected in all patients before starting treatment. Periodic monitoring of ECG and electrolytes (magnesium, potassium and calcium) should be considered during treatment. Blood calcium levels should be monitored at least monthly and calcium should be replaced as necessary during lenvatinib treatment. Lenvatinib dose should be interrupted or dose adjusted as necessary depending on severity, presence of ECG changes, and persistence of hypocalcaemia.

Impairment of thyroid stimulating hormone suppression / Thyroid dysfunction

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

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

Diarrhoea

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

Wound healing complications

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

Osteonecrosis of the jaw (ONJ)

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

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

Tumour lysis syndrome (TLS)

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

Special populations

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

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

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

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on lenvatinib

Chemotherapeutic agents

Concomitant administration of lenvatinib, carboplatin, and paclitaxel has no significant impact on the pharmacokinetics of any of these 3 substances. Additionally, in patients with RCC the pharmacokinetics of lenvatinib was not significantly affected by concomitant everolimus.

Effect of lenvatinib on other medicinal products

CYP3A4 substrates

A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma concentrations of midazolam (a sensitive CYP3A and Pgp substrate) were not altered in the presence of lenvatinib. Additionally, in patients with RCC the pharmacokinetics of everolimus was not significantly affected by concomitant lenvatinib. No significant drug-drug interaction is therefore expected between lenvatinib and other CYP3A4/Pgp substrates.

Oral contraceptives

It is currently unknown whether lenvatinib may reduce the effectiveness of hormonal contraceptives, and therefore women using oral hormonal contraceptives should add a barrier method (see section 4.6).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/ Contraception in females

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

Pregnancy

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

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

Breast‑feeding

It is not known whether lenvatinib is excreted in human milk. Lenvatinib and its metabolites are excreted in rat milk (see section 5.3).

A risk to newborns or infants cannot be excluded and, therefore, lenvatinib is contraindicated during breast‑feeding (see section 4.3).

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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%). Hypertension and proteinuria tend to occur early during lenvatinib treatment (see sections 4.4 and 4.8). The majority of Grade 3 to 4 adverse reactions occurred during the first 6 months of treatment except for diarrhoea, which occurred throughout treatment, and weight loss, which tended to be cumulative over time.

The most important serious adverse reactions 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 (cerebrovascular accident (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 taken for an adverse reaction in 63.1% and 19.5% of patients, respectively. Adverse reactions that most commonly led to dose reductions (in ≥5% of patients) were hypertension, proteinuria, diarrhoea, fatigue, PPE, decreased weight, and decreased appetite. Adverse reactions that most commonly led to discontinuation 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%), arterial thromboembolic events (2.0%) including myocardial infarction (0.8%), cerebral infarction (0.4%) and cerebrovascular accident (0.4%) and renal failure/impairment events (1.4%). There was a higher incidence of decreased neutrophil count in patients with HCC (8.7% on lenvatinib than in other non- HCC tumour types (1.4%)), which was not associated with infection, sepsis or bacterial peritonitis.

In 496 patients with HCC, dose modification (interruption or reduction) and discontinuation were the actions taken for an adverse reaction in 62.3% and 20.2% of patients, respectively. Adverse reactions that most commonly led to dose modifications (in ≥5% of patients) were decreased appetite, diarrhoea, proteinuria, hypertension, fatigue, PPE and decreased platelet count. Adverse reactions that most commonly led to discontinuation of lenvatinib were hepatic encephalopathy, fatigue, increased blood bilirubin, proteinuria and hepatic failure.

EC

The safety of lenvatinib in combination with pembrolizumab has been evaluated in 530 patients with advanced EC receiving 20 mg lenvatinib once daily and 200 mg pembrolizumab every 3 weeks. The most common (occurring in ≥20% of patients) adverse reactions were hypertension (63%), diarrhoea (57%), hypothyroidism (56%), nausea (51%), decreased appetite (47%), vomiting (39%), fatigue (38%), decreased weight (35%), arthralgia (33%), proteinuria (29%), constipation (27%), headache (27%), urinary tract infection (27%), dysphonia (25%), abdominal pain (23%), asthenia (23%), palmar-plantar erythrodysaesthesia syndrome (23%), stomatitis (23%), anaemia (22%), and hypomagnesaemia (20%).

The most common (occurring in ≥5% of patients) severe (Grade ≥3) adverse reactions were hypertension (37.2%), decreased weight (9.1%), diarrhoea (8.1%), increased lipase (7.7%), decreased appetite (6.4%), asthenia (6%), fatigue (6%), hypokalaemia (5.7%), anaemia (5.3%) and proteinuria (5.1%).

Discontinuation of lenvatinib occurred in 30.6% of patients, and discontinuation of both lenvatinib and pembrolizumab occurred in 15.3% of patients due to an adverse reaction. The most common (occurring in ≥1% of patients) adverse reactions leading to discontinuation of lenvatinib were hypertension (1.9%), diarrhoea (1.3%), asthenia (1.3%), decreased appetite (1.3%), proteinuria (1.3%) and decreased weight (1.1%).

Dose interruption of lenvatinib due to an adverse reaction occurred in 63.2% of patients. Dose interruption of lenvatinib and pembrolizumab due to an adverse reaction occurred in 34.3% of patients. The most common (occurring in ≥5% of patients) adverse reactions leading to interruption of lenvatinib were hypertension (12.6%), diarrhoea (11.5%), proteinuria (7.2%), vomiting (7%), fatigue (5.7%), and decreased appetite (5.7%).

