Lenvima 4 mg/10 mg Capsules

Endometrial Carcinoma
LENVIMA, in combination with pembrolizumab, is indicated for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Differentiated thyroid cancer (DTC)
LENVIMA is indicated for the treatment of adult patients (> 18 years of age) with progressive, locally advanced or metastatic, radioactive iodine (RAI) refractory differentiated thyroid cancer (DTC).

Renal Cell carcinoma (RCC)
LENVIMA, in combination with pembrolizumab, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). LENVIMA is indicated in combination with everolimus for the treatment of adult patients (> 18 years of age) with advanced renal cell carcinoma whose disease has progressed following one prior vascular endothelial growth factor targeted therapy.

Hepatocellular carcinoma
LENVIMA is indicated for the first-line treatment of adult patients (> 18 years of age) with unresectable hepatocellular carcinoma (HCC).

LENVIMA treatment should be supervised by a healthcare provider experienced in the use of anticancer therapies.

Posology

Starting dose in RAI u2013 Refractory DTC
The recommended dose of LENVIMA is 24 mg (two 10 mg capsules plus one 4 mg capsule) taken once daily. The daily dose is to be modified as needed according to the dose/toxicity management plan (see dose adjustment section below). Treatment should continue as long as there is clinical benefit or until unacceptable toxicity occurs.

Starting dose in Advanced Renal Cell Carcinoma
First line treatment of patients with advanced RCC
The recommended dosage of LENVIMA is 20 mg orally once daily in combination with pembrolizumab either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes until disease progression or until unacceptable toxicity. The daily dose should be modified as needed according to the dose/toxicity management plan (see dose adjustment schedule below). Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information.

Previously treated RCC
The recommended daily dose of LENVIMA is 18 mg (one 10 mg capsule and two 4 mg capsules) once daily in combination with 5 mg everolimus once daily. The daily doses of LENVIMA, and if necessary, everolimus are to be modified as needed according to the dose/toxicity management plan (see dose adjustment section below). Treatment should continue as long as there is clinical benefit or until unacceptable toxicity occurs.

Starting dose in Hepatocellular Carcinoma
The recommended daily dose of LENVIMA 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 u2265 60 kg. The daily dose is to be modified, as needed, according to the dose/toxicity management plan (see dose adjustment section below). Treatment should continue as long as there is clinical benefit or until unacceptable toxicity occurs.

Starting dose in endometrial carcinoma
The recommended dose of LENVIMA is 20 mg orally once daily, in combination with pembrolizumab either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The daily dose should be modified, as needed, according to the dose/toxicity management plan (see dose adjustment section below). Treatment should continue as long as there is clinical benefit or until unacceptable toxicity occurs. Refer to the pembrolizumab product information for recommended pembrolizumab dosing information.

Dose adjustment during therapy
Management of adverse reactions may require dose interruption, adjustment, or discontinuation of LENVIMA or LENVIMA and everolimus if treating in the combination (see section 4.4).

Hypersensitivity to LENVIMA or to any of the excipients listed in section 6.1. Patients with fistula(e), and/or patients at risk of developing fistula(e), such as after a major surgical procedure. Patients with severe and/or uncontrolled hypertension (BP u2264150 mmHg, diastolic BP u2264 95 mmHg). Patients with severe thrombocytopenia (< 50 x 103 per u03bcL) and/or active bleeding. Patients due to undergo surgery or radiotherapy.

Gastrointestinal toxicity: Diarrhoea and dehydration
Diarrhoea has been reported frequently in patients treated with LENVIMA usually occurring early in the course of treatment (see section 4.8). Prompt medical management of diarrhoea should be instituted in order to prevent dehydration. LENVIMA should be discontinued in the event of persistent Grade 4 diarrhoea despite medical management (see section 4.2). Gastrointestinal toxicity (including diarrhoea, nausea and vomiting) should be actively managed in order to reduce the risk of development of complications such as dehydration, electrolyte imbalances, and possible renal impairment or renal failure. Serious adverse events of both hypokalaemia and hyperkalaemia have occurred, as such, renal function and electrolytes should be monitored closely (see section 4.4 below).

