Lenvima

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

LENVIMA 4 mg hard capsules
LENVIMA 10 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

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

LENVIMA 10 mg hard capsules
A yellow body and yellowish-red cap, approximately 14.3 mm in length, marked in black ink with “Є” 
on the cap, and “LENV 10 mg” on the body.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

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

4.2 Posology and method of administration

LENVIMA treatment should be initiated and supervised by a health care 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 failure (see 
section 4.4, Renal failure and impairment).



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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 0-1 or baseline.

For lenvatinib related toxicities (see Table 3), upon resolution/improvement of an adverse reaction to 
Grade 0-1 or baseline, treatment should be resumed at a reduced dose of lenvatinib as suggested in 
Table 1. 

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 abnormality judged to be non-life-threatening, in which case they should be 
managed as severe reaction (e.g., Grade 3).

Hepatocellular Carcinoma
The recommended daily dose of lenvatinib is 8 mg (two 4 mg capsules) once daily for patients with a 
body weight of < 60 kg and 12 mg (three 4 mg capsules) once daily for patients with a body weight of 
≥ 60 kg. Dose adjustments are based only on toxicities observed and not on body weight changes 
during treatment. The daily dose is to be modified, as needed, according to the dose/toxicity 
management plan.

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



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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 2g/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).

Table 3  Adverse reactions requiring dose modification of lenvatinib in DTC and HCC

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 4 in section 4.4.

Grade 4 Discontinue Do not resume
Proteinuria ≥ 2 g / 24 hours Interrupt Resolves to less than 2 g 

/ 24 hours.
Nephrotic syndrome ------- Discontinue Do not resume
Renal impairment or 
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

PRES/RPLS Any grade Interrupt Consider resuming at 
reduced dose if resolves 



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Table 3  Adverse reactions requiring dose modification of lenvatinib in DTC and HCC

Adverse reaction Severity Action Dose reduce and 
resume lenvatinib
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

GI perforation or 
fistula

Grade 3 Interrupt Resolves to Grade 0-1 or 
baseline.

Grade 4 Discontinue Do not resume

Non-GI fistula Grade 4 Discontinue Do not resume

QT interval 
prolongation

>500 ms Interrupt Resolves to <480 ms 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

Elderly population

DTC
Patients of age ≥75 years, of Asian race, with comorbidities (such as hypertension, and hepatic or 
renal impairment), or body weight below 60 kg appear to have reduced tolerability to lenvatinib (see 
section 4.8, Other special populations). 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.

Patients with hypertension
Blood pressure should be well controlled prior to treatment with lenvatinib, and should be regularly 
monitored during treatment (see section 4.4). Refer also to section 4.8, Other special populations.

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 



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adjustments may be necessary on the basis of individual tolerability. Refer also to section 4.8, Other 
special populations.

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 imparement (Child-Pugh C) and is not recommended for use in these patients.

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. Refer also to section 4.8, Other special populations.

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.

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

Paediatric population
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). The safety and efficacy of lenvatinib in children aged 
2 to <18 years have not yet been established (see section 5.1). No data are available.

Race
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 (see also section 4.8, 
Other special populations).

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). The capsules should be swallowed whole with water. Caregivers should 
not open the capsule, in order to avoid repeated exposure to the contents of the capsule.

Alternatively, the lenvatinib capsules may be added without breaking or crushing them to a tablespoon 
of water or apple juice in a small glass to produce a suspension. The capsules must be left in the liquid 
for at least 10 minutes and stirred for at least 3 minutes to dissolve the capsule shells. The suspension 
is to be swallowed. After drinking, the same amount of water or apple juice (one tablespoon) must be 
added to the glass and swirled a few times. The additional liquid must be swallowed. 

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). 



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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, Description of selected adverse reactions). Blood pressure (BP) 
should be well controlled prior to treatment with lenvatinib and, if patients are known to be 
hypertensive, they should be on a stable dose of antihypertensive therapy for at least 1 week prior to 
treatment with lenvatinib. Serious complications of poorly controlled hypertension, including aortic 
dissection, have been reported. The early detection and effective management of hypertension are 
important to minimise the need for lenvatinib dose interruptions and reductions. Antihypertensive 
agents should be started as soon as elevated BP is confirmed. BP should be monitored after 1 week of 
treatment with lenvatinib, then every 2 weeks for the first 2 months, and monthly thereafter. The 
choice of antihypertensive treatment should be individualised to the patient’s clinical circumstances 
and follow standard medical practice. For previously normotensive subjects, monotherapy with one of 
the classes of antihypertensives should be started when elevated BP is observed. For those patients 
already on 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 4.

Table 4 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.



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Proteinuria

Proteinuria has been reported in patients treated with lenvatinib, usually occurring early in the course 
of treatment (see section 4.8, Description of selected adverse reactions). 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.

Hepatotoxicity

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

In HCC patients treated with lenvatinib in the REFLECT trial, liver-related adverse reactions 
including hepatic encephalopathy and hepatic failure (including fatal reactions) were reported at a 
higher frequency (see 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.

Close monitoring of the overall safety is recommended in patients with mild or moderate hepatic 
impairment (see also 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).

Renal failure and impairment

Renal impairment and renal failure have been reported in patients treated with lenvatinib (see 
section 4.8, Description of selected adverse reactions). The primary risk factor identified was 
dehydration and/or hypovolemia due to gastrointestinal toxicity. Gastrointestinal toxicity should be 
actively managed in order to reduce the risk of development of renal impairment or renal failure. 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).

Diarrhoea

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



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Cardiac dysfunction

Cardiac failure (<1%) and decreased left ventricular ejection fraction have been reported in patients 
treated with lenvatinib (see section 4.8, Description of selected adverse reactions). 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, Description of selected adverse reactions). PRES is a neurological disorder which can 
present with headache, seizure, lethargy, confusion, altered mental function, blindness, and other 
visual or neurological disturbances. Mild to severe hypertension may be present. Magnetic resonance 
imaging is necessary to confirm the diagnosis of PRES. Appropriate measures should be taken to 
control blood pressure (see section 4.4, Hypertension). In patients with signs or symptoms of PRES, 
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, Description of 
selected adverse reactions). Lenvatinib has not been studied in patients who have had an arterial 
thromboembolism within the previous 6 months, and therefore should be used with caution in such 
patients. A treatment decision should be made based upon an assessment of the individual patient's 
benefit/risk. Lenvatinib should be discontinued following an arterial thrombotic event.