Dose reduction of lenvatinib due to adverse reactions occurred in 67.0% of patients. The most common (occurring in ≥5% of patients) adverse reactions resulting in dose reduction of lenvatinib were hypertension (16.2%), diarrhoea (12.5%), palmar-plantar erythrodysaesthesia syndrome (9.1%), fatigue (8.7%), proteinuria (7.7%), decreased appetite (6.6%), nausea (5.5%), asthenia (5.1%), and decreased weight (5.1%).

Tabulated list of adverse reactions

The safety profile of lenvatinib as monotherapy is based on data from 452 DTC patients and 496 HCC patients; 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 in patients with EC is based on data from 530 EC patients treated with lenvatinib in combination with pembrolizumab (see section 5.1).

Adverse reactions observed in clinical trials in DTC, HCC and EC, and reported from post-marketing use of lenvatinib are listed in Table 8. The adverse reaction frequency category represents the most conservative estimate of frequency from the individual populations. Adverse reactions known to occur with lenvatinib or combination therapy components given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical studies with combination therapy.

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

Frequencies are defined as:

• Very common

• Common

• Uncommon

• Rare

• Very rare

• Not known

(≥1/10)

(≥1/100 to <1/10)

(≥1/1,000 to <1/100)

(≥1/10,000 to <1/1,000)

(<1/10,000)

(cannot be estimated from the available data)

Within each frequency category, undesirable effects are presented in order of decreasing seriousness.

Table 7 Adverse reactions reported in patients treated with lenvatinib§

System Organ Class

Lenvatinib monotherapy

Combination with pembrolizumab in EC patients

(MedDRA terminology)

