Lenvima

/ Neopharm Scientific

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.
Differentiated Thyroid carcinoma (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.
Clear cell renal cell carcinoma (RCC): The recommended daily dose of lenvatinib is 18 mg (one 10 mg capsule and two 4 mg capsules) once daily in combination with 5 mg of everolimus once daily. The daily doses of lenvatinib and, if necessary, everolimus are to be modified as needed according to the
dose/toxicity management plan.
Dose adjustment and discontinuations for DTC and Clear cell RCC: Management of adverse reactions may require dose interruption, adjustment, or discontinuation of lenvatinib or the combination therapy. Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not warrant interruption of lenvatinib or the combination therapy, unless intolerable to the patient despite optimal management. Severe (e.g., Grade 3) or intolerable adverse reactions require interruption of lenvatinib or the combination of medicines until improvement of the reaction to Grade 0-1 or baseline.
For lenvatinib related toxicities (see Table 1 at the attached doctor’s leaflet), 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 2 and Table 3 at the attached doctor’s leaflet.
For toxicities thought to be related to everolimus, treatment should be interrupted, reduced to alternate day dosing, or discontinued (see the everolimus prescribing information for advice on specific adverse reactions).
For toxicities thought to be related to both lenvatinib and everolimus, lenvatinib should be reduced (see Table 3) prior to reducing everolimus.
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).
Grades are based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).
Hepatocellular Carcinoma (HCC): 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 4 at the attached doctor’s leaflet.
For special populations please refer to the attached doctor’s leaflet.

LENVIMA is indicated for the treatment of adult patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine (RAI).
LENVIMA is indicated in combination with everolimus for the treatment of adult patients with advanced clear cell renal cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF)-targeted therapy.
LENVIMA is indicated as monotherapy for the treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have received no prior systemic therapy.

Hypersensitivity to the active substance or to any of the excipients.
Breast-feeding.

Hypertension: Hypertension has been reported in patients treated with lenvatinib, usually occurring early in the course of treatment. 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.
Proteinuria: Proteinuria has been reported in patients treated with lenvatinib, usually occurring early in the course of treatment. Urine protein should be monitored regularly. If urine dipstick proteinuria ≥2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary. Cases of
nephrotic syndrome have been reported in patients using lenvatinib. Lenvatinib should be discontinued in the event of nephrotic syndrome.
Hepatotoxicity:
DTC and Clear cell RCC: Liver-related adverse reactions most commonly reported in patients treated with lenvatinib included increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood bilirubin. Hepatic failure and acute hepatitis (<1%) have been reported in patients treated with lenvatinib. The hepatic  failure cases were generally reported in patients with progressive metastatic liver metastases disease.
In HCC patients treated with lenvatinib in the REFLECT trial, liver-related adverse reactions including hepatic encephalopathy and hepatic failure (including fatal reactions) were reported at a higher frequency compared to patients treated with sorafenib . Patients with worse hepatic impairment and/or greater liver tumour burden at baseline had a higher risk of developing hepatic encephalopathy and hepatic failure. Hepatic encephalopathy also occurred more frequently in patients aged 75 years and older. Approximately half of the events of hepatic failure and one third of the events of the hepatic encephalopathy were reported in patients with disease progression.
Renal failure and impairment: Renal impairment and renal failure have been reported in patients treated with lenvatinib. The primary risk factor identified was dehydration and/or hypovolemia due to gastrointestinal toxicity. Gastrointestinal toxicity: should be actively managed in order to reduce the risk of development of renal impairment or renal failure. Caution should be taken in patients receiving agents acting on the reninangiotensin aldosterone system given a potentially higher risk for acute renal failure with the combination treatment (for clear cell RCC patients). Dose interruptions, adjustments, or discontinuation may be necessary.
If patients have severe renal impairment, the initial dose of lenvatinib should be adjusted.
See prescribing information for full details.

DTC and Clear cell RCC: The most frequently reported adverse reactions in the clear cell RCC and DTC patient populations (occurring in ≥30% of patients) were diarrhoea (80.6%), hypertension (70.1%), fatigue (59.7%), decreased appetite (53.7%), weight decreased (52.6%), vomiting (48.4%), nausea (45.2%), proteinuria (38.9%), stomatitis (36.9%), headache (35.8%), dysphonia (35.6%), palmar-plantar erythrodysaesthesia syndrome (PPE) (34.1%), peripheral oedema (33.9%), and hypercholesterolemia (30.6%).
HCC: The most frequently reported adverse reactions (occurring in ≥30% of patients) are hypertension (44.0%), diarrhoea (38.1%), decreased appetite (34.9%), fatigue (30.6%), and decreased weight (30.4%).
See prescribing information for full details.

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.
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. 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.

Pregnancy: There are no data on the use of lenvatinib in pregnant women. Lenvatinib was embryotoxic and teratogenic when administered to rats and rabbits. 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.
Lactation: It is not known whether lenvatinib is excreted in human milk. Lenvatinib and its metabolites are excreted in rat milk.
A risk to newborns or infants cannot be excluded and, therefore, lenvatinib is contraindicated during breast-feeding.

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.
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.

Storage: Do not store above 25°C.