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

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

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).

Posology

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.

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 to 1 or baseline.

For lenvatinib-related toxicities (see Table 4), 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 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 abnormalities judged to be non-life-threatening, in which case they should be managed as severe reactions (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. For lenvatinib-related toxicities, see Table 4. 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 2 g/24 hours.
^e Excluding laboratory abnormalities judged to be nonlife-threatening, which should be managed as Grade 3.

Grades are based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).

Endometrial Carcinoma (EC)

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 unacceptable toxicity or disease progression (see section 5.1).

Refer to the Summary of Product Characteristics (SmPC) for pembrolizumab for additional dosing information.

Dose adjustments and Discontinuation for EC

For lenvatinib-related toxicities see Table 4. When administering LENVIMA in combination with pembrolizumab, interrupt, dose reduce, or discontinue LENVIMA as appropriate (see Table 3). Withhold or discontinue pembrolizumab in accordance with the instructions in the SmPC for pembrolizumab. No dose reductions are recommended for pembrolizumab.

Table 3. Dose modifications from recommended lenvatinib daily dose in EC patients:

^a Limited data are available for doses below 8 mg.
^b 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 4. Adverse reactions requiring dose modification of lenvatinib:

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

Special populations

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). 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 sections 4.4 and 4.8).

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.

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 impairment (Child-Pugh C) and is not recommended for use in these patients.

EC

Limited data are available for the combination of lenvatinib with pembrolizumab 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. Please refer to the SmPC for pembrolizumab for dosing in patients with hepatic impairment. Further dose adjustments may be necessary on the basis of individual tolerability.

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 (see section 4.8).

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.

EC

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 taken once daily. Please refer to the SmPC for pembrolizumab for dosing in patients with renal impairment. Further dose adjustments may be necessary based on individual tolerability. Patients with end-stage renal disease have not been studied, therefore the use of lenvatinib in these patients is not recommended.

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 section 4.8).

Paediatric population

The safety and efficacy of lenvatinib in children aged 2 to <18 years have not been established. Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made.

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).

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 section 4.8).

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

Lenvatinib capsules can be swallowed whole with water or administered as a suspension prepared by dispersing the whole capsule(s) in water, apple juice, or milk. The suspension may be administered orally or via a feeding tube. If administered via a feeding tube, then the suspension should be prepared using water (see section 6.6 for preparation and administration of suspension).

If not used at the time of preparation, lenvatinib suspension may be stored in a covered container and must be refrigerated at 2ºC to 8ºC for a maximum of 24 hours. After removal from the refrigerator the suspension should be shaken for approximately 30 seconds before use. If not administered within 24 hours, the suspension should be discarded.

For use in combination with pembrolizumab, refer to the SmPC for pembrolizumab.

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.

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.

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

Preparation and administration of suspension:

• The suspension may be prepared using water, apple juice, or milk. If administered via a feeding tube, then the suspension should be prepared using water.
• Place the capsule(s) corresponding to the prescribed dose (up to 5 capsules) in a small container (approximately 20 mL (4 tsp) capacity) or oral syringe (20 mL); do not break or crush the capsules.
• Add 3 mL of liquid to the container or oral syringe Wait 10 minutes for the capsule shell (outer surface) to disintegrate, then stir or shake the mixture for 3 minutes until the capsules are fully disintegrated.
  • If using an oral syringe, cap the syringe, remove plunger and use a second syringe or calibrated dropper to add the liquid to the first syringe, then replace plunger prior to mixing.
• Administer the entire contents of the container or oral syringe. The suspension may be administered from the container directly into the mouth, or from the oral syringe directly into the mouth or via feeding tube.
• Next, add an additional 2 mL of liquid to the container, or oral syringe using a second syringe or dropper, swirl or shake and administer. Repeat this step at least twice and until there is no visible residue to ensure all of the medication is taken.

Note: Compatibility has been confirmed for polypropylene syringes and for feeding tubes of at least 5 French diameter (polyvinyl chloride or polyurethane tube),at least 6 French diameter (silicone tube) and up to 16 French diameter for polyvinyl chloride, polyurethane, or silicone tubing.

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