Kisplyx
1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 
Kisplyx 4 mg hard capsules 
Kisplyx 10 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Kisplyx 4 mg hard capsules 
Each hard capsule contains 4 mg of lenvatinib (as mesylate).  
 
Kisplyx 10 mg hard capsules 
Each hard capsule contains 10 mg of lenvatinib (as mesylate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule. 
 
Kisplyx 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. 
 
Kisplyx 10 mg hard capsules 
A yellow body and yellowish-red cap, approximately 14.3 mm in length, marked in black ink with “Є” on 
the cap, and “LENV 10 mg” on the body. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Kisplyx is indicated in combination with everolimus for the treatment of adult patients with advanced renal 
cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF)-targeted therapy. 
 
4.2 Posology and method of administration 
 
Kisplyx treatment should be initiated and supervised by a health care professional experienced in the use of 
anticancer therapies. 
 
Posology 
The recommended daily dose of lenvatinib is 18 mg (one 10 mg capsule and two 4 mg capsules) once daily 
in combination with 5 mg of everolimus once daily. The daily doses of lenvatinib and, if necessary, 
everolimus are to be modified as needed according to the dose/toxicity management plan.  
 
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 there is clinical benefit or until unacceptable toxicity occurs. 
 



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Optimal medical management (i.e. treatment or therapy) for nausea, vomiting, and diarrhoea should be 
initiated prior to any lenvatinib therapy interruption or dose reduction; however, gastrointestinal toxicity 
should be actively treated in order to reduce the risk of development of renal impairment or renal failure (see 
section 4.4 Renal failure and impairment). 
 
Dose adjustment 
Management of adverse reactions may require dose interruption, adjustment, or discontinuation of 
the combination therapy (see section 4.4). Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally 
do not warrant interruption of the combination, unless intolerable to the patient despite optimal management. 
Severe (e.g., Grade 3) or intolerable adverse reactions require interruption of the combination of medicines 
until improvement of the reaction to Grade 0-1 or baseline. 
 
For toxicities thought to be related to lenvatinib (see Table 1), 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 2.  
 
For toxicities thought to be related to everolimus, treatment should be interrupted, reduced to alternate day 
dosing, or discontinued (see the everolimus SmPC for advice on specific adverse reactions).  
 
For toxicities thought to be related to both lenvatinib and everolimus, lenvatinib should be reduced (see 
Table 2) prior to reducing everolimus.  
 
Treatment should be discontinued in case of life-threatening reactions (e.g., Grade 4) with the exception of 
laboratory abnormalities judged to be non-life-threatening, in which case they should be managed as severe 
reactions (e.g., Grade 3).  
 
Grades are based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE). 
 
Table 1  Adverse reactions requiring dose modification of lenvatinib 
Adverse reaction Severity Action Dose reduce and  

resume lenvatinib 

Hypertension Grade 3  
(despite optimal antihypertensive 
therapy) 

Interrupt Resolves to Grade 0, 1 or 2. 
See detailed guidance  
in Table 3 in section 4.4. 

Grade 4 Discontinue Do not resume 

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

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

Renal impairment or 
failure 
 

Grade 3 Interrupt  Resolves to Grade 0-1 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 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 



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Table 1  Adverse reactions requiring dose modification of lenvatinib 
Adverse reaction Severity Action Dose reduce and  

resume lenvatinib 

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) 

 
Table 2 Dose modifications from recommended lenvatinib daily dose a 

Dose level Daily dose Number of capsules 
Recommended daily dose 18 mg orally once daily  One 10 mg capsule plus two 4 mg capsules  
First dose reduction 14 mg orally once daily One 10 mg capsule plus one 4 mg capsule  
Second dose reduction 10 mg orally once daily One 10 mg capsule  
Third dose reduction 8 mg orally once daily Two 4 mg capsules  
a Limited data are available for doses below 8 mg 
 
Special populations 
No data with the combination are available for most of the special populations. The following information is 
derived from the clinical experience on single agent lenvatinib in patients with differentiated thyroid cancer 
(DTC; see Lenvima SmPC). 
 
All patients other than those with severe hepatic or renal impairment (see below) should initiate treatment at 
the recommended dose of 18 mg of lenvatinib with 5 mg of everolimus taken once daily, 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 
No data with the combination is available in patients with hepatic impairment. No adjustment of starting 
dose of the combination is required on the basis of hepatic function in patients with mild (Child-Pugh A) or 
moderate (Child-Pugh B) hepatic impairment. In patients with severe (Child-Pugh C) hepatic impairment, 
the recommended starting dose of lenvatinib is 10 mg taken once daily in combination with the dose of 
everolimus recommended for patients with severe hepatic impairment in the everolimus SmPC. Further dose 
adjustments may be necessary on the basis of individual tolerability. The combination should be used in 
patients with severe hepatic impairment only if the anticipated benefit exceeds the risk. Refer also to 
section 4.8, Other special populations. 
 
Patients with renal impairment 
No adjustment of starting dose is required on the basis of renal function in patients with mild or moderate 
renal impairment. In patients with severe renal impairment, the recommended starting dose is 10 mg of 
lenvatinib with 5 mg of everolimus 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. 
 



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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). 
 
Body weight below 60 kg 
No adjustment of starting dose is required on the basis of body weight. Limited data are available on patients 
with a body weight below 60 kg with RCC (see also section 4.8, Other special populations). 
 
Patients with high ECOG performance status 
Patients with an ECOG (Eastern Cooperative Oncology Group) performance status of 2 or higher were 
excluded from the RCC study (see section 5.1). Benefit-risk in these patients has not been evaluated. 
 
Method of administration 
Lenvatinib is for oral use. The capsules should be taken at about the same time each day, with or without 
food (see section 5.2). The capsules can 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).  
 
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 antihypertensive should be started when elevated BP is observed. For 
those patients already on antihypertensive medication, the dose of the current agent may be increased, if 
appropriate, or one or more agents of a different class of antihypertensive should be added. When necessary, 
manage hypertension as recommended in Table 3.  
 



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Table 3  Recommended management of hypertension 
 
Blood pressure (BP) level 

 
Recommended action 

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

 
Continue lenvatinib and initiate antihypertensive therapy, if 
not already receiving 

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

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

 
1. Withhold lenvatinib 
2. When systolic BP ≤150 mmHg, diastolic BP 

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

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

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

 
Aneurysms and artery dissections 
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of 
aneurysms and/or artery dissections. Before initiating lenvatinib, this risk should be carefully considered in 
patients with risk factors such as hypertension or history of aneurysm. 
 
Women of childbearing potential 
Women of childbearing potential must use highly effective contraception while taking lenvatinib and for one 
month after stopping treatment (see section 4.6). It is currently unknown if lenvatinib increases the risk of 
thromboembolic events when combined with oral contraceptives. 
 
Proteinuria 
Proteinuria has been reported in patients treated with lenvatinib, usually occurring early in the course of 
treatment (see section 4.8, 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. 
 
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. Caution should be taken in patients 
receiving agents acting on the renin-angiotensin aldosterone system given a potentially higher risk for acute 
renal failure with the combination treatment. Dose interruptions, adjustments, or discontinuation may be 
necessary (see section 4.2). 
 
If patients have severe renal impairment, the initial dose of lenvatinib should be adjusted (see sections 4.2 
and 5.2). 
 
Cardiac dysfunction 
Cardiac failure (<1%) and decreased left ventricular ejection fraction have been reported in patients treated 
with lenvatinib (see section 4.8, 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). 
 



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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). 
 
