Kisplyx · 4.8 Undesirable effects · 1

HOS-217393 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile The safety profile of lenvatinib is based on pooled data from 497 RCC patients treated with lenvatinib in combination with pembrolizumab, including Study 307 (CLEAR); pooled data from 623 RCC patients treated with lenvatinib in combination with everolimus: 458 DTC patients and 496 HCC patients treated with lenvatinib as monotherapy. Lenvatinib in combination with pembrolizumab in RCC The safety profile of lenvatinib in combination with pembrolizumab is based on data from 497 RCC patients. The most frequently reported adverse reactions (occurring in ≥30% of patients) were diarrhoea (61.8%), hypertension (51.5%) fatigue (47.1%), hypothyroidism (45.1%), decreased appetite (42.1%), nausea (39.6%), stomatitis (36.6%), proteinuria (33.0%), dysphonia (32.8%), and arthralgia (32.4%). The most common severe (Grade ≥3) adverse reactions (≥5%) were hypertension (26.2%), lipase increased (12.9%), diarrhoea (9.5%), proteinuria (8.0%), amylase increased (7.6%), weight decreased (7.2%), and fatigue (5.2%). 11 Discontinuation of lenvatinib, pembrolizumab, or both due to an adverse reaction occurred in 33.4% of patients; 23.7% lenvatinib, and 12.9 % both drugs. The most common adverse reactions (≥1%) leading to discontinuation of lenvatinib, pembrolizumab, or both were myocardial infarction (2.4%), diarrhoea (2.0%), proteinuria (1.8%), and rash (1.4%). Adverse reactions that most commonly led to discontinuation of lenvatinib (≥1%) were myocardial infarction (2.2%), proteinuria (1.8%), and diarrhoea (1.0%). Dose interruptions of lenvatinib, pembrolizumab, or both due to an adverse reaction occurred in 80.1% of patients; lenvatinib was interrupted in 75.3%, and both drugs in 38.6% of patients. Lenvatinib was dose reduced in 68.4% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of lenvatinib were diarrhoea (25.6%), hypertension (16.1%), proteinuria (13.7%), fatigue (13.1%), appetite decreased (10.9%), palmar-plantar erythrodysaesthesia syndrome (PPE) (10.7%), nausea (9.7%), asthenia (6.6%), stomatitis (6.2%), lipase increased (5.6%), and vomiting (5.6%). Lenvatinib in combination with everolimus in RCC The safety profile of lenvatinib in combination with everolimus is based on data from 623 patients. The most frequently reported adverse reactions(occurring in ≥30% of patients) were diarrhoea (69.0%), fatigue (41.9%), hypertension (41.7%),

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HOS-217389 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Breast-feeding (see section 4.6).

HOS-217388 · has-indication-information · PDF-Seite 2

Kisplyx is indicated for the treatment of adults with advanced renal cell carcinoma (RCC):  in combination with pembrolizumab, as first-line treatment (see section 5.1).  in combination with everolimus, following one prior vascular endothelial growth factor (VEGF)-targeted therapy (see section 5.1).

HOS-217391 · has-interaction-information · PDF-Seite 10

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. Additionally, in patients with RCC the pharmacokinetics of lenvatinib was not significantly affected by concomitant everolimus. 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. Additionally, in patients with RCC the pharmacokinetics of everolimus was not significantly affected by concomitant 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). 10

HOS-217392 · has-pregnancy-information · PDF-Seite 11

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).

HOS-217390 · has-warning-information · PDF-Seite 6

Hypertension Hypertension has been reported in patients treated with lenvatinib, usually occurring early in the course of treatment (see section 4.8). 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 patients, monotherapy with one of the classes of antihypertensive should be started when elevated BP is observed. For those patients already on an antihypertensive medicinal product, the dose of the current agent may be increased, if appropriate, or one or more agents of a different class of antihypertensive should be added. When necessary, manage hypertension as recommended in Table 3. 6 Table 3 Recommended management of hypertension Blood pressure (BP) level Recommended action Systolic BP ≥140 mmHg up to <160 mmHg or Continue lenvatinib and initiate antihypertensive diastolic BP ≥90 mmHg up to <100 mmHg 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 1. Withhold lenvatinib diastolic BP ≥100 mmHg 2. When systolic BP ≤150 mmHg, diastolic BP despite optimal antihypertensive therapy ≤95 mmHg, and patient has been on a stable dose

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