Kisplyx 4 mg hard capsules
Kisplyx 10 mg hard capsules
Kisplyx 4 mg hard capsules
Each hard capsule contains 4 mg of lenvatinib (as mesilate).
Kisplyx 10 mg hard capsules
Each hard capsule contains 10 mg of lenvatinib (as mesilate).
For the full list of excipients, see section 6.1.
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.
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.
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.
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).
|
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
|
|
GI perforation or fistula
|
Grade 3
|
Interrupt
|
Resolves to Grade 0-1 or baseline.
|
|
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.
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 eva luated.
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.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Breast-feeding (see section 4.6).
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. 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.
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.
|
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). 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).
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 cases of haemorrhage have been reported in patients treated with lenvatinib (see section 4.8 Description of selected adverse reactions). Cases of fatal intracranial haemorrhage have been reported in some patients with brain metastases. In the case of bleeding, dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).
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).
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 tre