Hepatotoxicity 
Liver-related adverse reactions most commonly reported in patients treated with lenvatinib included 
increases in alanine aminotransferase, increases in aspartate aminotransferase, and increases in blood 
bilirubin. Hepatic failure and acute hepatitis (<1%; see section 4.8, Description of selected adverse reactions) 
have been reported in patients treated with lenvatinib. The hepatic failure cases were generally reported in 
patients with progressive liver metastases. Liver function tests should be monitored before initiation of 
treatment, then every 2 weeks for the first 2 months and monthly thereafter during treatment. In the case of 
hepatotoxicity, dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2). 
 
If patients have severe hepatic impairment, the initial dose of lenvatinib should be adjusted (see sections 4.2 
and 5.2). 
 
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. 
 
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.  
 
In the case of bleeding, dose interruptions, adjustments, or discontinuation may be required (see Section 4.2, 
Table 2). 
 
Gastrointestinal perforation and fistula formation 
Gastrointestinal perforation or fistulae have been reported in patients treated with lenvatinib (see 
section 4.8). In most cases, gastrointestinal perforation and fistulae occurred in patients with risk factors such 
as prior surgery or radiotherapy. In the case of a gastrointestinal perforation or fistula, dose interruptions, 
adjustments, or discontinuation may be necessary (see section 4.2). 
 
Non-Gastrointestinal fistula 
Patients may be at increased risk for the development of fistulae when treated with lenvatinib. Cases of 
fistula formation or enlargement that involve other areas of the body than stomach or intestines were 
observed in clinical trials and in post-marketing experience (e.g. tracheal, tracheo-oesophageal, oesophageal, 
cutaneous, female genital tract fistulae). In addition, pneumothorax has been reported with and without clear 
evidence of a bronchopleural fistula. Some reports of fistula and pneumothorax occurred in association with 



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tumour regression or necrosis. Prior surgery and radiotherapy may be contributing risk factors. Lung 
metastases may also increase the risk of pneumothorax. Lenvatinib should not be started in patients with 
fistulae to avoid worsening and lenvatinib should be permanently discontinued in patients with oesophageal 
or tracheobronchial tract involvement and any Grade 4 fistula (see section 4.2); limited information is 
available on the use of dose interruption or reduction in management of other events, but worsening was 
observed in some cases and caution should be taken. Lenvatinib may adversely affect the wound healing 
process as do other agents of the same class. 
 
QT interval prolongation 
QT/QTc interval prolongation has been reported at a higher incidence in patients treated with lenvatinib than 
in patients treated with placebo (see section 4.8, Description of selected adverse reactions). 
Electrocardiograms should be monitored in all patients with a special attention for those with congenital long 
QT syndrome, congestive heart failure, bradyarrhythmics, and those taking medicinal products known to 
prolong the QT interval, including Class Ia and III antiarrhythmics. Lenvatinib should be withheld in the 
event of development of QT interval prolongation greater than 500 ms. Lenvatinib should be resumed at a 
reduced dose when QTc prolongation is resolved to < 480 ms or baseline. 
 
Electrolyte disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia increase the risk of QT 
prolongation; therefore electrolyte abnormalities should be monitored and corrected in all patients before 
starting treatment. Periodic monitoring of ECG and electrolytes (magnesium, potassium and calcium) should 
be considered during treatment. Blood calcium levels should be monitored at least monthly and calcium 
should be replaced as necessary during lenvatinib treatment. Lenvatinib dose should be interrupted or dose 
adjusted as necessary depending on severity, presence of ECG changes, and persistence of hypocalcaemia. 
 
Impairment of thyroid stimulating hormone suppression / Thyroid dysfunction 
Hypothyroidism has been reported in patients treated with lenvatinib (see section 4.8, 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. 
 
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. 
 
Wound Healing Complications 
No formal studies of the effect of lenvatinib on wound healing have been conducted. Impaired wound 
healing has been reported in patients receiving lenvatinib. Temporary interruption of lenvatinib should be 
considered in patients undergoing major surgical procedures. There is limited clinical experience regarding 
the timing of reinitiation of lenvatinib following a major surgical procedure. Therefore, the decision to 
resume lenvatinib following a major surgical procedure should be based on clinical judgment of adequate 
wound healing. 
 
Osteonecrosis of the jaw (ONJ) 
Cases of ONJ have been reported in patients treated with lenvatinib. Some cases were reported in patients 
who had received prior or concomitant treatment with antiresorptive bone therapy, and/or other angiogenesis 
inhibitors, e.g. bevacizumab, TKI, mTOR inhibitors. Caution should therefore be exercised when lenvatinib 
is used either simultaneously or sequentially with antiresorptive therapy and/or other angiogenesis inhibitors. 
 
Invasive dental procedures are an identified risk factor. Prior to treatment with lenvatinib, a dental 
examination and appropriate preventive dentistry should be considered. In patients who have previously 



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received or are receiving intravenous bisphosphonates, invasive dental procedures should be avoided if 
possible (see section 4.8). 
 
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 of 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 
 
CYP3A4 substrates 
A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma concentrations of 
midazolam (a sensitive CYP3A and Pgp substrate) were not altered in the presence of lenvatinib. No 
significant drug-drug interaction is therefore expected between lenvatinib and other CYP3A4/Pgp substrates. 
 
Oral contraceptives 
It is currently unknown whether lenvatinib may reduce the effectiveness of hormonal contraceptives, and 
therefore women using oral hormonal contraceptives should add a barrier method (see section 4.6). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/ Contraception in females 
Women of childbearing potential should avoid becoming pregnant and use highly effective contraception 
while on treatment with lenvatinib and for at least one month after finishing treatment. It is currently 
unknown whether lenvatinib may reduce the effectiveness of hormonal contraceptives, and therefore women 
using oral hormonal contraceptives should add a barrier method. 
 
Pregnancy 
There are no data on the use of lenvatinib in pregnant women. Lenvatinib was embryotoxic and teratogenic 
when administered to rats and rabbits (see section 5.3). 
 
Lenvatinib should not be used during pregnancy unless clearly necessary and after a careful consideration of 
the needs of the mother and the risk to the foetus. 
 
Breast-feeding 
It is not known whether lenvatinib is excreted in human milk. Lenvatinib and its metabolites are excreted in 
rat milk (see section 5.3).  
 
A risk to newborns or infants cannot be excluded and, therefore, lenvatinib is contraindicated during 
breast-feeding (see section 4.3). 
 
Fertility 
Effects in humans are unknown. However, testicular and ovarian toxicity has been observed in rats, dogs, 
and monkeys (see section 5.3). 
 



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4.7 Effects on ability to drive and use machines 
 
Lenvatinib has a minor influence on the ability to drive and use machines, due to undesirable effects such as 
fatigue and dizziness. Patients who experience these symptoms should use caution when driving or operating 
machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety profile of lenvatinib in combination with everolimus is based on data from 62 subjects, allowing 
characterisation only of common adverse drug reactions in RCC patients. The adverse reactions presented in 
this section are based on the combined safety data of 62 RCC patients (see section 5.1) and 458 DTC patients 
(see Lenvima SmPC).  
 