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.

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, Description of selected adverse 
reactions). In post-marketing surveillance, serious and fatal carotid artery haemorrhages were seen 
more frequently in patients with anaplastic thyroid carcinoma (ATC) than in DTC or other tumour 
types. The degree of tumour invasion/infiltration of major blood vessels (e.g. carotid artery) should be 
considered because of the potential risk of severe haemorrhage associated with tumour 
shrinkage/necrosis following lenvatinib therapy. Some cases of bleeding have occurred secondarily to 
tumour shrinkage and fistula formation, e.g. 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).



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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 areas of the body other 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 fistula 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 for other agents of the same class.

QT interval prolongation 

QT/QTc interval prolongation has been reported at a higher incidence in patients treated with 
lenvatinib than in patients treated with placebo (see section 4.8, Description of selected adverse 
reactions). Electrocardiograms should be monitored at baseline and periodically during treatment in all 
patients with particular attention to those with congenital long QT syndrome, congestive heart failure, 
bradyarrhythmias, and those taking medicinal products known to prolong the QT interval, including 
Class Ia and III antiarrhythmics. Lenvatinib should be withheld in the event of development of QT 
interval prolongation greater than 500 ms. Lenvatinib should be resumed at a reduced dose when QTc 
prolongation is resolved to < 480 ms or baseline.

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

Impairment of thyroid stimulating hormone suppression/ Thyroid dysfunction

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

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



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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.

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, Other special populations).

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

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.

Effect of lenvatinib on other medicinal products

A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma concentrations of 
midazolam (a sensitive CYP3A and Pgp substrate) were not altered in the presence of lenvatinib. No 
significant drug-drug interaction is therefore expected between lenvatinib and other CYP3A4/Pgp 
substrates.

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

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

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



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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

The safety profile of lenvatinib 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).

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, Description of 
selected adverse reactions). 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%).



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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.

Tabulated list of adverse reactions

Similar adverse reactions were observed in clinical trials in DTC and HCC. 
Adverse reactions observed in clinical trials in DTC and HCC and reported from post-marketing use 
of lenvatinib are listed in Table 5. The adverse reaction frequency category represents the most 
conservative estimate of frequency from the two individual populations.

Frequencies are defined as:
 Very common (≥1/10)
 Common (≥1/100 to <1/10)
 Uncommon (≥1/1,000 to <1/100)
 Not known (cannot be estimated from the available data)

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

Table 5 Adverse reactions reported in patients treated with lenvatinib

System Organ 
Class
(MedDRA 
terminology*)

Very Common Common Uncommon Not known

Infections and 
infestation

Urinary tract 
infection

Perineal abscess 

Blood and 
lymphatic 
disorders

Thrombocytopeniaa

Leukopeniaa

Neutropeniaa

Lymphopeniaa Splenic infarction

Endocrine 
disorders

Hypothyroidism Increased blood 
thyroid stimulating 

hormone ‡

Metabolism and 
nutrition 
disorders

Hypocalcaemia‡
Hypokalaemia 

Decreased weight 
Decreased appetite

Dehydration
Hypomagnesaemiab

Hypercholesterolaemia
b

Psychiatric 
disorders

Insomnia



14

Table 5 Adverse reactions reported in patients treated with lenvatinib

System Organ 
Class
(MedDRA 
terminology*)

Very Common Common Uncommon Not known

Nervous system 
disorders

Dizziness
Headache
Dysgeusia

Cerebrovascular 
accident †

Posterior 
reversible 

encephalopathy 
syndrome 

Monoparesis
Transient 

ischaemic attack

Cardiac 
disorders

Myocardial 
infarctionc,†

Cardiac failure
Prolonged 

electrocardiogram QT 
Decreased ejection 

fraction 

Vascular 
disorders

Haemorrhaged, †,‡

Hypertensione,‡

Hypotension

Aneurysms 
and artery 
dissections

Respiratory, 
thoracic and 
mediastinal 
disorders

Dysphonia Pulmonary embolism†, Pneumothorax

Gastrointestinal 
disorders

Diarrhoea
Gastrointestinal and 

abdominal painsf

Vomiting
Nausea

Oral inflammationg

Oral painh

Constipation
Dyspepsia
Dry mouth

Anal fistula
Flatulence

Increased lipase 
Increased amylase 

Pancreatitis i,†

Hepatobiliary 
disorders

Increased blood 
bilirubin j, ‡

Hypoalbuminaemiaj
, ‡ 

Increased alanine 
aminotransferase ‡

Increased aspartate 
aminotransferase ‡

Hepatic failurek,‡,†

Hepatic 
encephalopathyl,‡,†

Increased blood 
alkaline phosphatase 

Hepatic function 
abnormal

Increased gamma-
glutamyltransferase 

Cholecystitis

Hepatocellular 
damage/hepatitis

m

Skin and 
subcutaneous 
tissue disorders

Palmar-plantar 
erythrodysaesthesia 

syndrome
Rash

Alopecia

Hyperkeratosis



15

Table 5 Adverse reactions reported in patients treated with lenvatinib

System Organ 
Class
(MedDRA 
terminology*)

Very Common Common Uncommon Not known

Musculoskeleta
l and 
connective 
tissue disorders

Back pain
Arthralgia
Myalgia

Pain in extremity
Musculoskeletal 

pain
Renal and 
urinary 
disorders

Proteinuria‡ Renal failure cases n, †

Renal impairment
Increased blood 

creatinine 
Increased blood urea 

Nephrotic 
syndrome

General 
disorders and 
administration 
site conditions

Fatigue
Asthenia

Peripheral oedema 

Malaise Impaired healing* Non-
gastrointestina

l fistulao

* Identified from post-marketing use of lenvatinib
†: Includes cases with a fatal outcome.
‡: See section 4.8 Description of selected adverse reactions for further characterisation.
The following terms have been combined:
a: Thrombocytopenia includes thrombocytopenia and decreased platelet count. Neutropenia 

includes neutropenia and decreased neutrophil count decreased. 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.

