Active Ingredient: Lenvatinib
Lenvatinib is indicated for the treatment of adults with advanced renal cell carcinoma (RCC) in combination with everolimus, following one prior vascular endothelial growth factor (VEGF)-targeted therapy.
For this indication, competent medicine agencies globally authorize below treatments:
For:
Oral, 18 milligrams lenvatinib, once daily.
The recommended daily dose of lenvatinib is 18 mg orally once daily in combination with 5 mg of everolimus once daily. The daily dose of lenvatinib and, if necessary, everolimus is to be modified as needed according to the dose/toxicity management plan.
See the SmPC for everolimus for full everolimus dosing information.
If a patient misses a dose of lenvatinib, and it cannot be taken within 12 hours, then that dose 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.
Management of 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. Severe (e.g., Grade 3) or intolerable adverse reactions require interruption of lenvatinib until improvement of the reaction to Grade 0 to 1 or baseline.
Optimal medical management (i.e., treatment or therapy) for nausea, vomiting, and diarrhoea should be initiated prior to any lenvatinib therapy interruption or dose reduction; gastrointestinal toxicity should be actively treated in order to reduce the risk of development of renal impairment or renal failure.
For toxicities thought to be related to lenvatinib (see Table 2), upon resolution/improvement of an adverse reaction to Grade 0 to 1 or baseline, treatment should be resumed at a reduced dose of lenvatinib as suggested in Table 1.
Table 1. Dose modifications from recommended lenvatinib daily dosea:
| Lenvatinib dose in combination with everolimus | |
|---|---|
| Recommended daily dose | 18 mg orally once daily |
| First dose reduction | 14 mg orally once daily |
| Second dose reduction | 10 mg orally once daily |
| Third dose reduction | 8 mg orally once daily |
a Limited data are available for doses below 8 mg
For toxicities thought to be related to everolimus, treatment should be interrupted, reduced to alternate day dosing, or discontinued (see the SmPC for everolimus for dose adjustment recommendations regarding specific adverse reactions).
For toxicities thought to be related to both lenvatinib and everolimus, lenvatinib should be reduced (see Table 1) prior to reducing everolimus.
All treatments should be discontinued in case of life-threatening reactions (e.g., Grade 4) with the exception of laboratory abnormalities judged to be non-life-threatening, in which case they should be managed as severe reactions (e.g., Grade 3).
Grades are based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).
Table 2. 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. |
| 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 | |
| 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)
Lenvatinib should be taken at about the same time each day.
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