The most frequently reported adverse reactions in the RCC and DTC patient populations (occurring in ≥30% 
of patients) were diarrhoea (80.6%), hypertension (70.1%)*, fatigue (59.7%), decreased appetite (53.7%), 
weight decreased (52.6%)*, vomiting (48.4%), nausea (45.2%), proteinuria (38.9%)*, stomatitis (36.9%)*, 
headache (35.8%)*, dysphonia (35.6%)*, palmar-plantar erythrodysaesthesia syndrome (PPE) (34.1%)*, 
peripheral oedema (33.9%), and hypercholesterolemia (30.6%). Hypertension and proteinuria tend to occur 
early during lenvatinib treatment (see sections 4.4 and 4.8, Description of selected adverse reactions; the 
asterisked frequencies are from the DTC patient population). 
 
The most important serious adverse reactions were renal failure and impairment (11.3%), 
arterial thromboembolisms (3.9%)*, cardiac failure (1.6%), cerebral haemorrhage (1.6%), intracranial 
tumour haemorrhage (0.7%)*, PRES / RPLS (0.2%)*, and hepatic failure (0.2%)* (the asterisked frequencies 
are from the DTC patient population).  
 
In the RCC study (see section 5.1), adverse reactions led to dose reductions in 67.7% of patients and 
18 (29.0%) patients discontinued the treatment. The most common adverse reactions (≥5%) resulting in dose 
reductions in the lenvatinib plus everolimus treated group were diarrhoea (21.0%), thrombocytopenia 
(6.5%), and vomiting (6.5%). 
 
Tabulated list of adverse reactions for RCC and DTC studies 
Similar adverse reactions were observed in clinical trials in RCC and DTC. Adverse reactions that occur 
more frequently with combination therapy compared to lenvatinib monotherapy are hypothyroidism, 
(including increased blood thyroid stimulating hormone), hypercholesterolaemia, and severe diarrhoea.  
 
Adverse reactions observed in clinical trials and reported from post-marketing use of lenvatinib are listed in 
Table 4. 
 
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 4  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  
 

Lymphopeniaa Splenic infarction  



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System Organ 
Class 
(MedDRA 
terminology*) 

Very Common Common Uncommon 

 

Not known 

Endocrine 
disorders 

Hypothyroidism**  
Blood thyroid stimulating 

hormone increased‡** 

   

Metabolism and 
nutrition disorders 

Hypocalcaemia‡ 

Hypercholesterolaemiab**  
 

Hypokalaemia  
Decreased appetite 
Weight decreased 

Dehydration 
Hypomagnesaemiab 

 

  

Psychiatric 
disorders 

Insomnia    

Nervous system 
disorders 

Dizziness 
Headache 
Dysgeusia 

Cerebrovascular accident  Posterior 
reversible 

encephalopathy 
syndrome 

Monoparesis 
Transient 

ischaemic attack 

 

Cardiac disorders  Myocardial infarctionc,† 

Cardiac failure 
Electrocardiogram QT 

prolonged 
Ejection fraction decreased 

  

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 

Lipase increased 
Amylase increased 

 

Pancreatitis  

Hepatobiliary 
disorders 

 Aspartate aminotransferase 
increased‡ 

Hypoalbuminaemia‡ 
Alanine aminotransferase 

increased‡ 
Blood alkaline phosphatase 

increased 
Hepatic function abnormal 

Gamma-glutamyltransferase 
increasedk 

Blood bilirubin increased‡  

Cholecystitis 

Hepatocellular 
damage/hepatitisi 

 



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System Organ 
Class 
(MedDRA 
terminology*) 

Very Common Common Uncommon 

 

Not known 

Skin and 
subcutaneous 
tissue disorders 

Palmar-plantar 
erythrodysaesthesia 

syndrome 
Palmar erythema 

Rash 
Alopecia 

Hyperkeratosis   

Musculoskeletal 
and connective 
tissue disorders 

Back pain 
Arthralgia 
Myalgia 

Pain in extremity 
Musculoskeletal pain 

 Osteonecrosis of 
the jaw 

 

Renal and urinary 
disorders 

Proteinuria‡ Renal failure j, †, ‡ 

Renal impairment‡ 
Blood creatinine increased 

Blood urea increased 

Nephrotic 
syndrome 

 

General disorders 
and 
administration 
site conditions 

Fatigue 
Asthenia 

Oedema peripheral 

Malaise Impaired 
healing*** 

Non-
gastrointestinal 

fistulak 

*:  Medical Dictionary for Regulatory Activities (MedDRA) version 17.1. Preferred terms have been 
reassigned to the SOC most relevant to the target organ. 

**: These adverse reactions occur more frequently with combination therapy compared to lenvatinib 
monotherapy.  

***: 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. Lymphopenia includes 

 lymphopenia and decreased lymphocyte count. 
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: Haemorrhage includes: epistaxis, haemoptysis, haematuria, contusion, haematochezia, gingival 

bleeding, petechiae, pulmonary haemorrhage, rectal haemorrhage, blood urine present, haematoma, 
vaginal haemorrhage, conjunctival haemorrhage, haemorrhoidal haemorrhage, intracranial tumour 
haemorrhage, laryngeal haemorrhage, ecchymosis, increased tendency to bruise, post procedural 
haemorrhage, purpura, skin haemorrhage, aneurysm ruptured, arterial haemorrhage, eye haemorrhage, 
gastric haemorrhage, gastroduodenitis haemorrhagic, gastrointestinal haemorrhage, haematemesis, 
haemorrhage, haemorrhagic stroke, melaena, metrorrhagia, nail bed bleeding, haemothorax, 
postmenopausal haemorrhage, proctitis haemorrhagic, renal haematoma, splenic haemorrhage, splinter 
haemorrhages, subarachnoid haemorrhage, tracheal haemorrhage, tumour haemorrhage. 

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

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

g: Oral inflammation includes: aphthous ulcer, stomatitis, glossitis, mouth ulceration, and mucosal 
inflammation.  

h: Oral pain includes: oral pain, glossodynia, and oropharyngeal pain. 
i: Hepatocellular damage and hepatitis includes: drug-induced liver injury, hepatic steatosis, and 

cholestatic liver injury. 
j: Renal failure includes: acute prerenal failure, renal failure, acute kidney injury, and renal tubular 

necrosis. 
k: 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. 



13 

 
Description of selected adverse reactions 
 
Hypertension (see section 4.4) 
In the RCC study (see section 5.1), hypertension was reported in 41.9% of patients in the lenvatinib plus 
everolimus-treated group (the incidence of Grade 3 or Grade 4 hypertension was 12.9%) and 10.0% of 
patients in the everolimus-treated group (the incidence of Grade 3 or Grade 4 hypertension was 2.0%). The 
median time to onset was 4.9 weeks (any grade) and 6.9 weeks (Grade ≥ 3) in the lenvatinib plus 
everolimus-treated group.  
 
In the DTC study (see Lenvima SmPC), hypertension (including hypertension, hypertensive crisis, blood 
pressure diastolic increased, and blood pressure increased) was reported in 72.8% of lenvatinib-treated 
patients and 16.0% of patients in the placebo-treated group. The median time to onset in lenvatinib-treated 
patients was 16 days. Reactions of Grade 3 or higher (including 1 reaction of Grade 4) occurred in 44.4% of 
lenvatinib-treated patients compared with 3.8% of placebo-treated patients. The majority of cases recovered 
or resolved following dose interruption or reduction, which occurred in 13.0% and 13.4% of patients, 
respectively. In 1.1% of patients, hypertension led to permanent treatment discontinuation. 
 
Proteinuria (see section 4.4) 
In the RCC study (see section 5.1), proteinuria was reported in 30.6% of patients in the lenvatinib plus 
everolimus-treated group (8.1% were Grade ≥ 3) and 14.0% of patients in the everolimus-treated group 
(2.0% were Grade ≥3). The median time to onset of proteinuria was 6.1 weeks (any grade) and 20.1 weeks 
(Grade ≥ 3) in the lenvatinib plus everolimus-treated group. Proteinuria led to permanent treatment 
discontinuation in 4.8% of patients. 
 