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

f: Gastrointestinal and abdominal pain 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: Hyperbilirubinaeamia 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. 



16

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.

Description of selected adverse reactions

DTC

Hypertension (see section 4.4)
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.

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.

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 



17

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.

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.

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.

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.



18

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%).

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.

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).



19

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. 

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.

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.

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 median latency of about 
3 months.



20

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%.

Increased blood thyroid stimulating hormone (see section 4.4 Impairment of thyroid stimulating 
hormone suppression / Thyroid dysfunction)

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. 

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).

Paediatric population

Clinical data are not available in this population (see section 4.2). 



21

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.

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.

Ethnic origin

DTC

Asian patients had a higher incidence than Caucasian patients of peripheral oedema, hypertension, 
fatigue, PPE, proteinuria, thrombocytopenia, and increased blood thyroid stimulating hormone.

HCC

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

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).



22

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.

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.

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.

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 national reporting system 
listed in Appendix V.

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.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


23

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01XE29

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

Mechanism of action

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of 
vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and 
VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including 
fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor 
(PDGF) receptor PDGFRα, KIT, and RET.

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

Although not studied directly with lenvatinib, the mechanism of action (MOA) for hypertension is 
postulated to be mediated by the inhibition of VEGFR2 in vascular endothelial cells. Similarly, 
although not studied directly, the MOA for proteinuria is postulated to be mediated by downregulation 
of VEGFR1 and VEGFR2 in the podocytes of the glomerulus.

The mechanism of action for hypothyroidism is not fully elucidated.

Clinical efficacy

Radioiodine-refractory differentiated thyroid cancer
The SELECT study was a multicentre, randomised, double-blind, placebo-controlled trial that was 
conducted in 392 patients with radioiodine-refractory differentiated thyroid cancer with independent, 
centrally reviewed, radiographic evidence of disease progression within 12 months (+1 month 
window) prior to enrolment. Radioiodine-refractory was defined as one or more measurable lesions 
either with a lack of iodine uptake or with progression in spite of radioactive-iodine (RAI) therapy, or 
having a cumulative activity of RAI of >600 mCi or 22 GBq with the last dose at least 6 months prior 
to study entry. Randomisation was stratified by geographic region (Europe, North America, and 
Other), prior VEGF/VEGFR-targeted therapy (patients may have received 0 or 1 prior 
VEGF/VEGFR-targeted therapy), and age (≤65 years or >65 years). The main efficacy outcome 
measure was progression-free survival (PFS) as determined by blinded independent radiologic review 
using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Secondary efficacy outcome 
measures included overall response rate and overall survival. Patients in the placebo arm could opt to 
receive lenvatinib treatment at the time of confirmed disease progression.

Eligible patients with measurable disease according to RECIST 1.1 were randomised 2:1 to receive 
lenvatinib 24 mg once daily (n=261) or placebo (n=131). Baseline demographics and disease 
characteristics were well balanced for both treatment groups. Of the 392 patients randomised, 76.3% 
were naïve to prior VEGF/VEGFR-targeted therapies, 49.0% were female, 49.7% were European, and 
the median age was 63 years. Histologically, 66.1% had a confirmed diagnosis of papillary thyroid 
cancer and 33.9% had follicular thyroid cancer which included Hürthle cell 14.8% and clear cell 3.8%.
Metastases were present in 99% of the patients: lungs in 89.3%, lymph nodes in 51.5%, bone in 



24

38.8%, liver in 18.1%, pleura in 16.3%, and brain in 4.1%. The majority of patients had an ECOG 
performance status of 0; 42.1% had a status of 1; 3.9% had a status above 1. The median cumulative 
RAI activity administered prior to study entry was 350 mCi (12.95 GBq).

A statistically significant prolongation in PFS was demonstrated in lenvatinib-treated patients 
compared with those receiving placebo (p<0.0001) (see figure 1). The positive effect on PFS was seen 
across the subgroups of age (above or below 65 years), sex, race, histological subtype, geographic 
region, and those who received 0 or 1 prior VEGF/VEGFR-targeted therapies. Following independent 
review confirmation of disease progression, 109 (83.2%) patients randomised to placebo had crossed 
over to open-label lenvatinib at the time of the primary efficacy analysis.

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

The median time to first dose reduction was 2.8 months. The median time to objective responsive was 
2.0 (95% CI: 1.9, 3.5) months; however, of the patients who experienced a complete or partial 
response to lenvatinib, 70.4% were observed to develop the response on or within 30 days of being on 
the 24-mg dose.

The overall survival analysis was confounded by the fact that placebo-treated subjects with confirmed 
disease progression had the option to cross over to open-label lenvatinib. There was no statistically 
significant difference in overall survival between the treatment groups at the time of the primary 
efficacy analysis (HR=0.73; 95% CI: 0.50, 1.07, p=0.1032). The median Overall Survival (OS) had 
not been reached for either the lenvatinib group or the placebo crossover group.

Table 6 Efficacy results in DTC patients

Lenvatinib
N=261

Placebo
N=131

Progression-Free Survival (PFS)a

Number of progressions or deaths (%) 107 (41.0) 113 (86.3)
Median PFS in months (95% CI) 18.3 (15.1, NE) 3.6 (2.2, 3.7)
Hazard ratio (99% CI)b,c 0.21 (0.14, 0.31)
P-valueb <0.0001

Patients who had received 0 prior 
VEGF/VEGFR-targeted therapy (%)

195 (74.7) 104 (79.4)

Number of progressions or deaths 76 88
Median PFS in months (95% CI) 18.7 (16.4, NE) 3.6 (2.1, 5.3)
Hazard ratio (95% CI)b,c 0.20 (0.14, 0.27)

Patients who had received 1 prior 
VEGF/VEGFR-targeted therapy (%)

66 (25.3) 27 (20.6)

Number of progressions or deaths 31 25
Median PFS in months (95% CI) 15.1 (8.8, NE) 3.6 (1.9, 3.7)
Hazard ratio (95% CI)b,c 0.22 (0.12, 0.41)