Renal failure and impairment
Patients with baseline renal function <60 mL/minute experienced more adverse events, including fatal and serious adverse events of Grade 3 or 4, than those with normal renal function and were more likely to require a treatment interruption, dose reduction or discontinuation of treatment. The recommended starting dose is lower for patients with renal impairment (see section 4.2) and it is also recommended these patients be monitored closely during treatment. There is no clinical trial experience of patients with severe renal impairment. Renal impairment (including renal failure) has been reported in patients treated with LENVIMA (see section 4.8). The primary risk factors identified were pre-existing renal impairment and dehydration and/or hypovolemia due to gastrointestinal toxicity (see section 4.4 below). 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 LENVIMA should be adjusted (see section 4.2).

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 LENVIMA, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Hypertension
Hypertension has been reported in patients treated with LENVIMA, usually occurring early in the course of treatment (see section 4.8). Blood pressure (BP) should be well controlled prior to treatment with LENVIMA and, if patients are known to be hypertensive, they should be on a stable dose of an antihypertensive therapy for at least 1 week prior to treatment with LENVIMA. The early detection and effective management of hypertension are important to minimise the need for LENVIMA dose interruptions and reductions. Serious complications of poorly controlled hypertension, including aortic dissection, have been reported. Antihypertensives should be started as soon as elevated BP is confirmed. Blood pressure should be monitored after 1 week of treatment with LENVIMA, then every 2 weeks for the first 2 months and monthly thereafter. The choice of antihypertensive treatment should be individualised to the patientu2019s clinical circumstances and follow standard medical practice.

For previously normotensive subjects, monotherapy with one of the classes of antihypertensives should be started when elevated BP is observed. For those patients already on antihypertensive medication, the dose of the current medicine may be increased, if appropriate, or one or more medicines of a different class of antihypertensive should be added. When necessary, manage hypertension as recommended in Table 3.

Effect of other medicines on LENVIMA
CYP3A, P-gp, and BCRP inhibitors or inducers
LENVIMA may be administered regardless of co-administration with CYP3A, P-gp, and BCRP inhibitors. In healthy subjects, ketoconazole (400 mg for 18 days) increased lenvatinib (administered as a single dose on Day 5) AUC 0-inf and AUC 0-t approximately 15 % while C max increased 19 %. This is supported by a population PK analysis which found CYP3A4 inhibitors decreased Cl/F by 7,8 %. LENVIMA may be co-administered without dose adjustment with CYP3A and P-gp inducers, based on a study in which healthy subjects were administered repeated doses of rifampicin (600 mg for 21 days) and a single dose of lenvatinib (24 mg, Day 15). AUC 0-inf and AUC 0-t decreased approximately 18 % while C max did not change. The effect of CYP3A induction alone was estimated by comparing the PK parameters for lenvatinib following single and multiple doses of rifampicin. Lenvatinib AUC and C max were predicted to decrease by 30 % and 15 %, respectively, after strong induction in the absence of acute P-gp inhibition. This is supported by a population PK analysis which found CYP3A4 inducers increased Cl/F by 30 %.

Gastric pH-altering medicines
In a population pharmacokinetic analysis of patients receiving LENVIMA up to 24 mg once daily, medicines which increase gastric pH (H2 receptor blockers, proton pump inhibitors, antacids) did not have a significant effect on lenvatinib exposure.

Other chemotherapeutic medicines
Concomitant administration of lenvatinib (e.g. LENVIMA), carboplatin, and paclitaxel had no significant impact on the pharmacokinetics of any of these 3 substances.

Effect of LENVIMA on other medicines
Cytochrome P450 or UGT enzyme substrates
Lenvatinib (e.g. LENVIMA) is considered neither a strong inhibitor nor an inducer of cytochrome P450 or uridine 5u2019-diphosphoglucuronosyl transferase (UGT) enzymes.