In the DTC study (see Lenvima SmPC), 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. 
 
Renal failure and impairment (see section 4.4) 
In the RCC study (see section 5.1), 8.1% of patients in the lenvatinib plus everolimus treated group 
developed renal failure and 3.2% developed renal impairment, (9.7% of patients had a Grade 3 event of renal 
failure or impairment). In the everolimus monotherapy group 2.0% of patients developed renal failure (2.0% 
were Grade 3). 
 
In the DTC study (see Lenvima SmPC), 5.0% of patients developed renal failure and 1.9% developed renal 
impairment, (3.1% of patients had a Grade ≥ 3 event of renal failure or impairment). In the placebo group 
0.8% of patients developed renal failure or impairment (0.8% were Grade ≥ 3). 
 
Cardiac dysfunction (see section 4.4) 
In the RCC study (see section 5.1), decreased ejection fraction/cardiac failure was reported in 4.8% of 
patients (3.2% were Grade ≥ 3) in the lenvatinib plus everolimus treated group, and 4.0% in the everolimus 
group (2.0% were Grade ≥ 3). The median time to onset of decreased ejection fraction and cardiac failure 
was 15.7 weeks (any grade) and 32.8 weeks (Grade ≥ 3) in the lenvatinib plus everolimus-treated group.  
 
In the DTC study (see Lenvima SmPC), 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). 
 
Posterior reversible encephalopathy syndrome (PRES) / Reversible posterior leucoencephalopathy syndrome 
(RPLS) (see section 4.4) 
In the RCC study (see section 5.1), there was 1 event of PRES (Grade 3) in the lenvatinib-treated group, 
occurring after 18.4 weeks of treatment. There were no reports in the lenvatinib plus everolimus or 
everolimus monotherapy groups.  



14 

 
In the DTC study (see Lenvima SmPC), there was 1 event of PRES (Grade 2) in the lenvatinib-treated group 
and no reports in the placebo group. 
 
Amongst 1,166 patients treated with lenvatinib, there were 4 cases (0.3%) of PRES (0.3% were Grade 3 or 
4), all of which resolved after treatment and/or dose interruption, or permanent discontinuation. 
 
Hepatotoxicity (see section 4.4) 
In the RCC study (see section 5.1), the most commonly reported liver-related adverse reactions in the 
lenvatinib plus everolimus-treated group were elevations of liver enzyme levels, including increases in 
alanine aminotransferase (9.7%), aspartate aminotransferase (4.8%), alkaline phosphatase (4.8%), and blood 
bilirubin (3.2%). The median time to onset of liver events was 6.7 weeks (any grade) and 14.2 weeks 
(Grade ≥ 3) in the lenvatinib plus everolimus-treated group. Grade 3 liver-related reactions occurred in 3.2% 
of lenvatinib plus everolimus-treated patients. Liver-related reactions led to dose interruptions and reductions 
in 1.6% and 1.6% of patients, respectively, and to permanent discontinuation in 3.2% of patients. 
 
In the DTC study (see Lenvima SmPC), 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. 
 
Arterial thromboembolisms (see section 4.4) 
In the RCC study (see section 5.1), 1.6% of patients in the lenvatinib plus everolimus-treated group reported 
arterial thromboembolic events. The time to onset was 69.6 weeks. In the everolimus group, 6.0% of patients 
reported an arterial thromboembolism (4.0% were Grade ≥ 3). In the DTC study (see Lenvima SmPC), 
arterial thromboembolic events were reported in 5.4% of lenvatinib-treated patients and 2.3% of patients in 
the placebo group. 
 
Amongst 1,166 patients treated with lenvatinib, there were 5 cases (0.4%) of arterial thromboembolisms 
(3 cases of myocardial infarction and 2 cases of cerebrovascular accident) with a fatal outcome. 
 
Haemorrhage (see section 4.4) 
In the RCC study (see section 5.1), haemorrhage was reported in 38.7% (8.1% were Grade ≥ 3) of patients in 
the lenvatinib plus everolimus-treated group. Reactions that occurred at an incidence of ≥2.0% were: 
epistaxis (22.6%), haematuria (4.8%), haematoma (3.2%), and gastric haemorrhage (3.2%). The median time 
to first onset of was 10.2 weeks (any grade) and 7.6 weeks (Grade ≥ 3) in the lenvatinib plus 
everolimus-treated group. The incidence of serious haemorrhage was 4.8% (cerebral haemorrhage, gastric 
haemorrhage and haemarthrosis). Discontinuation due to haemorrhagic events occurred in 3.2% of patients 
in the lenvatinib plus everolimus-treated group. There was one case of fatal cerebral haemorrhage in the 
lenvatinib plus everolimus-treated group and one case of fatal intracranial haemorrhage in the 
lenvatinib-treated group. 
 
In the DTC study (see Lenvima SmPC), 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. 



15 

 
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). 
 
Amongst 1,166 patients treated with lenvatinib, Grade 3 or greater haemorrhage was reported in 2% of 
patients, 3 patients (0.3%) had a Grade 4 haemorrhage and 5 patients (0.4%) had a Grade 5 reaction 
including arterial haemorrhage, haemorrhagic stroke, intracranial tumour haemorrhage, haemoptysis and 
tumour haemorrhage. 
 
Hypocalcaemia (see section 4.4, QT interval prolongation) 
In the RCC study (see section 5.1), hypocalcaemia was reported in 8.1% of patients in the lenvatinib plus 
everolimus-treated group (3.2% were Grade ≥ 3) and 4.0% of patients in the everolimus-treated group (none 
were Grade ≥ 3). The median time to onset of hypocalcaemia was 28.3 weeks (any grade) and 45.9 weeks 
(Grade ≥ 3) in the lenvatinib plus everolimus-treated group. There was one Grade 4 TEAE. No events of 
hypocalcaemia required dose reduction or interruption, and no patients discontinued treatment due to 
hypocalcaemia.  
 
In the DTC study (see Lenvima SmPC), 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. 
 
Gastrointestinal perforation and fistula formation (see section 4.4) 
In the RCC study (see section 5.1), 1.6% of cases of perforated appendicitis (of Grade 3) occurred in the 
lenvatinib plus everolimus-treated group; there were no reports in the lenvatinib or everolimus groups.  
 
In the DTC study, events of gastrointestinal perforation or fistula were reported in 1.9% of lenvatinib-treated 
patients and 0.8% of patients in the placebo group. 
 
Non-Gastrointestinal fistulae (see section 4.4) 
Lenvatinib use has been associated with cases of fistulae including reactions resulting in death. Reports of 
fistulae that involve areas of the body other than stomach or intestines were observed across various 
indications. Reactions were reported at various time points during treatment ranging from two weeks to 
greater than 1 year from initiation of lenvatinib, with a median latency of about 3 months. 
 
QT interval prolongation (see section 4.4) 
In the RCC study (see section 5.1), QTc interval increases greater than 60 ms were reported in 11% of 
patients in the lenvatinib plus everolimus-treated group. The incidence of QTc interval greater than 500 ms 
was 6% in the lenvatinib plus everolimus-treated group. No reports of QTc interval prolongation greater than 
500 ms or increases greater than 60 ms occurred in the everolimus-treated group.  
In the DTC study (see Lenvima SmPC), 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. 
 