Infections and infestations

Very common

Urinary tract infection

Urinary tract infection

Uncommon

Perineal abscess

Perineal abscess

Blood and lymphatic disorders

Very common

Thrombocytopeniaa, ‡

Lymphopeniaa,‡

Leukopeniaa,‡

Neutropeniaa,‡

Thrombocytopeniaa,‡

Lymphopeniaa,‡

Leukopeniaa,‡

Neutropeniaa,‡

Anaemia

Uncommon

Splenic infarction

Endocrine disorders

Very common

Hypothyroidism

Hypothyroidism

Increased blood thyroid stimulating hormone*,‡

Increased blood thyroid stimulating hormone*

Hyperthyroidism

Common

Adrenal insufficiency

Uncommon

Adrenal insufficiency

Metabolism and nutrition disorders

Very common

Hypocalcaemia*,‡

Hypokalaemia‡

Hypercholesterolaemiab,‡

Hypomagnesaemiab,‡

Decreased weight

Decreased appetite

Hypocalcaemia*,‡

Hypokalaemia‡

Hypercholesterolaemiab,‡

Hypomagnesaemiab,‡

Decreased weight

Decreased appetite

Common

Dehydration

Dehydration

Rare

Tumour lysis syndrome†

Tumour lysis syndrome†

Psychiatric disorders

Very common

Insomnia

Common

Insomnia

Nervous system disorders

Very common

Dizziness

Headache

Dysgeusia

Dizziness

Headache

Dysgeusia

Common

Cerebrovascular accident†

Uncommon

Posterior reversible encephalopathy syndrome

Monoparesis

Transient ischaemic attack

Posterior reversible encephalopathy syndrome

Cerebrovascular accident†

Monoparesis

Transient ischaemic attack

Cardiac disorders

Common

Myocardial infarctionc,†

Cardiac failure

Prolonged electrocardiogram QT

Decreased ejection fraction

Prolonged electrocardiogram QT

Uncommon

Myocardial infarctionc,†

Cardiac failure

Decreased ejection fraction

Vascular disorders

Very common

Haemorrhaged, *,†

Hypertensione,*

Hypotension

Haemorrhaged, *,†

Hypertensione,*

Common

Hypotension

Unknown

Aneurysms and artery dissections

Respiratory, thoracic and mediastinal disorders

Very common

Dysphonia

Dysphonia

Common

Pulmonary embolism†

Pulmonary embolism†

Uncommon

Pneumothorax

Pneumothorax

Gastrointestinal disorders

Very common

Diarrhoea

Gastrointestinal and abdominal painsf

Vomiting

Nausea

Oral inflammationg

Oral painh

Constipation

Dyspepsia

Dry mouth

Increased lipase‡

Increased amylase‡

Diarrhoea

Gastrointestinal and abdominal painsf

Vomiting

Nausea

Oral inflammationg

Oral painh

Constipation

Dry mouth

Increased lipase

Increased amylase‡

Common

Anal fistula

Flatulence

Gastrointestinal perforation

Pancreatitisi

Flatulence

Dyspepsia

Colitis

Gastrointestinal perforation

Uncommon

Pancreatitisi

Colitis

Anal fistula

Hepatobiliary disorders

Very common

Increased blood bilirubinj,* ,‡

Hypoalbuminaemiaj,* ,‡

Increased alanine aminotransferase*,‡

Increased aspartate aminotransferase*,‡

Increased blood alkaline phosphatase‡

Increased gamma-glutamyltransferase‡

Increased blood bilirubinj,*,‡

Hypoalbuminaemiaj,*,‡

Increased alanine aminotransferase*, ‡

Increased aspartate aminotransferase*, ‡

Increased blood alkaline phosphatase‡

Common

Hepatic failurek,*,†

Hepatic encephalopathyl,*,†

Abnormal hepatic function

Cholecystitis

Cholecystitis

Abnormal hepatic function

Increased gamma-glutamyltransferase

Uncommon

Hepatocellular damage/hepatitism

Hepatic failurek,*†

Hepatic encephalopathyl,†

Hepatocellular damage/hepatitism

Skin and subcutaneous tissue disorders

Very common

Palmar-plantar erythrodysaesthesia syndrome

Rash

Alopecia

Palmar-plantar erythrodysaesthesia syndrome

Rash

Common

Hyperkeratosis

Alopecia

Uncommon

Hyperkeratosis

Musculoskeletal and connective tissue disorders

Very common

Back pain

Arthralgia

Myalgia

Pain in extremity

Musculoskeletal pain

Back pain

Arthralgia

Myalgia

Pain in extremity

Common

Musculoskeletal pain

Uncommon

Osteonecrosis of the jaw

Renal and urinary disorders

Very common

Proteinuria*

Increased blood creatinine‡

Proteinuria*

Increased blood creatinine‡

Common

Renal failure n, *,†

Renal impairment*

Increased blood urea

Renal failure n, *,†

Uncommon

Nephrotic syndrome

Renal impairment*

Increased blood urea

General disorders and administration site conditions

Very common

Fatigue

Asthenia

Oedema peripheral

Fatigue

Asthenia

Oedema peripheral

Common

Malaise

Malaise

Uncommon

Impaired healing

Impaired healing

Not known

Non-gastrointestinal fistula o

§: Adverse reaction frequencies presented in Table 7 may not be fully attributable to lenvatinib alone, but may contain 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 includes neutropenia and decreased neutrophil count. Leukopenia includes leukopenia and decreased white blood cell count. Lymphopenia includes lymphopenia and lymphocyte count decreased.

b: Hypomagnesaemia includes hypomagnesaemia and decreased blood magnesium. Hypercholesterolaemia includes 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, blood urine present, haematoma and vaginal haemorrhage.

Haemorrhage terms that occurred in 5 or more subjects with HCC were: epistaxis, haematuria, gingival bleeding, 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, orthostatic hypertension, 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, oral mucosal blistering, stomatitis, glossitis, mouth ulceration, and mucosal inflammation.

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

i: Pancreatitis includes: pancreatitis and acute pancreatitis.

j: Increased blood bilirubin includes: hyperbilirubinaemia, increased blood bilirubin, jaundice and increased bilirubin 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 and encephalopathy.

m: Hepatocellular damage and hepatitis includes: drug-induced liver injury, hepatic steatosis, and cholestatic liver injury.

n: Renal failure cases includes: acute prerenal failure, renal failure, renal failure acute, acute kidney injury and renal tubular necrosis.

o: Non-gastrointestinal fistula includes cases of fistula occurring outside of the stomach and intestines such as tracheal, tracheo-oesophageal, oesophageal, female genital tract fistula, and cutaneous fistula.

RCC

The safety profile of lenvatinib is based on pooled data from 497 RCC patients treated with lenvatinib in combination with pembrolizumab, including Study 307 (CLEAR), pooled data from 623 RCC patients treated with lenvatinib in combination with everolimus: 458 DTC patients and 496 HCC patients 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 RCC patients. The most frequently reported adverse reactions (occurring in ≥30% of patients) were diarrhoea (61.8%), hypertension (51.5%) fatigue (47.1%), hypothyroidism (45.1%), decreased appetite (42.1%), nausea (39.6%), stomatitis (36.6%), proteinuria (33.0%), dysphonia (32.8%), and arthralgia (32.4%).

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

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

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

Lenvatinib in combination with everolimus in RCC

The safety profile of lenvatinib in combination with everolimus is based on data from 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% of patients; 21.7% lenvatinib, and 18.7% both drugs. The most common adverse reactions (≥1%) leading to discontinuation of lenvatinib, everolimus, or both were proteinuria (2.7%), diarrhoea (1.0%) and decreased 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% of patients; in patients where data on individual drug modifications were collected, lenvatinib was interrupted 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%).

Tabulated list of adverse reactions

Adverse reactions observed in clinical trials and reported from post-marketing use of lenvatinib are listed in Table 8. Adverse reactions known to occur with lenvatinib or combination therapy components given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical studies with combination therapy.

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

Frequencies are defined as:

• Very common

• Common

• Uncommon

• Rare

• Very rare

• Not known

(≥1/10)

(≥1/100 to <1/10)

(≥1/1,000 to <1/100)

(≥1/10,000 to <1/1,000)

(˂1/10,000)

(cannot be estimated from the available data)

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

Table 8 Adverse reactions reported in patients treated with lenvatinib§

System Organ Class

(MedDRA terminology)