P-gp and BCRP substrates
Lenvatinib as contained in LENVIMA showed minimal inhibitory activities toward P-gp-mediated and BCRP-mediated transport activities. Similarly, no induction of P-gp mRNA expression was observed.

OAT, OCT, OATP, BSEP, MATE and aldehyde oxidase substrates
Lenvatinib showed inhibitory effects on organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, OCT2, organic anion transporting polypeptide (OATP)1B1, and bile salt export pump (BSEP), but minimal or no inhibitory effect on OATP1B3 and multidrug and toxin extrusion 2 (MATE2)-K. Lenvatinib weakly inhibits MATE1. In human liver cytosol, lenvatinib did not inhibit aldehyde oxidase activity.

Women of childbearing potential / Contraception in males and females
Women of childbearing potential should avoid becoming pregnant and use highly effective contraception while on treatment with LENVIMA and for at least one month after finishing treatment. It is currently unknown whether LENVIMA may reduce the effectiveness of hormonal contraceptives, and therefore women using oral hormonal contraceptives should add a barrier method.

Pregnancy
LENVIMA should not be used during pregnancy. There is limited information on the use of LENVIMA in pregnant women. Lenvatinib was embryotoxic and teratogenic when administered to rats and rabbits during organogenesis at exposures below the clinical exposure (based on body surface area) at the maximum recommended human dose. Foetal anomalies included parietal oedema, cryptophthalmia, abnormal tail (rats), retroesophageal subclavian artery, fused ribs, and vertebral abnormalities (rabbits). These embryofoetal findings are probably related to the pharmacologic activity of lenvatinib as an antiangiogenic medicine.

Breastfeeding
LENVIMA should not be used during breastfeeding. It is not known whether LENVIMA is excreted in human milk. Lenvatinib and its metabolites are excreted in rat milk and neonatal rats were more sensitive to the toxicity of lenvatinib compared to adults (see section 4.4).

Fertility
Effects in humans are unknown. However, testicular and ovarian toxicity has been observed in rats, dogs, and monkeys. No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility. However, testicular and ovarian changes 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 u2013 week recovery period.

No studies on the effects on the ability to drive and use machines have been performed. LENVIMA may cause side effects such as fatigue and dizziness. Patients who experience these symptoms should be cautious when driving or operating machines.

Summary of the safety profile (DTC, RCC, HCC and EC)
The safety profile of LENVIMA is based on the combined safety data of 623 RCC patients in combination with everolimus, 452 DTC patients and 496 HCC patients; allowing characterisation of common adverse drug reactions in DTC, RCC and HCC patients. The safety of lenvatinib in combination with pembrolizumab has been evaluated in 530 patients with advanced EC, and 497 RCC patients. The adverse reactions presented in this section are based on safety data of DTC, RCC and HCC patients.

Tabulated list of adverse reactions for EC, DTC, RCC and HCC studies Table 4 shows the frequency categories of adverse reactions observed in clinical trials for EC, DTC, RCC and HCC, and reported from post-marketing use of LENVIMA. The adverse reaction frequency category represents the most conservative estimate of frequency from the three individual populations. For additional safety information when lenvatinib is administered in combination, refer to the Professional Information for the respective combination therapy components. Frequencies are defined as:
u2022 Very common (u22651/10)
u2022 Common (u22651/100 to <1/10)
u2022 Uncommon (u22651/1,000 to <1/100)
u2022 Not known (cannot be estimated from the available data)

There have been reports of overdose with LENVIMA including a single administration of 144 mg, 6 times the recommended daily dose. These cases were associated with adverse reactions consistent with the known safety profile of LENVIMA or were without adverse reactions. Death due to multiorgan dysfunction occurred in a patient who received a single dose of LENVIMA 120 mg orally. There is no specific antidote for overdose with LENVIMA, due to the high plasma protein binding, lenvatinib is not expected to be dialysable. In case of suspected overdose, LENVIMA should be withheld and appropriate supportive care given as required.