Objective Response Ratea

Number of objective responders (%) 169 (64.8) 2 (1.5)
(95% CI) (59.0, 70.5) (0.0, 3.6)
P-valueb <0.0001
Number of complete responses 4 0
Number of partial responses 165 2
Median time to objective response,d months (95% CI) 2.0 (1.9, 3.5) 5.6 (1.8, 9.4)
Duration of response,d months, median (95% CI) NE (16.8, NE) NE (NE, NE)



25

Overall Survival
Number of deaths (%) 71 (27.2) 47 (35.9)
Median OS in months (95% CI) NE (22.0, NE) NE (20.3, 

NE)
Hazard ratio (95% CI)b, e 0.73 (0.50, 1.07)
P-value b, e 0.1032

CI, confidence interval; NE, not estimable; OS, overall survival; PFS, progression-free survival; 
RPSFT, rank preserving structural failure time model; VEGF/VEGFR, vascular endothelial growth 
factor / vascular endothelial growth factor receptor. 
a: Independent radiologic review.
b: Stratified by region (Europe vs. North America vs. Other), age group (≤65 years vs >65 years), 

and previous VEGF/VEGFR-targeted therapy (0 vs. 1).
c: Estimated with Cox proportional hazard model.
d: Estimated using the Kaplan-Meier method; the 95% CI was constructed with a generalised 

Brookmeyer and Crowley method in patients with a best overall response of complete response 
or partial response.

e: Not adjusted for crossover effect.

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

CI, confidence interval; NE, not estimable.

Hepatocellular Carcinoma

The clinical efficacy and safety of lenvatinib have been evaluated in an international, multicenter, 
open-label, randomised phase 3 study (REFLECT) in patients with unresectable hepatocellular 
carcinoma (HCC).

In total, 954 patients were randomised 1:1 to receive either lenvatinib (12 mg [baseline body weight 
≥60 kg] or 8 mg [baseline body weight <60 kg]) given orally once daily or sorafenib 400 mg given 
orally twice daily.



26

Patients were eligible to participate if they had a liver function status of Child-Pugh class A and 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1. Patients were excluded 
who had prior systemic anticancer therapy for advanced/unresectable HCC or any prior anti-VEGF 
therapy. Target lesions previously treated with radiotherapy or locoregional therapy had to show 
radiographic evidence of disease progression. Patients with ≥50% liver occupation, clear invasion into 
the bile duct or a main branch of the portal vein (Vp4) on imaging were also excluded.

 Demographic and baseline disease characteristics were similar between the lenvatinib and the 
sorafenib groups and are shown below for all 954 randomised patients:

 Median age: 62 years 
 Male: 84% 
 White: 29%, Asian: 69%, Black or African American: 1.4%
 Body weight: <60 kg -31%, 60-80 kg – 50%, >80 kg - 19%
 Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0: 63%, ECOG PS of 

1: 37% 
 Child-Pugh A: 99%, Child-Pugh B: 1% 
 Aetiology: Hepatitis B (50%), Hepatitis C (23%), alcohol (6%) 
 Absence of macroscopic portal vein invasion (MPVI): 79%
 Absence of MPVI, extra-hepatic tumour spread (EHS) or both: 30% 
 Underlying cirrhosis (by independent imaging review): 75%
 Barcelona Clinic Liver Cancer (BCLC) stage B: 20%; BCLC stage C: 80% 
 Prior treatments: hepatectomy (28%), radiotherapy (11%), loco-regional therapies including 

transarterial (chemo)embolisation (52%), radiofrequency ablation (21%) and percutaneous 
ethanol injection (4%)

The primary efficacy endpoint was Overall Survival (OS). Lenvatinib was non-inferior for OS to 
sorafenib with HR = 0.92 [95% CI of (0.79, 1.06)] and a median OS of 13.6 months vs 12.3 months 
(see Table 7 and Figure 2). The results for surrogate endpoints (PFS and ORR) are presented in Table 
7 below.



27

Table 7: Efficacy Results from the REFLECT study in HCC

Efficacy parameter
Hazard
ratioa, b (95%
CI)

P-value d
Median (95% CI) e

Lenvatinib
(N= 478)

Sorafenib
(N=476)

OS
0.92 
(0.79,1.06)

NA 13.6 (12.1, 14.9)
12.3 (10.4, 
13.9)

PFSg (mRECIST) 0.64 (0.55, 
0.75)

<0.00001 7.3 (5.6, 7.5) 3.6 (3.6, 3.7)

Percentages (95% CI)

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

Data cut-off date: 13 Nov 2016.
a. Hazard ratio is for lenvatinib vs. sorafenib, based on a Cox model including treatment group as 

a factor.
b. Stratified by region (Region 1: Asia-Pacific; Region 2: Western), macroscopic portal vein 

invasion or extrahepatic spread or both (yes, no), ECOG PS (0, 1) and body weight (<60 kg, 
≥60 kg).

c. Results are based on confirmed and unconfirmed responses.
d. P-value is for the superiority test of lenvatinib versus sorafenib.
e. Quartiles are estimated by the Kaplan-Meier method, and the 95% CIs are estimated with a 

generalised Brookmeyer and Crowley method
f. Response rate (complete or partial response)
g. Per independent radiology review retrospective analysis. The median duration of objective 

response was 7.3 (95% CI 5.6, 7.4) months in the lenvatinib arm and 6.2 (95% CI 3.7, 11.2) 
months in the sorafenib arm.



28

Figure 2 Kaplan-Meier Curve of Overall Survival - HCC

1. Data cut-off date = 13 Nov 2016.
2. Noninferiority margin for hazard ratio (HR: lenvatinib vs sorafenib = 1.08).
3. Median was estimated with the Kaplan-Meier method and the 95% confidence interval was constructed 

with a generalised Brookmeyer and Crowley method.
4. HR was estimated from the Cox proportional hazard model with treatment as independent variable and 

stratified by IxRS stratification factors. The Efron method was used for ties.
5. + = censored observations.