Lenvatinib monotherapy

Combination with everolimus

Combination with pembrolizumab in RCC patients

Infections and infestations

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‡

Lymphopenia‡

Leukopenia‡

Neutropenia‡

Thrombocytopenia‡

Lymphopenia‡

Leukopenia‡

Neutropenia‡

Thrombocytopenia‡

Lymphopenia‡

Leukopenia‡

Neutropenia‡

Uncommon

Splenic infarction

Endocrine disorders

Very common

Hypothyroidism*

Increased blood thyroid stimulating hormone*,‡

Hypothyroidism*

Increased blood thyroid stimulating hormone*, ‡

Hypothyroidism*

Increased blood thyroid stimulating hormone*, ‡

Common

Adrenal insufficiency

Uncommon

Adrenal insufficiency

Adrenal insufficiency

Metabolism and nutrition disorders

Very common

Hypocalcaemia*, ‡

Hypokalaemia‡

Hypomagnesaemia‡

Hypercholesterolaemia‡

Decreased weight

Decreased appetite

Hypocalcaemia‡

Hypokalaemia‡

Hypomagnesaemia‡

Hypercholesterolaemia *, ‡

Decreased weight

Decreased appetite

Hypocalcaemia‡

Hypokalaemia‡

Hypomagnesaemia‡

Hypercholesterolaemia *, ‡

Decreased weight

Decreased appetite

Common

Dehydration

Dehydration

Dehydration

Rare

Tumour lysis syndrome†

Tumour lysis syndrome†

Tumour lysis syndrome†

Psychiatric disorders

Very common

Insomnia

Insomnia

Insomnia

Nervous system disorders

Very common

Dizziness

Headache

Dysgeusia

Headache

Dysgeusia

Dizziness

Headache

Dysgeusia

Common

Cerebrovascular accident†

Dizziness

Uncommon

Posterior reversible encephalopathy syndrome

Monoparesis

Transient ischaemic attack

Cerebrovascular accident†

Transient ischaemic attack

Cerebrovascular accident

Posterior reversible encephalopathy syndrome

Transient ischaemic attack

Cardiac disorders

Common

Myocardial infarctiona,†

Cardiac failure

Prolonged electrocardiogram QT

Decreased ejection fraction

Myocardial infarctiona,†

Cardiac failure†

Prolonged electrocardiogram QT

Myocardial infarctiona

Prolonged electrocardiogram QT

Uncommon

Decreased ejection fraction

Cardiac failure†

Decreased ejection fraction

Vascular disorders

Very common

Haemorrhageb, *, †

Hypertensionc,*

Hypotension

Haemorrhageb, *, †

Hypertensionc,*

Haemorrhageb, *, †

Hypertensionc,*

Common

Hypotension

Hypotension

Not known

Aneurysms and artery dissections

Aneurysms and artery dissections

Aneurysms and artery dissections

Respiratory, thoracic and mediastinal disorders

Very common

Dysphonia

Dysphonia

Dysphonia

Common

Pulmonary embolism†

Pulmonary embolism

Pneumothorax

Pulmonary embolism

Uncommon

Pneumothorax

Pneumothorax

Gastrointestinal disorders

Very common

Diarrhoea*

Gastrointestinal and abdominal painsd

Vomiting

Nausea

Oral inflammatione

Oral painf

Constipation

Dyspepsia

Dry mouth

Increased lipase‡

Increased amylase‡

Diarrhoea*

Gastrointestinal and abdominal painsd

Vomiting

Nausea

Oral inflammatione

Oral painf

Constipation

Dyspepsia

Increased lipase‡

Increased amylase‡

Diarrhoea*

Gastrointestinal and abdominal painsd

Vomiting

Nausea

Oral inflammatione

Oral painf

Constipation

Dyspepsia

Dry mouth

Increased lipase‡

Increased amylase‡

Common

Anal fistula

Flatulence

Gastrointestinal perforation

Dry mouth

Flatulence

Gastrointestinal perforation

Pancreatitisg

Colitis

Flatulence

Gastrointestinal perforation

Uncommon

Pancreatitisg

Colitis

Pancreatitisg

Anal fistula

Colitis

Anal fistula

Hepatobiliary disorders

Very common

Increased blood bilirubin*, ‡

Hypoalbuminaemia*, ‡

Increased alanine aminotransferase*, ‡

Increased aspartate aminotransferase*, ‡

Increased blood alkaline phosphatase‡

Increased gamma-glutamyltransferase‡

Hypoalbuminaemia*, ‡

Increased alanine aminotransferase‡

Increased aspartate aminotransferase‡

Increased blood alkaline phosphatase‡

Increased blood bilirubin ‡

Hypoalbuminaemia‡

Increased alanine aminotransferase‡

Increased aspartate aminotransferase‡

Increased blood alkaline phosphatase‡

Common

Hepatic failureh,†

Hepatic encephalopathyi, †

Cholecystitis

Abnormal hepatic function

Cholecystitis

Abnormal hepatic function

Increased gamma-glutamyltransferase

Increased blood bilirubin*, ‡

Cholecystitis

Abnormal hepatic function

Increased gamma-glutamyltransferase

Uncommon

Hepatocellular damage/hepatitisj

Hepatic failureh, †

Hepatic encephalopathyi

Hepatic failureh,,†

Hepatic encephalopathyi

Hepatocellular damage/hepatitisj

Skin and subcutaneous tissue disorders

Very common

Palmar-plantar erythrodysaesthesia syndrome

Rash

Alopecia

Palmar-plantar erythrodysaesthesia syndrome

Rash

Palmar-plantar erythrodysaesthesia syndrome

Rash

Common

Hyperkeratosis

Alopecia

Hyperkeratosis

Alopecia

Uncommon

Hyperkeratosis

Musculoskeletal and connective tissue disorders

Very common

Back pain

Arthralgia

Myalgia

Pain in extremity

Musculoskeletal pain

Back pain

Arthralgia

Back pain

Arthralgia

Myalgia

Pain in extremity

Musculoskeletal pain

Common

Myalgia

Pain in extremity Musculoskeletal pain

Uncommon

Osteonecrosis of the jaw

Osteonecrosis of the jaw

Renal and urinary disorders

Very common

Proteinuria*

Increased blood creatinine‡

Proteinuria*

Increased blood creatinine‡

Proteinuria*

Increased blood creatinine‡

Common

Renal failurek, *, †

Renal impairment*

Increased blood urea

Renal failurek, *, †

Renal impairment*

Increased blood urea

Renal failurek, *

Increased blood urea

Uncommon

Nephrotic syndrome

Nephrotic syndrome

Renal impairment*

General disorders and administration site conditions

Very common

Fatigue

Asthenia

Oedema peripheral

Fatigue

Asthenia

Oedema peripheral

Fatigue

Asthenia

Oedema peripheral

Common

Malaise

Malaise

Malaise

Uncommon

Impaired healing

Impaired healing

Non-gastrointestinal fistulal

Impaired healing

Non-gastrointestinal fistulal

Not known

Non-gastrointestinal fistulal

§: Adverse reaction frequencies presented in Table 8 may not be fully attributable to lenvatinib alone but may contain 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: 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 hypertension and increased blood pressure.

