Posology : מינונים

4.2   Posology and method of administration

LENVIMA treatment should be initiated and supervised by a health care professional experienced in the use of anticancer therapies.

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

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

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

Posology

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

Lenvima in combination with everolimus as second-line treatment of clear cell renal cell carcinoma (RCC):
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.

See the SmPC for everolimus for full everolimus dosing information.

Lenvima in combination with pembrolizumab as first-line treatment in adult patients with advanced RCC

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

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

Dose adjustment and discontinuations for lenvatinib
Management of adverse reactions may require dose interruption, adjustment, or discontinuation of lenvatinib or the combination therapy (see section 4.4). Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not warrant interruption of lenvatinib or the combination therapy, unless intolerable to the patient despite optimal management. Severe (e.g., Grade 3) or intolerable adverse reactions require interruption of lenvatinib or the combination of medicines until improvement of the reaction to Grade 0-1 or baseline.
For lenvatinib related toxicities (see Table 5), upon resolution/improvement of an adverse reaction to Grade 0-1 or baseline, treatment should be resumed at a reduced dose of lenvatinib as suggested in Table 1 and Table 2.

For toxicities thought to be related to everolimus, treatment should be interrupted, reduced to alternate day dosing, or discontinued (see the everolimus prescribing information 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).

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

Dose adjustments and Discontinuation for HCC
Management of some adverse reactions may require dose interruption, adjustment, or discontinuation of lenvatinib therapy. Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not warrant interruption of lenvatinib, unless intolerable to the patient despite optimal management. Details for monitoring, dose adjustment and discontinuation are provided in Table 3.

Table 1          Dose modifications from recommended lenvatinib daily dose in DTC patientsa Dose level                           Daily dose          Number of capsules 
Recommended daily dose        24 mg orally once daily    Two 10 mg capsules plus one 4 mg capsule 
First dose reduction          20 mg orally once daily    Two 10 mg capsules 
Second dose reduction         14 mg orally once daily    One 10 mg capsule plus one 4 mg capsule 
Third dose reduction          10 mg orally once dailya   One 10 mg capsule a:
Further dose reductions should be considered on an individual patient basis as limited data are available for doses below 10 mg.

Table 2     Dose modifications from recommended lenvatinib daily dose in renal cell carcinoma (RCC)a
Lenvatinib dose in combination with      Lenvatinib dose in combination with pembrolizumab                                everolimus
Dose level
Recommended                 20 mg orally once daily                      18 mg orally once daily daily dose                   (two 10-mg capsules)               (One 10 mg capsule plus two 4 mg capsules) Lenvatinib dose in combination with           Lenvatinib dose in combination with pembrolizumab                                   everolimus
Dose level
First dose                   14 mg orally once daily                      14 mg orally once daily reduction            (one 10-mg capsule + one 4-mg capsule)      (One 10 mg capsule plus one 4 mg capsule) Second dose                  10 mg orally once daily                       10 mg orally once daily reduction                     (one 10-mg capsule)                           (One 10 mg capsule) Third dose                   8 mg orally once daily                        8 mg orally once daily reduction                     (two 4 mg capsules)                          (Two 4 mg capsules) 
When used in combination with pembrolizumab, one or both medicines should be interrupted as appropriate.
Lenvatinib should be withheld, dose reduced, or discontinued as appropriate. Withhold or discontinue pembrolizumab in accordance with the instructions in the SmPC for pembrolizumab. No dose reductions are recommended for pembrolizumab.
Table 3 Dose modifications from recommended lenvatinib daily dose in HCC patients ≥60 kg BW                             <60 kg BW
Starting Dose                                12 mg (three 4 mg capsules            8 mg (two 4 mg capsules orally once daily)                    orally once daily)
Persistent and Intolerable Grade 2 or Grade 3 Toxicitiesa
Adverse                                            Adjusted Doseb                  Adjusted Doseb Reaction               Modification                (≥60 kg BW)                     (<60 kg BW) 8 mg                            4 mg
Interrupt until resolved to
First occurrence c                                 (two 4 mg capsules)             (one 4 mg capsule) Grade 0-1 or baselined orally once daily               orally once daily
Second occurrence                                         4 mg                            4 mg Interrupt until resolved to
(same reaction or                                  (one 4 mg capsule) orally       (one 4 mg capsule) Grade 0-1 or baselined new reaction)                                      once daily                      orally every other day 
Third occurrence                                                                   Discontinue 4 mg
(same reaction or      Interrupt until resolved to
(one 4 mg capsule) orally new reaction)          Grade 0-1 or baselined every other day