In subgroup analyses by stratification factors (presence or absence of MPVI or EHS or both, ECOG 
PS 0 or 1, BW <60 kg or ≥60 kg and region) the HR consistently favoured lenvatinib over sorafenib, 
with the exception of Western region [HR of 1.08 (95% CI 0.82, 1.42], patients without EHS [HR of 
1.01 (95% CI 0.78, 1.30)] and patients without MPVI, EHS or both [HR of 1.05 (0.79, 1.40)]. The 
results of subgroup analyses should be interpreted with caution.
The median duration of treatment was 5.7 months (Q1: 2.9, Q3: 11.1) in the lenvatinib arm and 
3.7 months (Q1: 1.8, Q3: 7.4) in the sorafenib arm.
In both treatment arms in the REFLECT study, median OS was approximately 9 months longer in 
subjects who received post-treatment anticancer therapy than in those who did not. In the lenvatinib 
arm, median OS was 19.5 months (95% CI: 15.7, 23.0) for subjects who received post-treatment 
anticancer therapy (43%) and 10.5 months (95% CI: 8.6, 12.2) for those who did not. In the sorafenib 
arm, median OS was 17.0 months (95% CI: 14.2, 18.8) for subjects who received posttreatment 
anticancer therapy (51%) and 7.9 months (95% CI: 6.6, 9.7) for those who did not. Median OS was 
longer by approximately 2.5 months in the lenvatinib compared with the sorafenib arm in both subsets 
of subjects (with or without post-treatment anticancer therapy).

QT interval prolongation

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

Paediatric population

The European Medicines Agency (EMA) has deferred the obligation to submit the results of a study 
with lenvatinib in one or more subsets of the paediatric population in the treatment of radioiodine-
refractory differentiated thyroid cancer and has has waived the obligation to submit the results of 
studies with lenvatinib in one or more subsets of the paediatric population in the treatment of 
hepatocellular carcinoma (HCC).



29

5.2 Pharmacokinetic properties

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

Absorption

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

Distribution

In vitro binding of lenvatinib to human plasma proteins is high and ranged from 98% to 99% 
(0.3 - 30 μg/mL, mesilate). This binding was mainly to albumin with minor binding to α1-acid 
glycoprotein and γ-globulin.

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

Lenvatinib is a substrate for P-gp and BCRP. Lenvatinib is not a substrate for OAT1, OAT3, 
OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K or the bile salt export pump BSEP.

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

Biotransformation

In vitro, cytochrome P450 3A4 was demonstrated as the predominant (>80%) isoform involved in the 
P450-mediated metabolism of lenvatinib. However, in vivo data indicated that non-P450-mediated 
pathways contributed to a significant portion of the overall metabolism of lenvatinib. Consequently, in 
vivo, inducers and inhibitors of CYP 3A4 had a minimal effect on lenvatinib exposure (see 
section 4.5).

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

In plasma samples collected up to 24 hours after administration, lenvatinib constituted 97% of the 
radioactivity in plasma radiochromatograms while the M2 metabolite accounted for an additional 
2.5%. Based on AUC(0 – inf), lenvatinib accounted for 60% and 64% of the total radioactivity in plasma 
and blood, respectively.



30

Data from a human mass balance/excretion study indicate lenvatinib is extensively metabolised in 
humans. The main metabolic pathways in humans were identified as oxidation by aldehyde oxidase, 
demethylation via CYP3A4, glutathione conjugation with elimination of the O-aryl group 
(chlorophenyl moiety), and combinations of these pathways followed by further biotransformations 
(e.g., glucuronidation, hydrolysis of the glutathione moiety, degradation of the cysteine moiety, and 
intramolecular rearrangement of the cysteinylglycine and cysteine conjugates with subsequent 
dimerisation). These in vivo metabolic routes align with the data provided in the in vitro studies using 
human biomaterials.

In vitro transporter studies

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

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

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

Elimination

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

Following administration of radiolabelled lenvatinib to 6 patients with solid tumours, approximately 
two-thirds and one-quarter of the radiolabel were eliminated in the faeces and urine, respectively. The 
M3 metabolite was the predominant analyte in excreta (~17% of the dose), followed by M2’ (~11% of 
the dose) and M2 (~4.4 of the dose).

Linearity/non-linearity

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

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

Special populations

Hepatic impairment
The pharmacokinetics of lenvatinib following a single 10-mg dose were evaluated in 6 subjects each 
with mild and moderate hepatic impairment (Child-Pugh A and Child-Pugh B, respectively). A 5-mg 
dose was evaluated in 6 subjects with severe hepatic impairment (Child-Pugh C). Eight healthy, 
demographically matched subjects served as controls and received a 10-mg dose. Lenvatinib exposure, 
based on dose-adjusted AUC0-t and AUC0-inf data, was 119%, 107%, and 180% of normal for subjects 
with mild, moderate, and severe hepatic impairment, respectively. It has been determined that plasma 
protein binding in plasma from hepatically impaired subjects was similar to the respective matched 
healthy subjects and no concentration dependency was observed. See section 4.2 for dosing 
recommendation.



31

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

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

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

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

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

Paediatric Population
Paediatric patients have not been studied.

5.3 Preclinical safety data

In the repeated-dose toxicity studies (up to 39 weeks), lenvatinib caused toxicologic changes in 
various organs and tissues related to the expected pharmacologic effects of lenvatinib including 
glomerulopathy, testicular hypocellularity, ovarian follicular atresia, gastrointestinal changes, bone 
changes, changes to the adrenals (rats and dogs), and arterial (arterial fibrinoid necrosis, medial 
degeneration, or haemorrhage) lesions in rats, dogs, and cynomolgus monkeys. Elevated transaminase 
levels asociated with signs of hepatotoxicity, were also observed in rats, dogs and monkeys.
Reversibility of the toxicologic changes was observed at the end of a 4-week recovery period in all 
animal species investigated.

Genotoxicity

Lenvatinib was not genotoxic.

Carcinogenicity studies have not been conducted with lenvatinib.

Reproductive and developmental toxicity

No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility.
However, testicular (hypocellularity of the seminiferous epithelium) and ovarian changes (follicular 
atresia) were observed in repeated-dose toxicity studies in animals at exposures 11 to 15 times (rat) or 
0.6 to 7 times (monkey) the anticipated clinical exposure (based on AUC) at the maximum tolerated 
human dose. These findings were reversible at the end of a 4-week recovery period.