Blood thyroid stimulating hormone increased (see section 4.4 Impairment of thyroid stimulating hormone 
suppression / Thyroid dysfunction) (see section 4.4) 
In the RCC study (see section 5.1), hypothyroidism occurred in 24% of patients in the lenvatinib plus 
everolimus-treated group and 2% of patients in the everolimus-treated group. All events of hypothyroidism 
in the lenvatinib plus everolimus-treated group were of Grade 1 or 2. In patients with a normal TSH at 
baseline, an elevation of TSH level was observed post baseline in 60.5% of lenvatinib plus 
everolimus-treated patients as compared with none in patients receiving everolimus alone. 
 



16 

In the DTC study (see Lenvima SmPC), 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. 
 
Diarrhoea (see section 4.4) 
In the RCC study (see section 5.1), diarrhoea was reported in 80.6% of patients in the lenvatinib plus 
everolimus-treated group (21.0% were Grade ≥ 3) and in 34.0% of patients in the everolimus-treated group 
(2.0% were Grade ≥ 3). The median time to onset was 4.1 weeks (any grade) and 8.1 weeks (Grade ≥ 3) in 
the lenvatinib plus everolimus-treated group. Diarrhoea was the most frequent cause of dose 
interruption/reduction and recurred despite dose reduction. Diarrhoea resulted in discontinuation in one 
patient. 
 
In the DTC study (see Lenvima SmPC), 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). 
 
Paediatric population 
See section 4.2 for information on paediatric use. 
 
Other special populations 
 
Elderly 
There are limited data on patients of age ≥75 years with RCC. However, in DTC, patients of age ≥75 years 
were more likely to experience Grade 3 or 4 hypertension, proteinuria, decreased appetite, and dehydration.  
 
Gender 
In patients with DTC, females had a higher incidence of hypertension (including Grade 3 or 4 hypertension), 
proteinuria, and PPE, while males had a higher incidence of decreased ejection fraction and gastrointestinal 
perforation and fistula formation. 
 
Ethnic origin 
There are limited data on Asian patients with RCC. However, in DTC Asian patients had a higher incidence 
than Caucasian patients of peripheral oedema, hypertension, fatigue, PPE, proteinuria, stomatitis, 
thrombocytopenia, and myalgia; while Caucasian patients had a higher incidence of diarrhoea, weight 
decreased, nausea, vomiting, constipation, asthenia, abdominal pain, pain in extremity, and dry mouth.  
 
Baseline hypertension 
In DTC, patients with baseline hypertension had a higher incidence of Grade 3 or 4 hypertension, 
proteinuria, diarrhoea, and dehydration, and experienced more serious cases of dehydration, hypotension, 
pulmonary embolism, malignant pleural effusion, atrial fibrillation, and GI symptoms (abdominal pain, 
diarrhoea, vomiting). In RCC, patients with baseline hypertension had a higher incidence of Grade 3 or 4 
dehydration, fatigue, and hypertension.  
 
Baseline diabetes 
In RCC, patients with baseline diabetes had a higher incidence of Grade 3 or 4 hypertension, 
hypertriglyceridemia and acute renal failure. 
 
Hepatic impairment 
There are limited data on patients with hepatic impairment in RCC. However in DTC, patients with baseline 
hepatic impairment had a higher incidence of hypertension and PPE, and a higher incidence of Grade 3 or 4 
hypertension, asthenia, fatigue, and hypocalcaemia compared with patients with normal hepatic function.  
 
Renal impairment 
In DTC, patients with baseline renal impairment had a higher incidence of Grade 3 or 4 hypertension, 
proteinuria, fatigue, stomatitis, oedema peripheral, thrombocytopenia, dehydration, prolonged 
electrocardiogram QT, hypothyroidism, hyponatraemia, blood thyroid stimulating hormone increased, 
pneumonia compared with subjects with normal renal function. These patients also had a higher incidence of 



17 

renal reactions and a trend towards a higher incidence of liver reactions. In RCC, patients with baseline renal 
impairment had a higher incidence of Grade 3 fatigue. 
 
Patients with body weight <60 kg 
There are limited data on patients with body weight <60 kg in RCC. However in DTC patients with low 
body weight (<60 kg) had a higher incidence of PPE, proteinuria, of Grade 3 or 4 hypocalcaemia and 
hyponatraemia, and a trend towards a higher incidence of Grade 3 or 4 decreased appetite. 
 
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 also occurred in clinical trials. The most frequently 
observed adverse drug reactions at these doses were hypertension, nausea, diarrhea, 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. 
 
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 
 
Mechanism of action 
Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of 
vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 
(FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth 
factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor (PDGF) receptor PDGFRα, 
KIT, and RET. The combination of lenvatinib and everolimus showed increased antiangiogenic and 
antitumour activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and 
VEGF signalling in vitro and tumour volume in mouse xenograft models of human renal cell cancer greater 
than each drug alone. 
 
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. 
 
The mechanism of action for the worsening of hypercholesterolemia with the combination has not been 
studied directly and is not fully elucidated. 
 
Although not studied directly, the MOA for the worsening of diarrhoea with the combination is postulated to 
be mediated by the impairment of intestinal function related to the MOAs for the individual agents – 
VEGF/VEGFR and c-KIT inhibition by lenvatinib coupled with mTOR/NHE3 inhibition by everolimus. 
 

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


18 

Clinical efficacy and safety 
A multicentre, randomised, open-label, trial was conducted to determine the safety and efficacy of lenvatinib 
administered alone or in combination with everolimus in subjects with unresectable advanced or metastatic 
RCC. The study consisted of a Phase 1b dose finding and a Phase 2 portion. The Phase 1b portion included 
11 patients who received the combination of 18 mg of lenvatinib plus 5 mg of everolimus. The Phase 2 
portion enrolled a total of 153 patients with unresectable advanced or metastatic RCC following 1 prior 
VEGF-targeted treatment. A total of 62 patients received the combination of lenvatinib and everolimus at the 
recommended dose. Patients were required, among others, to have histological confirmation of predominant 
clear cell RCC, radiographic evidence of disease progression according to Response Evaluation Criteria in 
Solid Tumours Version 1.1 (RECIST 1.1), one prior VEGF-targeted therapy and Eastern Cooperative 
Oncology Group (ECOG) Performance Status (PS) of 0 or 1. 
 
Patients were randomly allocated to one of 3 arms: 18 mg of lenvatinib plus 5 mg of everolimus, 24 mg of 
lenvatinib or 10 mg of everolimus using a 1:1:1 ratio. Patients were stratified by haemoglobin level 
(≤13 g/dL vs. >13 g/dL for males and ≤11.5 g/dL vs >11.5 g/dL for females) and corrected serum calcium 
(≥10 mg/dL vs. <10 mg/dL). The median of average daily dose in the combination arm per subject was 
13.5 mg of lenvatinib (75.0% of the intended dose of 18 mg) and 4.7 mg of everolimus (93.6% of the 
intended dose of 5 mg). The final dose level in the combination arm was 18 mg for 29% of patients, 14 mg 
for 31% of patients, 10 mg for 23% of patients, 8 mg for 16% of patients and 4 mg for 2% of patients. 
 
Of the 153 patients randomly allocated, 73% were male, the median age was 61 years, 37% were 65 years or 
older, 7% were 75 years or older, and 97% were Caucasian. Metastases were present in 95% of the patients 
and unresectable advanced disease was present in 5%. All patients had a baseline ECOG PS of either 0 
(55%) or 1 (45%) with similar distribution across the 3 treatment arms. Memorial Sloan Kettering Cancer 
Centre (MSKCC) poor risk was observed in 39% of patients in the lenvatinib plus everolimus arm, 44% in 
the lenvatinib arm and 38% in the everolimus arm. International mRCC Database Consortium (IMDC) poor 
risk was observed in 20% of patients in the lenvatinib plus everolimus arm, 23% in the lenvatinib arm, and 
24% in the everolimus arm. The median time from diagnosis to first dose was 32 months in the lenvatinib 
plus everolimus-treatment arm, 33 months in the lenvatinib arm and 26 months in the everolimus arm. All 
patients had been treated with 1 prior VEGF-inhibitor; 65% with sunitinib, 23% with pazopanib, 4% with 
tivozanib, 3% with bevacizumab, and 2% each with sorafenib or axitinib. 
 
The primary efficacy outcome measure, based on investigator assessed tumour response, was 
progression-free survival (PFS) of the lenvatinib plus everolimus arm vs the everolimus arm and of the 
lenvatinib arm vs the everolimus arm. Other efficacy outcome measures included overall survival (OS) and 
investigator-assessed objective response rate (ORR). Tumour assessments were evaluated according to 
RECIST 1.1.  
 
The lenvatinib plus everolimus arm showed a statistically significant and clinically meaningful improvement 
in PFS compared with the everolimus arm (see Table 5 and Figure 1). Based on the results of a post-hoc 
exploratory analysis in a limited number of patients per subgroup, the positive effect on PFS was seen 
regardless of which prior VEGF-targeted therapy was used: sunitinib (Hazard ratio [HR] = 0.356 [95% CI: 
0.188, 0.674] or other therapies (HR = 0.350 [95% CI: 0.148, 0.828]). The lenvatinib arm also showed an 
improvement in PFS compared with the everolimus arm. Overall survival was longer in the lenvatinib plus 
everolimus arm (see Table 5 and Figure 2). The study was not powered for the OS analysis. 
 
The treatment effect of the combination on PFS and ORR was also supported by a post-hoc retrospective 
independent blinded review of scans. The lenvatinib plus everolimus arm showed a statistically significant 
and clinically meaningful improvement in PFS compared with the everolimus arm. Results for ORR were 
consistent with that of the investigators’ assessments, 35.3% in the lenvatinib plus everolimus arm, with one 
complete response and 17 partial responses; no subject had an objective response in the everolimus arm (P < 
0.0001) in favour of the lenvatinib plus everolimus arm. 
 



19 

Table 5 Efficacy results in renal cell carcinoma 

 

lenvatinib 18 mg + 
everolimus 5 mg 

(N=51) 

lenvatinib 24 mg  
 

(N=52) 

everolimus 10 mg 
 

(N=50) 
Progression-free survival (PFS)a by Investigator Assessment 
Median PFS in months (95% CI) 14.6 (5.9, 20.1) 7.4 (5.6, 10.2) 5.5 (3.5, 7.1) 
Hazard Ratio (95% CI)b 

lenvatinib + everolimus vs everolimus 
0.40 (0.24, 0.67) - - 

P Value 
lenvatinib + everolimus vs everolimus 

0.0005 - - 

Progression-free survival (PFS)a by Post-hoc Retrospective Independent Review  
Median PFS in months (95% CI) 12.8 (7.4, 17.5) 9.0 (5.6, 10.2) 5.6 (3.6, 9.3) 
Hazard Ratio (95% CI)b 

lenvatinib + everolimus vs everolimus 
0.45 (0.26, 0.79) - - 

P Value 
lenvatinib + everolimus vs everolimus 

0.003 - - 

Overall Survivalc 

Number of deaths, n (%) 32 (63) 34 (65) 37 (74) 
Median OS in months (95% CI) 25.5 (16.4, 32.1) 19.1 (13.6, 26.2) 15.4 (11.8, 20.6) 
Hazard Ratio (95% CI) b 

lenvatinib + everolimus vs everolimus 
0.59 (0.36, 0.97) - - 

Objective Response Rate n (%) by Investigator Assessment 
Complete responses 1 (2) 0 0 
Partial responses 21 (41) 14 (27) 3 (6) 
Objective Response Rate 22 (43) 14 (27) 3 (6) 
Stable disease 21 (41) 27 (52) 31 (62) 
Duration of response, months, median 
(95% CI)  

13.0 (3.7, NE) 7.5 (3.8, NE) 8.5 (7.5, 9.4) 

Tumour assessment was based on RECIST 1.1 criteria. Data cut-off date = 13 Jun 2014 
Percentages are based on the total number of subjects in the Full Analysis Set within relevant treatment group. 
CI = confidence interval, NE = not estimable 
aPoint estimates are based on Kaplan-Meier method and 95% CIs are based on the Greenwood formula using log-log transformation. 
bStratified hazard ratio is based on a stratified Cox regression model including treatment as a covariate factor and haemoglobin and 
corrected serum calcium as strata. The Efron method was used for correction for tied events.  
cData cut-off date = 31 Jul 2015 
 

Figure 1: Kaplan-Meier Plot of Progression-Free Survival 
 (Investigator Assessment) 

 
 
 



20 

Figure 2: Kaplan-Meier Plot of Overall Survival 

 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with lenvatinib in 
all subsets of the paediatric population in Renal Cell Carcinoma (RCC). 
 
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 suggests that it is in the order 
of 85%. 
 
Distribution 
In vitro binding of lenvatinib to human plasma proteins is high and ranged from 98% to 99% 
(0.3 - 30 μg/mL, mesylate). 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, 
mesylate). 
 
In vitro studies indicate that lenvatinib is a substrate for P-gp and BCRP. Lenvatinib shows minimal or no 
inhibitory activities toward P-gp mediated and BCRP mediated transport activities. Similarly, no induction of 
P-gp mRNA expression was observed. Lenvatinib is not a substrate for OAT1, OAT3, OATP1B1, 
OATP1B3, OCT1, OCT2, or the BSEP. In human liver cytosol, lenvatinib did not inhibit aldehyde oxidase 
activity. 
 
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. 
 



21 

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. 
 
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 
Please see distribution section. 
 
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-fourth of the radiolabel were eliminated in the faeces and urine, respectively. The M3 
metabolite was the predominant analyte in excreta (~17% of the dose), followed by M2’ (~11% of the dose) 
and M2 (~4.4 of the dose). 
 
Linearity/non-linearity 
Dose proportionality and accumulation 
In patients with solid tumours administered single and multiple doses of lenvatinib once daily, exposure to 
lenvatinib (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). 
 
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. 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). 
 
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 



22 

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. 
 
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 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.  
 



23 

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. 
 
6.5 Nature and contents of container 
 
Polyamide/Aluminium/PVC/Aluminium blisters containing 10 capsules. Each carton contains 
30, 60, or 90hard capsules.Not all pack sizes may be marketed. 
 



24 

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) 
 
Kisplyx 4 mg hard capsules 
EU/1/16/1128/001 
EU/1/16/1128/003 
EU/1/16/1128/004 
 
Kisplyx 10 mg hard capsules 
EU/1/16/1128/002 
EU/1/16/1128/005 
EU/1/16/1128/006 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 25 August 2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
  



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 



26 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
Eisai Manufacturing Ltd. 
Mosquito Way 
Hatfield 
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 requirements for submission of periodic safety update reports for this medicinal product are set out in 
the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates 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. 

 



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



29 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kisplyx 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. 
 
 



30 

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/1/16/1128/001 (Pack size of 30 hard capsules) 
EU/1/16/1128/003 (Pack size of 60 hard capsules) 
EU/1/16/1128/004 (Pack size of 90 hard capsules) 
 
 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kisplyx 4 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



31 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kisplyx 4 mg hard capsules 
lenvatinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Eisai  
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



32 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kisplyx 10 mg hard capsules  
lenvatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 10 mg lenvatinib (as mesyilate). 
 
 
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. 
 
 



33 

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/1/16/1128/002 (Pack size of 30 hard capsules) 
EU/1/16/1128/005 (Pack size of 60 hard capsules) 
EU/1/16/1128/006 (Pack size of 90 hard capsules) 
 
 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kisplyx 10 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
 



34 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kisplyx 10 mg hard capsules 
lenvatinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Eisai 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



35 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



36 

 
Package leaflet: Information for the user 

 
Kisplyx 4 mg hard capsules 

Kisplyx 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 Kisplyx is and what it is used for  
2. What you need to know before you take Kisplyx 
3. How to take Kisplyx 
4. Possible side effects  
5. How to store Kisplyx 
6. Contents of the pack and other information 
 
 
1. What Kisplyx is and what it is used for 
 
What Kisplyx is 
Kisplyx is a medicine that contains the active substance lenvatinib. It is used in combination with everolimus 
to treat patients with advanced kidney cancer (advanced renal cell carcinoma) where other treatments 
(so-called “VEGF-targeted therapy”) have not helped stop the disease. 
 
How Kisplyx works 
Kisplyx 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 Kisplyx 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 Kisplyx 
 
Do not take Kisplyx 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). 
 
Warnings and precautions 
Talk to your doctor before taking Kisplyx if you: 
• have high blood pressure  
• are a woman able to become pregnant (see the section “Contraception, pregnancy and breast-feeding” 

below) 



37 

• 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 Kisplyx if you will be 

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

• are over 75 years old 
• belong to an ethnic group other than White or Asian  
• weigh less than 60 kg 
• have a history of abnormal passageways (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. 
• have or have had pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or 

a feeling of heaviness in the jaw, or loosening of a tooth.  You may be advised to have a dental check-
up before starting Kisplyx as bone damage in the jaw (osteonecrosis) has been reported in patients 
treated with Kisplyx.  If you need to undergo an invasive dental treatment or dental surgery, tell your 
dentist that you are being treated with Kisplyx, particularly when you are also receiving or have 
received injections of bisphosphonates (used to treat or prevent bone disorders). 

• are receiving or have received some medicines used to treat osteoporosis (antiresorptive medicines) or 
cancer medicines which alter formation of blood vessels (so called angiogenesis inhibitors), as the risk 
of bone damage in the jaw may be increased. 
 

 
Before taking Kisplyx, your doctor may carry out some blood 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 Kisplyx. You may need to have additional treatment with other medicines, to take 
a lower dose of Kisplyx, or to take extra care due to an increased risk of side effects. 
 
If you are not sure talk to your doctor before taking Kisplyx. 
 
Children and adolescents 
Kisplyx is not recommended for use in children and adolescents. The effects of Kisplyx in people younger 
than 18 years old are not known. 
 
Other medicines and Kisplyx 
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. 
• Use highly effective contraception while taking this medicine, and for at least one month after you 

finish treatment.  
• Do not take Kisplyx 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 Kisplyx, tell your doctor immediately. Your doctor 

will help you decide whether the treatment should be continued. 
• Do not breast-feed if you are taking Kisplyx. This is because the medicine passes into breast milk and 

may seriously harm your breastfed baby. 
 
Driving and using machines 
Kisplyx 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. 
 



38 

 
3. How to take Kisplyx 
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 
• The recommended daily dose of Kisplyx is 18 mg once a day (one 10 mg capsule and two 4 mg 

capsules) in combination with one 5 mg tablet of everolimus once a day. 
• If you have severe liver or kidney problems the recommended dose of Kisplyx is 10 mg once a day 

(1 capsule of 10 mg) in combination with one 5 mg tablet of everolimus once a day. 
• Your doctor may reduce your dose if you experience 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 capsules to avoid exposure to the contents of the capsule. 
 
How long to takeKisplyx 
You will usually carry on taking this medicine as long as you are getting benefit. 
 
If you take more Kisplyx than you should 
If you take more Kisplyx than you should, talk to a doctor or pharmacist straight away. Take the medicine 
pack with you. 
 
If you forget to take Kisplyx 
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. 
 
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 in 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. 



39 

• 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. 

• pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of 
 heaviness in the jaw, or loosening of a tooth - these could be signs of bone damage in the jaw 
 (osteonecrosis).  

 
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 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 
• high levels of protein in the urine 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 (hand-foot syndrome) 
• changes in blood test results for potassium levels (low), calcium levels (low), cholesterol (high) and 

thyroid stimulating hormone (high) 
• underactive thyroid (tiredness, weight gain, constipation, feeling cold, dry skin) 
• low levels of platelets in the blood which may lead to bruising and difficulty in wound healing 
 
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 gas in the bowel  
• heart problems or blood clots in the lungs (difficulty breathing, chest pain) or other organs 
• feeling unwell 
• stroke 
• inflammation of the gallbladder 
• anal fistula (a small channel that forms between the anus and the surrounding skin) 
• changes in blood test results for liver enzymes, white blood cells (low), blood magnesium (low) 
• 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 



40 

• inflammation of the pancreas 
• wound healing problems 
• bone damage in the jaw (osteonecrosis) 
 
Not Known (the following side effects have been reported since the marketing of lenvatinib but the 
frequency for them to occur is not known) 
• other types of fistulae (an abnormal connection between different organs in the body or from the skin 

to an underlying structure such as throat and windpipe). Symptoms would 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 Kisplyx 
 
• 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 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. 
 
 
6. Contents of the pack and other information 
 
What Kisplyx contains 
• The active substance is lenvatinib.  

− Kisplyx 4 mg hard capsules: - Each hard capsule contains 4 mg of lenvatinib (as mesylate). 
− Kisplyx 10 mg hard capsules: - Each hard capsule contains 10 mg of lenvatinib (as mesylate). 

 
• 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 Kisplyx looks like and contents of the pack 
• Kisplyx 4 mg hard capsule: 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. 
• Kisplyx 10 mg hard capsule: 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  
 

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


41 

Manufacturer 
Eisai Manufacturing Ltd 
Mosquito Way 
Hatfield 
Herts 
AL10 9SN 
United Kingdom. 
 
Or 
 
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) 800 158 58 
 
 

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) 800 158 58 
(Belgique/Belgien) 
 

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) 
 



42 

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) 

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

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

Slovenija 
Eisai GmbH 
Edmund-Rumpler-Straße 3  
60549 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) 
 

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
{'Title': '1. what kisplyx is and what it is used for', 'Section_Content': 'what kisplyx is kisplyx is a medicine that contains the active substance lenvatinib. it is used in combination with everolimus to treat patients with advanced kidney cancer (advanced renal cell carcinoma) where other treatments (so-called "vegf-targeted therapy") have not helped stop the disease. how kisplyx works kisplyx 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 kisplyx 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.', 'Entity_Recognition': [{'Text': 'kisplyx', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'a medicine', 'Type': 'TREATMENT', 'BeginOffset': 27, 'EndOffset': 37}, {'Id': 1, 'BeginOffset': 73, 'EndOffset': 83, 'Score': 0.9983657002449036, 'Text': 'lenvatinib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.437279611825943}]}, {'Id': 2, 'BeginOffset': 116, 'EndOffset': 126, 'Score': 0.9943109750747681, 'Text': 'everolimus', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'advanced kidney cancer', 'Type': 'PROBLEM', 'BeginOffset': 150, 'EndOffset': 172}, {'Text': 'advanced renal cell carcinoma', 'Type': 'PROBLEM', 'BeginOffset': 174, 'EndOffset': 203}, {'Text': 'other treatments', 'Type': 'TREATMENT', 'BeginOffset': 211, 'EndOffset': 227}, {'Text': 'vegf-targeted therapy', 'Type': 'TREATMENT', 'BeginOffset': 240, 'EndOffset': 261}, {'Text': 'the disease', 'Type': 'PROBLEM', 'BeginOffset': 285, 'EndOffset': 296}, {'Text': 'receptor tyrosine kinases', 'Type': 'TREATMENT', 'BeginOffset': 361, 'EndOffset': 386}, {'Text': 'new blood vessels', 'Type': 'PROBLEM', 'BeginOffset': 436, 'EndOffset': 453}, {'Id': 5, 'BeginOffset': 466, 'EndOffset': 472, 'Score': 0.5319892168045044, 'Text': 'oxygen', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'these proteins', 'Type': 'PROBLEM', 'BeginOffset': 519, 'EndOffset': 533}, {'Text': 'high amounts in cancer cells', 'Type': 'PROBLEM', 'BeginOffset': 552, 'EndOffset': 580}, {'Text': 'the cancer cells', 'Type': 'PROBLEM', 'BeginOffset': 646, 'EndOffset': 662}]}
{'Title': '2. what you need to know before you take kisplyx', 'Section_Content': 'do not take kisplyx 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). warnings and precautions talk to your doctor before taking kisplyx if you: have high blood pressure are a woman able to become pregnant (see the section "contraception, pregnancy and breast-feeding" below) 37 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 kisplyx if you will be undergoing a major surgical procedure as kisplyx may affect wound healing. kisplyx may be restarted once adequate wound healing is established. are over 75 years old belong to an ethnic group other than white or asian weigh less than 60 kg have a history of abnormal passageways (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. have or have had pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth. you may be advised to have a dental check- up before starting kisplyx as bone damage in the jaw (osteonecrosis) has been reported in patients treated with kisplyx. if you need to undergo an invasive dental treatment or dental surgery, tell your dentist that you are being treated with kisplyx, particularly when you are also receiving or have received injections of bisphosphonates (used to treat or prevent bone disorders). are receiving or have received some medicines used to treat osteoporosis (antiresorptive medicines) or cancer medicines which alter formation of blood vessels (so called angiogenesis inhibitors), as the risk of bone damage in the jaw may be increased. before taking kisplyx, your doctor may carry out some blood 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 kisplyx. you may need to have additional treatment with other medicines, to take a lower dose of kisplyx, or to take extra care due to an increased risk of side effects. if you are not sure talk to your doctor before taking kisplyx. children and adolescents kisplyx is not recommended for use in children and adolescents. the effects of kisplyx in people younger than 18 years old are not known. other medicines and kisplyx 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. use highly effective contraception while taking this medicine, and for at least one month after you finish treatment. do not take kisplyx 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 kisplyx, tell your doctor immediately. your doctor will help you decide whether the treatment should be continued. do not breast-feed if you are taking kisplyx. this is because the medicine passes into breast milk and may seriously harm your breastfed baby. driving and using machines kisplyx 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.', 'Entity_Recognition': [{'Text': 'kisplyx', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 21, 'BeginOffset': 12, 'EndOffset': 19, 'Score': 0.7260539531707764, 'Text': 'kisplyx', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.7507663369178772}]}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 32, 'EndOffset': 40}, {'Id': 22, 'BeginOffset': 44, 'EndOffset': 54, 'Score': 0.9949885010719299, 'Text': 'lenvatinib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 90, 'EndOffset': 103}, {'Id': 59, 'BeginOffset': 176, 'EndOffset': 189, 'Score': 0.501973569393158, 'Text': 'contraception', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 32, 'BeginOffset': 191, 'EndOffset': 200, 'Score': 0.9074728488922119, 'Text': 'pregnancy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8962827920913696}]}, {'Id': 23, 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{'Title': '3. how to take kisplyx', 'Section_Content': '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 the recommended daily dose of kisplyx is 18 mg once a day (one 10 mg capsule and two 4 mg capsules) in combination with one 5 mg tablet of everolimus once a day. if you have severe liver or kidney problems the recommended dose of kisplyx is 10 mg once a day (1 capsule of 10 mg) in combination with one 5 mg tablet of everolimus once a day. your doctor may reduce your dose if you experience 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 capsules to avoid exposure to the contents of the capsule. how long to takekisplyx you will usually carry on taking this medicine as long as you are getting benefit. if you take more kisplyx than you should if you take more kisplyx than you should, talk to a doctor or pharmacist straight away. take the medicine pack with you. if you forget to take kisplyx 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.', 'Entity_Recognition': [{'Text': 'kisplyx', 'Type': 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the following side effects may happen with this medicine. 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 in 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. 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. pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth - these could be signs of bone damage in the jaw (osteonecrosis). 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 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 high levels of protein in the urine 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 (hand-foot syndrome) changes in blood test results for potassium levels (low), calcium levels (low), cholesterol (high) and thyroid stimulating hormone (high) underactive thyroid (tiredness, weight gain, constipation, feeling cold, dry skin) low levels of platelets in the blood which may lead to bruising and difficulty in wound healing 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 gas in the bowel heart problems or blood clots in the lungs (difficulty breathing, chest pain) or other organs feeling unwell stroke inflammation of the gallbladder anal fistula (a small channel that forms between the anus and the surrounding skin) changes in blood test results for liver enzymes, white blood cells (low), blood magnesium (low) 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 40 inflammation of the pancreas wound healing problems bone damage in the jaw (osteonecrosis) not known (the following side effects have been reported since the marketing of lenvatinib but the frequency for them to occur is not known) other types of fistulae (an abnormal connection between different organs in the body or from the skin to an underlying structure such as throat and windpipe). symptoms would 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.', 'Entity_Recognition': [{'Text': 'kisplyx', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 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{'Title': '5. how to store kisplyx', 'Section_Content': " 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 blister after 'exp'. the expiry date refers to the last day of that month. do not store above 25. 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.", 'Entity_Recognition': None}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what kisplyx contains the active substance is lenvatinib. − kisplyx 4 mg hard capsules: - each hard capsule contains 4 mg of lenvatinib (as mesylate). − kisplyx 10 mg hard capsules: - each hard capsule contains 10 mg of lenvatinib (as mesylate). 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 kisplyx looks like and contents of the pack kisplyx 4 mg hard capsule: 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. kisplyx 10 mg hard capsule: 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 .', 'Entity_Recognition': [{'Text': 'kisplyx', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 2, 'BeginOffset': 46, 'EndOffset': 56, 'Score': 0.9979181885719299, 'Text': 'lenvatinib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.44939684867858887, 'RelationshipScore': 0.9988448619842529, 'RelationshipType': 'FORM', 'Id': 5, 'BeginOffset': 73, 'EndOffset': 86, 'Text': 'hard capsules', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.5708025693893433, 'RelationshipScore': 0.9877254366874695, 'RelationshipType': 'FORM', 'Id': 6, 'BeginOffset': 100, 'EndOffset': 107, 'Text': 'capsule', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 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