KISPLYX Hard capsule Ref.[27667] Active ingredients: Lenvatinib

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

Posology

Kisplyx in combination with pembrolizumab as first-line treatment

The recommended dose of lenvatinib is 20 mg (two 10-mg capsules) 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 of lenvatinib is to be modified as needed according to the dose/toxicity management plan. Lenvatinib treatment should continue until disease progression or unacceptable toxicity. Pembrolizumab should be continued until disease progression, unacceptable toxicity or the maximum duration of therapy as specified for pembrolizumab.

See the Summary of Product Characteristics (SmPC) for pembrolizumab for full pembrolizumab dosing information.

Kisplyx in combination with everolimus as second-line treatment

The recommended daily dose of lenvatinib is 18 mg (one 10-mg capsule and two 4-mg capsules) orally once daily in combination with 5 mg of everolimus once daily. The daily dose of lenvatinib and, if necessary, everolimus is to be modified as needed according to the dose/toxicity management plan.

See the SmPC for everolimus for full everolimus dosing information.

If a patient misses a dose of lenvatinib, 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.

Dose adjustment and discontinuation for lenvatinib

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.

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 renal failure (see section 4.4).

For toxicities thought to be related to lenvatinib (see Table 2), 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^a:

^a Limited data are available for doses below 8 mg

When used in combination with pembrolizumab, one or both medicines should be interrupted as appropriate. Lenvatinib should be withheld, dose reduced, or discontinued as appropriate. Withhold or discontinue pembrolizumab in accordance with the instructions in the SmPC for pembrolizumab. No dose reductions are recommended for pembrolizumab.

For toxicities thought to be related to everolimus, treatment should be interrupted, reduced to alternate day dosing, or discontinued (see the SmPC for everolimus for dose adjustment recommendations regarding specific adverse reactions).

For toxicities thought to be related to both lenvatinib and everolimus, lenvatinib should be reduced (see Table 1) prior to reducing everolimus.

All treatments 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).

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

Table 2. 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

For information about clinical experience with the combination treatment of lenvatinib and pembrolizumab, see section 4.8.

Patients of age ≥65 years, with baseline hypertension or those with renal impairment appear to have reduced tolerability to lenvatinib (see section 4.8).

No data for the combination of lenvatinib and everolimus are available for most of the special populations. The following information is derived from clinical experience of single agent lenvatinib in patients with differentiated thyroid cancer (DTC; see SmPC for Lenvima).

All patients other than those with severe hepatic or renal impairment (see below) should initiate treatment at the recommended dose of 20 mg of lenvatinib daily with pembrolizumab or 18 mg of lenvatinib with 5 mg of everolimus taken once daily as indicated, 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

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. The combination should be used in patients with severe hepatic impairment only if the anticipated benefit exceeds the risk (see section 4.8).

No data for the combination of lenvatinib with everolimus are 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 SmPC for everolimus. 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 (see section 4.8).

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 taken once daily. Please refer to the SmPC for pembrolizumab or everolimus 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 (see section 4.8).

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).

Ethnic Origin

No adjustment of starting dose is required on the basis of race (see section 5.2). Currently available data are described in section 4.8.

Body weight below 60 kg

No adjustment of starting dose is required on the basis of body weight. Limited data are available on treatment with lenvatinib in combination with everolimus in patients with a body weight below 60 kg with RCC (see section 4.8).

Performance status

Patients with an ECOG (Eastern Cooperative Oncology Group) performance status of 2 or higher were excluded from RCC Study 205 (see section 5.1). Patients with a KPS (Karnofsky Performance Status) <70 were excluded from Study 307 (CLEAR). Benefit-risk in these patients has not been evaluated.

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.

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 also 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.

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.