Administration of lenvatinib during organogenesis resulted in embryolethality and teratogenicity in 
rats (foetal external and skeletal anomalies) at exposures below the clinical exposure (based on AUC) 
at the maximum tolerated human dose, and rabbits (foetal external, visceral or skeletal anomalies) 
based on body surface area; mg/m2 at the maximum tolerated human dose. These findings indicate that 



32

lenvatinib has a teratogenic potential, likely related to the pharmacologic activity of lenvatinib as an 
antiangiogenic agent.

Lenvatinib and its metabolites are excreted in rat milk. 

Juvenile animal toxicity studies

Mortality was the dose-limiting toxicity in juvenile rats in which dosing was initiated on postnatal day 
(PND) 7 or PND21 and was observed at exposures that were respectively 125- or 12-fold lower 
compared with the exposure at which mortality was observed in adult rats, suggesting an increasing 
sensitivity to toxicity with decreasing age. Therefore, mortality may be attributed to complications 
related to primary duodenal lesions with possible contribution from additional toxicities in immature 
target organs.
The toxicity of lenvatinib was more prominent in younger rats (dosing initiated on PND7) compared 
with those with dosing initiated on PND21 and mortality and some toxicities were observed earlier in 
the juvenile rats at 10 mg/kg compared with adult rats administered the same dose level. Growth 
retardation, secondary delay of physical development, and lesions attributable to pharmacologic 
effects (incisors, femur [epiphyseal growth plate], kidneys, adrenals, and duodenum) were also 
observed in juvenile rats.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule contents
Calcium carbonate
Mannitol
Microcrystalline cellulose
Hydroxypropylcellulose
Low-substituted hydroxypropylcellulose
Talc

Capsule shell 
Hypromellose
Titanium dioxide (E171)
Yellow iron oxide (E172)
Red iron oxide (E172)

Printing ink
Shellac
Black iron oxide (E172)
Potassium hydroxide
Propylene glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

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



33

6.5 Nature and contents of container

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

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

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

7. MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany
E-mail: medinfo_de@eisai.net

8. MARKETING AUTHORISATION NUMBER(S) 

Lenvima 4mg hard capsules
EU/1/15/1002/001
EU/1/15/1002/003
EU/1/15/1002/004

Lenvima 10 mg hard capsules
EU/1/15/1002/002
EU/1/15/1002/005
EU/1/15/1002/006

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 28 May 2015
Date of latest renewal:

10. DATE OF REVISION OF THE TEXT



34

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT



35

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Eisai Manufacturing Ltd
European Knowledge Centre
Mosquito Way
Hatfield
Herfordshire
AL10 9SN
United Kingdom

Or

Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 

 Periodic Safety Update Reports (PSURs)

The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 
months following authorisation. Subsequently, the marketing authorisation holder shall submit 
periodic safety update reports for this product in accordance with the requirements set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and 
published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 
OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

If the submission of a PSUR and the update of an RMP coincide, they can be submitted at the same 
time.



36

ANNEX III

LABELLING AND PACKAGE LEAFLET



37

A. LABELLING



38

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

LENVIMA 4 mg hard capsules
lenvatinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 hard capsules
60 hard capsules
90 hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



39

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/15/1002/001 (Pack size of 30 hard capsules)
EU/1/15/1002/003 (Pack size of 60 hard capsules)
EU/1/15/1002/004 (Pack size of 90 hard capsules)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

LENVIMA 4 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



40

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS 

1. NAME OF THE MEDICINAL PRODUCT

LENVIMA 4 mg hard capsules
lenvatinib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Eisai 

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



41

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

LENVIMA 10 mg hard capsules 
lenvatinib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 hard capsules
60 hard capsules
90 hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



42

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/15/1002/002 (Pack size of 30 hard capsules)
EU/1/15/1002/005 (Pack size of 60 hard capsules)
EU/1/15/1002/006 (Pack size of 90 hard capsules)

13. BATCH NUMBER

Lot 

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

LENVIMA 10 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



43

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS 

1. NAME OF THE MEDICINAL PRODUCT

LENVIMA 10 mg hard capsules
lenvatinib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Eisai 

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



44

B. PACKAGE LEAFLET



45

Package leaflet: Information for the user

LENVIMA 4 mg hard capsules
LENVIMA 10 mg hard capsules

lenvatinib

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
 Keep this leaflet. You may need to read it again.
 If you have any further questions, ask your doctor or pharmacist.
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. What LENVIMA is and what it is used for 
2. What you need to know before you take LENVIMA
3. How to take LENVIMA
4. Possible side effects 
5. How to store LENVIMA
6. Contents of the pack and other information

1. What LENVIMA is and what it is used for

What LENVIMA is
LENVIMA is a medicine that contains the active substance lenvatinib. It is used on its own to treat 
progressive or advanced thyroid cancer in adults when radioactive iodine treatment has not helped to 
stop the disease.

LENVIMA can also be used on its own to treat liver cancer (hepatocellular carcinoma) in adults who 
have not previously been treated with another anticancer medicine that travels through the 
bloodstream. People get LENVIMA when their liver cancer has spread or cannot be taken out by 
surgery. 

How LENVIMA works
LENVIMA blocks the action of proteins called receptor tyrosine kinases (RTKs), which are involved 
in the development of new blood vessels that supply oxygen and nutrients to cells and help them to 
grow. These proteins can be present in high amounts in cancer cells, and by blocking their action 
LENVIMA may slow the rate at which the cancer cells multiply and the tumour grows and help to cut 
off the blood supply that the cancer needs.

2. What you need to know before you take LENVIMA

Do not take LENVIMA if:
 you are allergic to lenvatinib or any of the other ingredients of this medicine (listed in 

section 6).
 you are breast-feeding (see the section below on Contraception, pregnancy and breast-feeding).