Life-threatening toxicities (Grade 4): Discontinuee a.    Initiate medical management for nausea, vomiting, or diarrhoea prior to interruption or dose reduction.
b.    Reduce dose in succession based on the previous dose level (12 mg, 8 mg, 4 mg or 4 mg every other day).
c.    Haematologic toxicity or proteinuria-no dose adjustment required for first occurrence.
d.    For haematologic toxicity, dosing can restart when resolved to Grade 2; proteinuria, resume when resolves to less than 2g/24 hours e.    Excluding laboratory abnormalities judged to be nonlife-threatening, which should be managed as Grade 3.

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

Endometrial Carcinoma (EC)
The recommended dosage of LENVIMA is 20 mg orally once daily, in combination with pembrolizumab 200 mg every 3 weeks, administered as an intravenous infusion over 30 minutes, until unacceptable toxicity or disease progression (see section 5.1).

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

Dose adjustments and Discontinuation for EC

For lenvatinib-related toxicities see Table 5. When administering LENVIMA in combination with pembrolizumab, interrupt, dose reduce, or discontinue LENVIMA as appropriate (see Table 4). Withhold or discontinue pembrolizumab in accordance with the instructions in the SmPC for pembrolizumab. No dose reductions are recommended for pembrolizumab.

Table 4 Dose modifications from recommended lenvatinib daily dose in EC patients a Starting Dose                                        20 mg orallay once daily in combination with pembrolizumab                    (two 10-mg capsules) 
Persistent and Intolerable Grade 2 or Grade 3 Toxicities
Adverse
Reaction          Modification                  Adjusted Dose
14 mg orally once daily
Interrupt until resolved to
First occurrence                                (one 10-mg capsule + one 4-mg Grade 0-1 or baseline capsule)
Second occurrence
Interrupt until resolved to   10 mg orally once daily
(same reaction
Grade 0-1 or baseline         (one 10-mg capsule) or new reaction)

Third occurrence
Interrupt until resolved to       8 mg orally once daily
(same reaction
Grade 0-1 or baseline             (two 4-mg capsules) or new reaction)

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

Table 5 Adverse reactions requiring dose modification of lenvatinib

Adverse reaction       Severity                        Action      Dose reduce and resume lenvatinib
Hypertension           Grade 3                         Interrupt   Resolves to Grade 0, (despite optimal                            1 or 2.
antihypertensive therapy)                   See detailed guidance in Table 6 in section
4.4.
Grade 4                         Discontinue Do not resume.
Table 5 Adverse reactions requiring dose modification of lenvatinib

Adverse reaction         Severity                      Action      Dose reduce and resume lenvatinib
Proteinuria              ≥ 2 g / 24 hours              Interrupt   Resolves to less than 2 g / 24 hours.
Nephrotic syndrome       -------                       Discontinue Do not resume.
Renal impairment or      Grade 3                       Interrupt   Resolves to Grade 0- failure                                                            1 or baseline.
Grade 4*                      Discontinue Do not resume.
Cardiac dysfunction      Grade 3                       Interrupt   Resolves to Grade 0- 1 or baseline.
Grade 4                           Discontinue Do not resume.
Posterior reversible Any grade                         Interrupt   Consider resuming at encephalopathy                                                     reduced dose if syndrome                                                           resolves to Grade 0- (PRES)/reversible                                                  1.
posterior leukoencephalopathy syndrome (RPLS)
Hepatotoxicity       Grade 3                           Interrupt   Resolves to Grade 0- 1 or baseline.
Grade 4*                      Discontinue Do not resume.
Arterial                 Any grade                     Discontinue Do not resume.
thromboembolisms
Haemorrhage              Grade 3                       Interrupt   Resolves to Grade 0- 1.
Grade 4                       Discontinue Do not resume.
Gastrointestinal         Grade 3                       Interrupt   Resolves to Grade 0- perforation or fistula                                             1 or baseline.
Grade 4                       Discontinue Do not resume.
Non-gastrointestinal     Grade 4                       Discontinue Do not resume.
fistula
QT interval              >500 ms                       Interrupt   Resolves to <480 ms prolongation                                                       or baseline.
Diarrhoea                Grade 3                       Interrupt   Resolves to Grade 0- 1 or baseline.
Grade 4 (despite medical      Discontinue Do not resume.
management)
*Grade 4 laboratory abnormalities judged to be non-life-threatening, may be managed as severe reactions (e.g., Grade 3).

Special populations

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

Patients of age ≥65 years, with baseline hypertension or those with renal impairment appear to have reduced tolerability to lenvatinib (see section 4.8).
DTC
Patients of age ≥75 years, of Asian race, with comorbidities (such as hypertension, and hepatic or renal impairment), or body weight below 60 kg appear to have reduced tolerability to lenvatinib (see section 4.8, Other special populations).

Clear cell RCC
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 clear cell RCC (see also section 4.8, Other 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 carcinoma (DTC).

DTC and Clear cell RCC
All patients other than those with severe hepatic or renal impairment (see below) should initiate treatment at the recommended dose (see Table 1 and Table 2 above), following which the dose should be further adjusted on the basis of individual tolerability.

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

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

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

Patients with hepatic impairment

RCC
Limited data are available for the combination of lenvatinib with pembrolizumab in patients with hepatic impairment. No adjustment of starting dose of the combination is required on the basis of hepatic function in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. In patients with severe (Child-Pugh C) hepatic impairment, the recommended starting dose of lenvatinib is 10 mg taken once daily. Please refer to the SmPC for pembrolizumab for dosing in patients with hepatic impairment. Further dose adjustments may be necessary on the basis of individual tolerability. The combination should be used in patients with severe hepatic impairment only if the anticipated benefit exceeds the risk (see section 4.8).
No data for the combination of lenvatinib with everolimus are available in patients with hepatic impairment. No adjustment of starting dose of the combination is required on the basis of hepatic function in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. In patients with severe (Child-Pugh C) hepatic impairment, the recommended starting dose of lenvatinib is 10 mg taken once daily in combination with the dose of everolimus recommended for patients with severe hepatic impairment in the SmPC for everolimus. Further dose adjustments may be necessary on the basis of individual tolerability. The combination should be used in patients with severe hepatic impairment only if the anticipated benefit exceeds the risk (see section 4.8).
DTC
No adjustment of starting dose is required on the basis of hepatic function in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. In patients with severe (Child-Pugh C) hepatic impairment, the recommended starting dose is 14 mg taken once daily. Further dose adjustments may be necessary on the basis of individual tolerability. Refer also to section 4.8.

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

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

Patients with renal impairment

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

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

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

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

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
The safety and efficacy of lenvatinib in children aged 2 to <18 years have not been established. Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made.
Lenvatinib should not be used in children younger than 2 years of age because of safety concerns identified in animal studies (see section 5.3).

Race
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).

Patients with high ECOG performance status
Patients with an ECOG (Eastern Cooperative Oncology Group) performance status of 2 or higher were excluded from the clear cell RCC study 205 (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 should be swallowed whole with water.
Caregivers should not open the capsule, in order to avoid repeated exposure to the contents of the capsule.

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

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