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

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

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

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 tubular necrosis.

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.

Description of selected adverse reactions

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 in 72.8% of lenvatinib-treated patients and 16.0% of patients in the placebo-treated group. The median time to onset in lenvatinib-treated patients was 16 days. Reactions of Grade 3 or higher (including 1 reaction of Grade 4) occurred in 44.4% of lenvatinib-treated patients compared with 3.8% of placebo-treated patients. The majority of cases recovered or resolved following dose interruption or reduction, which occurred in 13.0% and 13.4% of patients, respectively. In 1.1% of patients, hypertension led to permanent treatment discontinuation.

HCC

In the Phase 3 REFLECT trial (see section 5.1), hypertension (including hypertension, increased blood pressure, increased diastolic blood pressure and orthostatic hypertension) was reported in 44.5% of lenvatinib-treated patients and Grade 3 hypertension occurred in 23.5%. The median time to onset was 26 days. The majority of cases recovered following dose interruption or reduction, which occurred in 3.6% and 3.4% of patients, respectively. One subject (0.2%) discontinued lenvatinib due to hypertension.

EC

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

RCC

In CLEAR (see section 5.1), hypertension was reported in 56.3% of patients in the lenvatinib plus pembrolizumab-treated group and 42.6% of patients in the sunitinib-treated group. The exposure-adjusted frequency of hypertension was 0.65 episodes per patient year in the lenvatinib plus pembrolizumab-treated group and 0.73 episodes per patient year in the sunitinib-treated group. The median time to onset in lenvatinib plus pembrolizumab-treated patients was 0.7 months. Reactions of Grade 3 or higher occurred in 28.7% of lenvatinib plus pembrolizumab-treated group compared with 19.4% of the sunitinib-treated group. 16.8% of patients with hypertension had dose modifications of lenvatinib (9.1% dose interruption and 11.9% dose reduction). In 0.9% of patients, hypertension led to permanent treatment discontinuation of lenvatinib.

In the pooled RCC population treated with lenvatinib and everolimus, hypertension was reported in 42.5% of patients (the incidence of Grade 3 or Grade 4 hypertension was 19.7%). In patients where data on individual drug modifications were collected, 9.8% of patients with hypertension had dose modifications of lenvatinib (5.3% dose reduction and 6.2% dose interruption) and led to permanent treatment discontinuation in 0.9% of patients. The median time to onset of hypertension events in lenvatinib plus everolimus-treated patients was 0.5 months.

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 was 6.7 weeks. Grade 3 reactions occurred in 10.7% of lenvatinib-treated patients and none in placebo-treated patients. The majority of cases had an outcome of recovered or resolved following dose interruption or reduction, which occurred in 16.9% and 10.7% of patients, respectively. Proteinuria led to permanent treatment discontinuation in 0.8% of patients.

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. The majority of cases recovered following dose interruption or reduction, which occurred in 6.9% and 2.5% of patients, respectively. Proteinuria led to permanent treatment discontinuation in 0.6% of patients.

EC

In the Phase 3 Study 309 (see section 5.1), proteinuria was reported in 29.6% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 5.4% of patients. The median time to onset was 34.5 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in 6.2%, 7.9% and 1.2% of patients, respectively.

RCC

In the pooled RCC population treated with lenvatinib and everolimus, proteinuria was reported in 34.8% of patients (9.0% were Grade ≥3). In patients where data on individual drug modifications were collected, 15.1% of patients with proteinuria had dose modifications of lenvatinib (9.6% reduction and 9.8% interruption) and led to permanent treatment discontinuation in 2.1% of patients. The median time to onset of proteinuria events in lenvatinib plus everolimus-treated patients was 1.4 months.

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 and 1.9% developed renal impairment (3.1% of patients had a Grade ≥ 3 event of renal failure or impairment). In the placebo group 0.8% of patients developed renal failure or impairment (0.8% were Grade ≥ 3).

HCC

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

EC

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

RCC

In the pooled RCC population treated with lenvatinib and everolimus, 1.3% of patients developed renal 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 on individual drug modifications were collected, 5.5% of patients with renal events had dose modifications of lenvatinib (2.3% reduction and 4.0% interruption) and led to permanent treatment discontinuation in 1.9% of patients. The median time to onset of renal events in lenvatinib plus everolimus-treated patients was 3.5 months.

Cardiac dysfunction (see section 4.4)

DTC

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

HCC

In the Phase 3 REFLECT trial (see section 5.1), cardiac dysfunction (including congestive cardiac failure, cardiogenic shock, and cardiopulmonary failure) was reported in 0.6% of patients (0.4% were Grade ≥ 3) in the lenvatinib-treated group.

EC

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

RCC

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

Posterior reversible encephalopathy syndrome (PRES) / Reversible posterior leucoencephalopathy syndrome (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 the lenvatinib-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 the lenvatinib-treated group.

Amongst 1,823 patients treated with lenvatinib monotherapy in clinical trials, there were 5 cases (0.3%) of PRES (0.2% were Grade 3 or 4), all of which resolved after treatment and/or dose interruption, or permanent discontinuation.

EC

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

RCC

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

Hepatotoxicity (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), the most commonly reported liver-related adverse reactions were hypoalbuminaemia (9.6% lenvatinib vs. 1.5% placebo) and elevations of liver enzyme levels, including increases in alanine aminotransferase (7.7% lenvatinib vs. 0 placebo), aspartate aminotransferase (6.9% lenvatinib vs. 1.5% placebo), and blood bilirubin (1.9% lenvatinib vs. 0 placebo). The median time to onset of liver reactions in lenvatinib-treated patients was 12.1 weeks. Liver-related reactions of Grade 3 or higher (including 1 Grade 5 case of hepatic failure) occurred in 5.4% of lenvatinib-treated patients compared with 0.8% in placebo-treated patients. Liver-related reactions led to dose interruptions and reductions in 4.6% and 2.7% of patients, respectively, and to permanent discontinuation in 0.4%.

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

HCC

In the Phase 3 REFLECT trial (see section 5.1), the most commonly reported hepatotoxicity adverse reactions were increased blood bilirubin (14.9%), increased aspartate aminotransferase (13.7%), increased alanine aminotransferase (11.1%), hypoalbuminaemia (9.2%), hepatic encephalopathy (8.0%), increased gamma-glutamyltransferase (7.8%) and increased blood alkaline phosphatase (6.7%). The median time to onset of hepatotoxocity adverse reactions was 6.4 weeks. Hepatotoxicity reactions of ≥ Grade 3 occurred in 26.1% of lenvatinib-treated patients. Hepatic failure (including fatal events in 12 patients) occurred in 3.6% of patients (all were ≥ Grade 3). Hepatic encephalopathy (including fatal events in 4 patients) occurred in 8.4% of patients (5.5% were ≥ Grade 3). There were 17 (3.6%) deaths due to hepatotoxicity events in the lenvatinib arm and 4 (0.8%) deaths in the sorafenib arm. Hepatotoxicity adverse reactions led to dose interruptions and reductions in 12.2% and 7.4% of lenvatinib-treated patients respectively, and to permanent discontinuation in 5.5%.

Across clinical 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 in 2 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 plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 12.1% of patients. The median time to onset was 56.0 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in 5.2%, 3.0% and 1.2 % of patients, respectively.

RCC

In CLEAR (see section 5.1), the most commonly reported liver‑related adverse reactions in the lenvatinib plus pembrolizumab‑treated group were elevations of liver enzyme levels, including increases in alanine aminotransferase (11.9%), aspartate aminotransferase (11.1%) and blood bilirubin (4.0%). Similar events occurred in the sunitinib-treated group at rates of 10.3%, 10.9% and 4.4% respectively. The median time to onset of liver events was 3.0 months (any grade) in the lenvatinib plus pembrolizumab‑treated group and 0.7 months in the sunitinib-treated group. The exposure-adjusted frequency of hepatoxicity events was 0.39 episodes per patient year in the lenvatinib plus pembrolizumab-treated group and 0.46 episodes per patient year in the sunitinib-treated group. Grade 3 liver‑related reactions occurred in 9.9% of lenvatinib plus pembrolizumab‑treated patients and 5.3% of sunitinib-treated patients. Liver‑related reactions led to dose interruptions and reductions of lenvatinib in 8.5% and 4.3% of patients, respectively, and to permanent discontinuation of lenvatinib in 1.1% of patients.

In the pooled RCC population treated with lenvatinib and everolimus, the most commonly reported liver-related adverse reactions were elevations of liver enzyme levels, including increases in alanine aminotransferase (11.9%), aspartate aminotransferase (11.4%) and gamma-glutamyltransferase increased (2.7%). Grade 3 liver related reactions occurred in 6.1% of lenvatinib plus everolimus-treated patients. In patients where data on individual drug modifications were collected, 6.0% of patients 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 to onset of liver-related reactions in lenvatinib plus everolimus-treated patients was 1.8 months.

Arterial thromboembolisms (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), arterial thromboembolic events were reported in 5.4% 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 cerebrovascular accident) with a fatal outcome.

EC

In the Phase 3 Study 309 (see section 5.1), arterial thromboembolisms were reported in 3.7% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 2.2% of patients. The median time to onset was 59.0 days. Dose interruption and discontinuation of lenvatinib occurred in 0.2% and 2.0% of patients, respectively

RCC

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

In the pooled RCC population treated with lenvatinib and everolimus, arterial thromboembolic events were reported in 2.7% of patients (2.2% were Grade ≥3). In patients where data on individual drug modifications were collected, 0.6% of patients with arterial thromboembolic events had dose modifications of lenvatinib (0.6% interruption) and led to permanent treatment discontinuation in 1.5% of patients. The most commonly reported arterial thromboembolic event in the lenvatinib plus everolimus-treated group was myocardial infarction (1.3%). The median time to onset of arterial thromboembolic events in lenvatinib plus everolimus-treated patients was 6.8 months.

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-treated patients. Reactions that occurred at an incidence of ≥ 0.75% above placebo were: epistaxis (11.9%), haematuria (6.5%), contusion (4.6%), gingival bleeding (2.3%), haematochezia (2.3%), rectal haemorrhage (1.5%), haematoma (1.1%), haemorrhoidal haemorrhage (1.1%), laryngeal haemorrhage (1.1%), petechiae (1.1%), and intracranial tumour haemorrhage (0.8%). In this trial, there was 1 case of fatal intracranial haemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline.

The median time to first onset in lenvatinib-treated patients was 10.1 weeks. No differences between lenvatinib- 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 dose interruption (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 and 5.0% were Grade ≥ 3. Grade 3 reactions occurred in 3.4%, Grade 4 reactions in 0.2% and 7 patients (1.5%) had a grade 5 reaction including cerebral haemorrhage, upper gastrointestinal haemorrhage, intestinal haemorrhage and tumour haemorrhage. The median time to first onset was 11.9 weeks. A haemorrhage event led to dose interruption or reduction in 3.2% and 0.8% patients respectively and to treatment discontinuation in 1.7% of patients.

Across clinical 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 plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 3.0% of patients. The median time to onset was 65.0 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in 1.7%, 1.2% and 1.7% of patients, respectively.

RCC

In the pooled RCC population treated with lenvatinib and everolimus, haemorrhage events were reported in 28.6% of patients (3.2% were Grade ≥3). In patients where data on individual drug modifications were collected, 4.9% of patients with haemorrhage events had dose modifications of lenvatinib (4.2% interruption and 0.8% reduction) and led to permanent treatment discontinuation in 0.6% of patients. The most commonly reported haemorrhage events in the lenvatinib plus everolimus-treated group were epistaxis (19.4%) and haematuria (4.2%). The median time to onset of haemorrhage events in lenvatinib plus everolimus-treated patients was 1.9 months.

Hypocalcaemia (see section 4.4, QT interval prolongation)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), hypocalcaemia was reported in 12.6% of lenvatinib-treated patients vs. no cases in the placebo arm. The median time to first onset in lenvatinib-treated patients was 11.1 weeks. Reactions of Grade 3 or 4 severity occurred in 5.0% of lenvatinib-treated vs 0 placebo-treated patients. Most reactions resolved following supportive treatment, without dose interruption or reduction, which occurred in 1.5% and 1.1% of patients, respectively; 1 patient with Grade 4 hypocalcaemia discontinued treatment permanently.

HCC

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

EC

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

RCC

In the pooled RCC population treated with lenvatinib and everolimus, hypocalcaemia was reported in 4.8% of patients (1.1% were Grade ≥3). In patients where data on individual drug modifications were collected, 0.8% of patients with hypocalcaemia had dose modifications of lenvatinib (0.6% dose interruption 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 was 2.9 months.

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 fistula were 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 were reported 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% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 2.5% of patients. The median time to onset was 117.0 days. Discontinuation of lenvatinib occurred in 1.0% of patients. Events of gastrointestinal perforation were reported in 3.9% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 3.0% of patients. The median time to onset was 42 days. Dose interruption and discontinuation of lenvatinib occurred in 0.5% and 3.0% of patients, respectively.

RCC

In the pooled RCC population treated with lenvatinib and everolimus, GI perforation events were reported in 3.7% of patients (2.9% were Grade ≥3). In patients where data on individual drug modifications were collected, 2.1% of patients with GI perforations had dose modifications of lenvatinib (1.5% interruption and 0.6% reduction) and led to permanent treatment discontinuation in 1.1% 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 were reported in 1.0% of patients (0.5% were Grade ≥3). In patients where data on individual drug modifications were collected, 0.8% of patients with GI perforations had dose modifications of lenvatinib (0.8% interruption) and led to permanent treatment discontinuation in 0.4% of patients. The median time to onset of fistula formation events in lenvatinib plus everolimus-treated patients was 3.7 months.

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 observed across various indications. Reactions were reported at various time points during treatment ranging from two weeks to greater than 1 year from initiation of lenvatinib, with a median latency of about 3 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 in 8.8% of lenvatinib-treated patients and 1.5% of patients in the placebo group. The incidence of QT interval prolongation of greater than 500 ms was 2% in the lenvatinib-treated patients compared to no reports in the placebo group.

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 was 2.4%.

EC

In the Phase 3 Study 309 (see section 5.1), QT interval prolongation was reported in 3.9% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 0.5% of patients.

The median time to onset was 115.5 days. Dose interruption and reduction of lenvatinib occurred in 0.2% and 0.5% of patients, respectively.

RCC

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

Increased blood thyroid stimulating hormone / hypothyroidism (see section 4.4)

DTC

In the pivotal Phase 3 SELECT trial (see section 5.1), 88% of all patients had a baseline TSH level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of lenvatinib-treated patients as compared with 14% of placebo-treated patients.

HCC

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

EC

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

Blood TSH increased was reported in 12.8% of lenvatinib plus pembrolizumab-treated patients with no patients reporting Grade ≥3 reactions. Dose interruption occurred in 0.2% of patients.

RCC

In CLEAR (see section 5.1), hypothyroidism occurred in 47.2% of patients in the lenvatinib plus pembrolizumab‑treated group and 26.5% of patients in the sunitinib‑treated group. The exposure-adjusted frequency of hypothyroidism was 0.39 episodes per patient year in the lenvatinib plus pembrolizumab-treated group and 0.33 episodes per patient year in the sunitinib-treated group. In general, the majority of hypothyroidism events in the lenvatinib plus pembrolizumab‑treated group were of Grade 1 or 2. Grade 3 hypothyroidism was reported in 1.4% of patients in the lenvatinib plus pembrolizumab‑treated group versus none in the sunitinib-treated group. At baseline, 90.0% of patients in the lenvatinib plus pembrolizumab-treated group and 93.1% of patients in the sunitinib-treated group had baseline TSH levels ≤ upper limit of normal. Elevations of TSH > upper limit of normal were observed post baseline in 85.0% of lenvatinib plus pembrolizumab‑treated patients versus 65.6% of sunitinib-treated patients. In lenvatinib plus pembrolizumab-treated patients, hypothyroidism events resulted in dose modification of lenvatinib (reduction or interruption) in 2.6% patients and discontinuation of lenvatinib in 1 patient.

In the pooled RCC population treated with lenvatinib and everolimus, hypothyroidism occurred in 24.1% of patients. In general, the majority of hypothyroidism events were of Grade 1 or 2. Grade 3 hypothyroidism 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 was 2.7 months. At baseline, 83.0% of patients in the lenvatinib plus everolimus-treated group had TSH levels ≤ upper limit of normal. Elevations of TSH > upper limit of normal were observed post-baseline in 71.3% of lenvatinib plus everolimus-treated patients. In patients where data on individual drug modifications 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)

DTC

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

HCC

In the Phase 3 REFLECT trial (see section 5.1), diarrhoea was reported in 38.7% of patients treated with 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 plus pembrolizumab-treated patients (7.6% were Grade ≥ 3). Dose interruption, reduction and discontinuation of lenvatinib occurred in 10.6%, 11.1% and 1.2% of patients, respectively.

RCC

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 were collected, 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.

Paediatric population

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

In patients with relapsed/refractory osteosarcoma, pneumothorax was reported at a frequency higher than that observed in adults with DTC, HCC, RCC and EC. In Study 207, pneumothorax occurred in 6 patients (10.9%) treated with single-agent lenvatinib and 7 patients (16.7%) treated with lenvatinib in combination with ifosfamide and etoposide. Overall, 2 patients discontinued study treatment due to pneumothorax. 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 ifosfamide and 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 8 patients (6.3%) with spindle cell sarcoma, undifferentiated sarcoma, RMS, malignant peripheral nerve sheath tumour, synovial sarcoma, spindle cell carcinoma, and malignant fibromyxoid ossifying tumour; all 8 patients had lung metastases or primary disease in the chest wall or pleural cavity at baseline. For Studies 216 and 230, no patient discontinued study treatment due to pneumothorax; in Study 231, one patient discontinued study treatment due to pneumothorax. Pneumothorax occurrence appeared to be mainly associated with pulmonary metastases and underlying disease.

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

In the combination dose-finding cohort of Study 207, the most frequently (≥50%) reported adverse drug reactions were vomiting, anaemia, nausea, diarrhoea, hypothyroidism, abdominal pain, arthralgia, epistaxis, neutropenia, constipation, headache, and pain in extremity; and in the combination expansion 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%) reported adverse drug reactions were hypertension, hypothyroidism, hypertriglyceridemia, abdominal pain, and diarrhoea; 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 were hypothyroidism, anaemia, nausea, platelet count decreased, proteinuria, vomiting, back pain, febrile neutropenia, 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.

Other special populations

Elderly

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 disease characteristics at baseline or with the use of concomitant medicinal products. Arterial thromboembolic events 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 ≥3 hypertension (≥ 10% increase compared to patients of age <65 years).

RCC

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

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

Gender

DTC

Females had a higher incidence of hypertension (including Grade 3 or 4 hypertension), proteinuria, and PPE, while males had a higher incidence of decreased ejection fraction and gastrointestinal perforation and fistula formation.

HCC

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

RCC

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.

Ethnic origin

DTC

Asian patients had a higher (≥10% difference) incidence than Caucasian patients of peripheral oedema, hypertension, fatigue, PPE, proteinuria, stomatitis, thrombocytopenia, and myalgia; while Caucasian patients had a higher incidence of diarrhoea, weight decreased, nausea, vomiting, constipation, asthenia, abdominal pain, pain in extremity, and dry mouth. A larger proportion of Asian patients had a lenvatinib dose reduction compared to Caucasian patients. the median time to first dose reduction and the average daily dose taken were lower in Asian than in Caucasian patients.

HCC

Asian patients had a higher incidence than Caucasian patients of proteinuria, decreased neutrophil count, decreased platelet count, decreased white blood count and PPE, while Caucasian patients had a higher 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 Caucasian patients had a higher incidence of mucosal inflammation, abdominal pain, diarrhoea, urinary tract infection, weight decreased, hypomagnesaemia, dizziness, asthenia and fatigue.

RCC

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

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

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 (abdominal pain, diarrhoea, vomiting).

RCC

In CLEAR, patients with baseline hypertension had a higher incidence of proteinuria than patients without baseline hypertension.

Baseline diabetes

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

Hepatic impairment

DTC

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

HCC

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

RCC

There are limited data on patients with hepatic impairment in RCC Study 205.

Renal impairment

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 compared with subjects with normal renal function. These patients also had a higher incidence of renal reactions and a trend towards a higher incidence of liver reactions.

HCC

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

RCC

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

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 4 hypocalcaemia and hyponatraemia, and a trend towards a higher incidence of Grade 3 or 4 decreased appetite.

RCC

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play and Apple App store.

4.9. Overdose

The highest doses of lenvatinib studied clinically were 32 mg and 40 mg per day. Accidental medication errors resulting in single doses of 40 to 48 mg have occurred in clinical trials. The most frequently observed adverse drug reactions at these doses were hypertension, nausea, diarrhoea, fatigue, stomatitis, proteinuria, headache, and aggravation of PPE. There have also been reports of overdose with lenvatinib involving single administrations of 6 to 10 times the recommended daily dose. These cases were associated with adverse reactions consistent with the known safety profile of lenvatinib (i.e., renal and cardiac failure), or were without adverse reactions.

Symptoms and Management

There is no specific antidote for overdose with lenvatinib. In case of suspected overdose, lenvatinib should be withheld and appropriate supportive care given as required.