46

Warnings and precautions
Talk to your doctor before taking LENVIMA if you:
 have high blood pressure 
 are a woman able to become pregnant (see the section below on Contraception, pregnancy and 

breast-feeding)
 have a history of heart problems or stroke
 have liver or kidney problems
 have had recent surgery or radiotherapy
 need to have a surgical procedure. Your doctor may consider stopping LENVIMA if you will be 

undergoing a major surgical procedure as LENVIMA may affect wound healing. LENVIMA 
may be restarted once adequate wound healing is established.

 are over 75 years 
 belong to an ethnic group other than White or Asian 
 weigh less than 60 kg
 have a history of abnormal connections (known as a fistula) between different organs in the 

body or from an organ to the skin
 If you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a 

tear in a blood vessel wall.

Before taking LENVIMA, your doctor may carry out some tests, for example to check your blood 
pressure and your liver or kidney function and to see if you have low levels of salt and high levels of 
thyroid stimulating hormone in your blood. Your doctor will discuss the results of these tests with you 
and decide whether you can be given LENVIMA. You may need to have additional treatment with 
other medicines, to take a lower dose of LENVIMA, or to take extra care due to an increased risk of 
side effects.

If you are not sure talk to your doctor before taking LENVIMA.

Children and adolescents
LENVIMA is not recommended for use in children and adolescents. The effects of LENVIMA in 
people younger than 18 years old are not known.

Other medicines and LENVIMA
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This includes herbal preparations and medicines without a prescription.

Contraception, pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.
 If you could become pregnant, use highly effective contraception while taking this medicine, 

and for at least one month after you finish treatment. Because it is not known if LENVIMA can 
reduce the effect of the oral contraceptive pill, if this is your normal method of contraception 
you should ensure you also add a barrier method such as the cap or condoms if you have sex 
during treatment with LENVIMA.

 Do not take LENVIMA if you are planning to become pregnant during your treatment. This is 
because it may seriously harm your baby.

 If you become pregnant while being treated with LENVIMA, tell your doctor immediately. 
Your doctor will help you decide whether the treatment should be continued.

 Do not breast-feed if you are taking LENVIMA. This is because the medicine passes into breast 
milk and may seriously harm your breastfed baby.

Driving and using machines
LENVIMA may cause side effects that can affect your ability to drive or use machines. Avoid driving 
or using machines if you feel dizzy or tired.



47

3. How to take LENVIMA

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.

How much to take
Thyroid cancer
 The recommended dose of LENVIMA is usually 24 mg once a day 

(2 capsules of 10 mg and 1 capsule of 4 mg).
 If you have severe liver or kidney problems the recommended dose is 14 mg once a day 

(1 capsule of 10 mg and 1 capsule of 4 mg).
 Your doctor may reduce your dose if you have problems with side effects.

Liver cancer
 The recommended dose of LENVIMA depends on your body weight when you first start 

treatment. The dose is usually 12 mg once a day (3 capsules of 4 mg) if you weigh 60 kg or 
more and 8 mg once a day (2 capsules of 4 mg) if you weigh less than 60kg. 

 Your doctor may reduce your dose if you have problems with side effects.

Taking this medicine 
 You can take the capsules with or without food.
 Swallow the capsules whole with water or dissolved. To dissolve them, pour a tablespoon of 

water or apple juice into a small glass and put the capsules into the liquid without breaking or 
crushing them. Leave for at least 10 minutes then stir for at least 3 minutes to dissolve the 
capsule shells. Drink the mixture. After drinking, add the same amount of water or apple juice, 
swirl and swallow. 

 Take the capsules at about the same time each day.
 Caregivers should not open the capsules to avoid exposure to the contents of the capsule.

How long to take LENVIMA
You will usually carry on taking this medicine as long as you are getting benefit.

If you take more LENVIMA than you should
If you take more LENVIMA than you should, talk to a doctor or pharmacist straight away. Take the 
medicine pack with you.

If you forget to take LENVIMA
Do not take a double dose (two doses at the same time) to make up for a forgotten dose.

What to do if you forget to take your dose depends on how long it is until your next dose.
 If it is 12 hours or more until your next dose: take the missed dose as soon as you remember. 

Then take the next dose at the normal time.
 If it is less than 12 hours until your next dose: skip the missed dose. Then take the next dose at 

the normal time.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. The 
following side effects may happen with this medicine.



48

Tell your doctor straight away if you notice any of the following side effects - you may need
urgent medical treatment: 
 feeling numb or weak on one side of your body, severe headache, seizure, confusion, difficulty 

talking, vision changes or feeling dizzy - these may be signs of a stroke, bleeding on your brain, 
or the effect on your brain of a severe increase in blood pressure.

 chest pain or pressure, pain in your arms, back, neck or jaw, being short of breath, rapid or 
irregular heart rate, coughing, bluish colour to lips or fingers, feeling very tired – these may be 
signs of a heart problem, a blood clot in your lung or a leak of air from your lung into your chest 
so your lung cannot inflate.

 severe pain in your belly (abdomen) - this may be due to a hole in the wall of your gut or a 
fistula (a hole in your gut which links through a tube-like passage to another part of your body 
or skin).

 black, tarry, or bloody stools, or coughing up of blood - these may be signs of bleeding inside 
your body.

 yellow skin or yellowing of the whites of the eyes (jaundice) or drowsiness, confusion, poor 
concentration – these may be signs of liver problems.

 diarrhoea, feeling and being sick - these are very common side effects that can become serious 
if they cause you to become dehydrated, which can lead to kidney failure. Your doctor can give 
you medicine to reduce these side effects.

Tell your doctor straight away if you notice any of the side effects above.

