LENVIMA Hard capsule Ref.[9037] Active ingredients: Lenvatinib

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 Cancer (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.

Dose adjustments and discontinuations for DTC

Management of adverse reactions may require dose interruption, adjustment, or discontinuation of lenvatinib therapy (see section 4.4). 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 0-1 or baseline.

For lenvatinib related toxicities (see Table 3), 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.

Table 1. Dose modifications from recommended lenvatinib daily dose in DTC patients^a:

^a Further dose reductions should be considered on an individual patient basis as limited data are available for doses below 10 mg.

Treatment should be discontinued in case of life-threatening reactions (e.g., Grade 4) with the exception of laboratory abnormality judged to be non-life-threatening, in which case they should be managed as severe reaction (e.g., Grade 3).

Hepatocellular Carcinoma

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 2.

Table 2. Dose modifications from recommended lenvatinib daily dose in HCC patients:

^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.

Table 3. Adverse reactions requiring dose modification of lenvatinib in DTC and HCC:

* Grade 4 laboratory abnormalities judged to be non-life-threatening, may be managed as severe reactions (e.g., Grade 3)

Special populations

Elderly population

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). All patients other than those with severe hepatic or renal impairment (see below) should initiate treatment at the recommended 24 mg dose, 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

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, Other special populations.

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.

Patients with renal impairment

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. Refer also to section 4.8, Other special populations.

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.

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).

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.

The highest doses of lenvatinib studied clinically were 32 mg and 40 mg per day. Accidental medication errors resulting in single doses of 40 to 48 mg have occurred in clinical trials. The most frequently observed adverse drug reactions at these doses were hypertension, nausea, diarrhoea, fatigue, stomatitis, proteinuria, headache, and aggravation of PPE. There have also been reports of overdose with lenvatinib involving single administrations of 6 to 10 times the recommended daily dose. These cases were associated with adverse reactions consistent with the known safety profile of lenvatinib (i.e., renal and cardiac failure), or were without adverse reactions.

Symptoms and Management

There is no specific antidote for overdose with lenvatinib. In case of suspected overdose, lenvatinib should be withheld and appropriate supportive care given as required.

Shelf life: 4 years.

Do not store above 25°C. Store in the original blister in order to protect from moisture.

Polyamide/Aluminium/PVC/Aluminium blisters containing 10 capsules. Each carton contains 30 ,60,or 90 hard capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Caregivers should not open the capsule, in order to avoid repeated exposure to the contents of the capsule.