Other side effects include:

Very common (may affect more than 1 in 10 people)
 high or low blood pressure
 loss of appetite or weight loss
 feeling sick and being sick, constipation, diarrhoea, abdominal pain, indigestion
 feeling very tired or weak
 hoarse voice
 swelling of the legs
 rash
 dry, sore, or inflamed mouth, odd taste sensation
 joint or muscle pain
 feeling dizzy
 hair loss
 bleeding (most commonly nose bleeds, but also other types of bleeding such as blood in the 

urine, bruising, bleeding from the gums or gut wall)
 trouble sleeping
 changes in urine tests for protein (high) and urinary infections (increased frequency in urination 

and pain in passing urine)
 headache and back pain
 redness, soreness and swelling of the skin on the hands and feet (palmar-plantar 

erythrodysesthesia))
 underactive thyroid (tiredness, weight gain, constipation, feeling cold, dry skin)
 changes in blood test results for potassium levels (low) and calcium levels (low)
 decrease in the number of white blood cells
 changes in blood test results for liver function
 low levels of platelets in the blood which may lead to bruising and difficulty in wound healing



49

Common (may affect up to 1 in 10 people)
 loss of body fluids (dehydration) 
 heart palpitations
 dry skin, thickening and itching of the skin
 feeling bloated or having excess wind
 heart problems or blood clots in the lungs (difficulty breathing, chest pain) or other organs
 liver failure
 drowsiness, confusion, poor concentration, loss of consciousness that may be signs of liver 

failure
 feeling unwell
 inflammation of the gallbladder
 stroke
 anal fistula (a small channel that forms between the anus and the surrounding skin)
 changes in blood test results for magnesium (low), cholesterol (high) and thyroid stimulating 

hormone (high)
 changes in blood test results for kidney function and kidney failure
 increase in lipase and amylase (enzymes involved in digestion)

Uncommon (may affect up to 1 in 100 people)
 painful infection or irritation near the anus
 mini-stroke
 liver damage
 severe pain in the upper left part of the belly (abdomen) which may be associated with fever, 

chills, nausea and vomiting (splenic farction)
 inflammation of the pancreas
 wound healing problems

Not Known (the following side effects have been reported since the marketing of LENVIMA but the 
frequency for them to occur is not known)
 other types of fistulae (an abnormal connection between different organs in the body or between 

the skin and an underlying structure such as throat and windpipe). Symptoms depend on where 
the fistula is located. Talk to your doctor if you experience any new or unsual symptoms such as 
coughing when swallowing. 

 An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall 
(aneurysms and artery dissections).

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects, you can help provide more information on the safety 
of this medicine.

5. How to store LENVIMA

 Keep this medicine out of the sight and reach of children.
 Do not use this medicine after the expiry date which is stated on the carton and on each blister 

after ‘EXP’. The expiry date refers to the last day of that month.
 Do not store above 25°C. Store in the original blister in order to protect from moisture.
 Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 

how to throw away medicines you no longer use. These measures will help protect the 
environment.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


50

6. Contents of the pack and other information

What LENVIMA contains
 The active substance is lenvatinib. 

 LENVIMA 4 mg hard capsules: - Each hard capsule contains 4 mg of lenvatinib (as
mesilate).

 LENVIMA 10 mg hard capsules: - Each hard capsule contains 10 mg of lenvatinib (as 
mesilate ).

 The other ingredients are calcium carbonate, mannitol, microcrystalline cellulose, 
hydroxypropylcellulose, low-substituted hydroxypropyl cellulose, talc. The capsule shell 
contains hypromellose, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide 
(E172). The printing ink contains shellac, black iron oxide (E172), potassium hydroxide, 
propylene glycol.

What LENVIMA looks like and contents of the pack
 The 4 mg capsule is a yellowish red body and yellowish red cap, approximately 14.3 mm in 

length, marked in black ink with “Є” on the cap, and “LENV 4 mg” on the body.
 The 10 mg capsule is a yellow body and yellowish red cap, approximately 14.3 mm in length, 

marked in black ink with “Є” on the cap, and “LENV 10 mg” on the body.
 The capsules come in blisters of polyamide/aluminium/PVC with a push through aluminium foil 

lidding in cartons of 30,60 or 90 hard capsules. Not all pack sizes may be marketed .

Marketing Authorisation Holder
Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany
E-mail: medinfo_de@eisai.net

Manufacturer
Eisai Manufacturing Ltd
Mosquito Way
Hatfield,
Herts AL10 9SN, 
United Kingdom.

Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Eisai SA/NV
Tél/Tel: + 32 (0) 2 502 58 04

Lietuva
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Vokietija)

България
Eisai GmbH
Teл.: + 49 (0) 69 66 58 50
(Германия)

Luxembourg/Luxemburg
Eisai SA/NV
Tél/Tel: + 32 (0) 2 502 58 04
(Belgique/Belgien)



51

Česká republika
Eisai GesmbH organizačni složka
Tel.: + 420 242 485 839

Magyarország
Eisai GmbH
Tel.: + 49 (0) 69 66 58 50
(Németország)

Danmark
Eisai AB
Tlf: + 46 (0) 8 501 01 600
(Sverige)

Malta
Eisai GmbH
Tel.: + 49 (0) 69 66 58 50
(Germany)

Deutschland
Eisai GmbH
Tel: + 49 (0) 69 66 58 50

Nederland
Eisai B.V.
Tel: + 31 (0) 900 575 3340

Eesti
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Saksamaa)

Norge
Eisai AB
Tlf: + 46 (0) 8 501 01 600
(Sverige)

Ελλάδα
Arriani Pharmaceutical S.A.
Τηλ: + 30 210 668 3000

Österreich
Eisai GesmbH
Tel: + 43 (0) 1 535 1980-0

España
Eisai Farmacéutica, S.A.
Tel: + (34) 91 455 94 55

Polska
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Niemcy)

France
Eisai SAS
Tél: + (33) 1 47 67 00 05

Portugal
Eisai Farmacêutica, Unipessoal Lda
Tel: + 351 214 875 540

Hrvatska
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Njemačka)
Ireland
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Germany)

România
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Germania)

Slovenija
Eisai GmbH
Lyoner Straße 36
60528 Frankfurt am Main
(Nemčija)

Ísland
Eisai AB
Sími: + 46 (0) 8 501 01 600
(Svíþjóð)

Slovenská republika
Eisai GesmbH organizační složka
Tel.: +420 242 485 839
(Česká republika)

Italia
Eisai S.r.l.
Tel: + 39 02 5181401

Suomi/Finland
Eisai AB
Puh/Tel: + 46 (0) 8 501 01 600
(Ruotsi/Sverige)



52

Κύπρος
Arriani Pharmaceuticals S.A.
Τηλ: + 30 210 668 3000
(Ελλάδα)

Sverige
Eisai AB
Tel: + 46 (0) 8 501 01 600

Latvija
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Vācija)

United Kingdom
Eisai Europe Ltd.
Tel: + 44 (0) 208 600 1400

This leaflet was last revised in:

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET