Lenvatinib

1.1 Differentiated Thyroid Cancer

Lenvatinib is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory DTC.

1.2 Renal Cell Carcinoma

​Lenvatinib is indicated in combination with everolimus for the treatment of patients with advanced RCC following one prior anti-angiogenic therapy.

Lenvatinib (Lenvatinib) is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Lenvatinib is used to treat thyroid cancer.

Lenvatinib is usually given after radioactive iodine has been tried without success.

Lenvatinib is also used together with everolimus (Afinitor) for the treatment of patients with advanced advanced kidney cancer who have been previously treated with an anti-angiogenic therapy.

Recommended Dose For DTC

The recommended daily dose of Lenvatinib is 24 mg (two 10 mg capsules and one 4 mg capsule) orally taken once daily with or without food. Continue Lenvatinib until disease progression or until unacceptable toxicity.

Take Lenvatinib at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Recommended Dose For RCC

The recommended daily dose of Lenvatinib is 18 mg (one 10 mg capsule and two 4 mg capsules) in combination with 5 mg everolimus orally taken once daily with or without food. Continue Lenvatinib plus everolimus until disease progression or until unacceptable toxicity.

Take Lenvatinib and everolimus at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Administration Instructions

Lenvatinib capsules should be swallowed whole. Alternatively, the capsules can be dissolved in a small glass of liquid. Measure 1 tablespoon of water or apple juice and put the capsules into the liquid without breaking or crushing them. Leave the capsules in the liquid for at least 10 minutes. Stir for at least 3 minutes. Drink the mixture. After drinking, add the same amount (1 tablespoon) of water or apple juice to the glass. Swirl the contents a few times and swallow the additional liquid.

Dose Modifications For DTC And RCC

Table 1: Adverse Reactions Requiring Dose Modification of Lenvatinib in DTC and RCC

Recommendations For Dose Modification Of Everolimus In RCC

Review the Full Prescribing Information for everolimus for recommended dose modifications. For toxicities thought to be related to everolimus alone, discontinue, interrupt, or use alternate day dosing. For toxicities thought to be related to both Lenvatinib and everolimus, first reduce Lenvatinib and then everolimus.

Severe Renal Or Hepatic Impairment In RCC

For patients with RCC, the recommended dose of Lenvatinib is 10 mg taken orally once daily in patients with severe renal impairment (CLcr less than 30 mL/min calculated by the Cockcroft-Gault equation) or severe hepatic impairment (Child-Pugh C).

How supplied

Dosage Forms And Strengths

4 mg hard capsule: A yellowish-red body and yellowish-red cap, marked in black ink with “€” on the cap and “LENV 4 mg” on the body.

10 mg hard capsule: A yellow body and yellowish-red cap, marked in black ink with “€” on the cap and “LENV 10 mg” on the body.

Storage And Handling

Lenvatinib 4 mg capsules are supplied as hard hypromellose capsules with yellowish-red body and yellowish-red cap, marked in black ink with “€” on the cap and “LENV 4 mg” on the body.

Lenvatinib 10 mg capsules are supplied as hard hypromellose capsules with yellow body and yellowish-red cap, marked in black ink with “€” on the cap and “LENV 10 mg” on the body.

Lenvatinib capsules are supplied in cartons of 6 cards. Each card is a 5-day blister card as follows:

NDC 62856-724-30: 24 mg, carton with 6 cards NDC 62856-724-05 (ten 10 mg capsules and five 4 mg capsules per card).

NDC 62856-720-30: 20 mg, carton with 6 cards NDC 62856-720-05 (ten 10 mg capsules per card).

NDC 62856-718-30: 18 mg, carton with 6 cards NDC 62856-718-05 (five 10 mg capsules and ten 4 mg capsules per card).

NDC 62856-714-30: 14 mg, carton with 6 cards NDC 62856-714-05 (five 10 mg capsules and five 4 mg capsules per card).

NDC 62856-710-30: 10 mg, carton with 6 cards NDC 62856-710-05 (five 10 mg capsules per card).

NDC 62856-708-30: 8 mg, carton with 6 cards NDC 62856-708-05 (ten 4 mg capsules per card).

Store at 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F).

Manufactured by: Patheon Inc., Mississauga, Ontario, Canada Distributed by: Eisai Inc., Woodcliff Lake, NJ 07677. Revised: May 2016

See also:
What is the most important information I should know about Lenvatinib?

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to Lenvatinib or any component of the formulation.

Use Lenvatinib as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Lenvatinib. Talk to your pharmacist if you have questions about this information.
• Take Lenvatinib by mouth with or without food.
• Take Lenvatinib at the same time of day.
• Take as you have been told, even if you feel well.
• To gain the most benefit, do not miss doses.
• If you miss a dose of Lenvatinib, take it as soon as possible. If it is less than 12 hours until the next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Lenvatinib.

Use: Labeled Indications

Endometrial carcinoma, advanced: Treatment of advanced endometrial carcinoma (in combination with pembrolizumab) that is not microsatellite instability-high or mismatch repair deficient, in patients who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.

Hepatocellular carcinoma, unresectable: First-line treatment of unresectable hepatocellular carcinoma.

Renal cell carcinoma, advanced: Treatment of advanced renal cell carcinoma (in combination with everolimus) following one prior anti-angiogenic therapy.

Thyroid cancer, differentiated: Treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.

See also:
What other drugs will affect Lenvatinib?

Effect of Other Medicinal Products on Lenvatinib: CYP3A, P-gp, and BCRP Substrates: No dose adjustment of Lenvatinib is recommended when co-administering with CYP3A, Pglycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors and CYP3A and P-gp inducers.

Other Chemotherapeutic Agents: Concomitant administration of Lenvatinib, carboplatin, and paclitaxel has no significant impact on the pharmacokinetics of any of these 3 drugs.

Effect of Lenvatinib on Other Medicinal Products: No data is available that can be used to exclude the risk that Lenvatinib could be an inducer of CYP3A4 or Pgp in the gastrointestinal tract. This could potentially lead to decreased exposure to oral CYP3A4/Pgp substrates. This should be considered if co-administering oral CYP3A4/Pgp substrates for which retained efficacy is very important. CYP3A4 substrates known to have a narrow therapeutic index (e.g. astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine) should therefore be administered with caution in patients receiving Lenvatinib.

Oral Contraceptives:

See also:
What are the possible side effects of Lenvatinib?

The following adverse reactions are discussed elsewhere in the label:

• Hypertension
• Cardiac Dysfunction
• Arterial Thromboembolic Events
• Hepatotoxicity
• Proteinuria
• Diarrhea
• Renal Failure and Impairment
• Gastrointestinal Perforation and Fistula Formation
• QT Interval Prolongation
• Hypocalcemia
• Reversible Posterior Leukoencephalopathy Syndrome
• Hemorrhagic Events
• Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the WARNINGS AND PRECAUTIONS section reflect exposure to Lenvatinib as a single agent in 261 DTC patients (Study 1) and Lenvatinib + everolimus in 62 RCC patients (Study 2). Safety data obtained in 1160 patients with advanced solid tumors who received Lenvatinib as a single agent across multiple clinical studies was used to further characterize the risks of serious adverse reactions. In the entire single agent population, the median age was 60 years (range 21-89 years), the dose range was 0.2 mg to 32 mg, and the median duration of exposure was 5.5 months.

Differentiated Thyroid Cancer

The safety data described below are derived from Study 1 which randomized (2:1) patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) to Lenvatinib (n=261) or placebo (n=131). The median treatment duration was 16.1 months for Lenvatinib and 3.9 months for placebo. Among 261 patients who received Lenvatinib in Study 1, median age was 64 years, 52% were women, 80% were White, 18% were Asian, and 2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity.

In Study 1, the most common adverse reactions observed in Lenvatinib-treated patients (greater than or equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).

Adverse reactions led to dose reductions in 68% of patients receiving Lenvatinib and 5% of patients receiving placebo; 18% of patients discontinued Lenvatinib and 5% discontinued placebo for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of Lenvatinib were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of Lenvatinib were hypertension (1%) and asthenia (1%).

Table 4 presents the percentage of patients in Study 1 experiencing adverse reactions at a higher rate in Lenvatinib-treated patients than patients receiving placebo in the double-blind phase of the DTC study.

Table 4: Adverse Reactions Occurring in Patients with a Between-Group Difference of Greater than or Equal to 5% in All Grades or Greater than or Equal to 2% in Grades 3 and 4

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. These receptor tyrosine kinases (RTKs) located in the cell membrane play a central role in the activation of signal transduction pathways involved in the normal regulation of cellular processes, such as cell proliferation, migration, apoptosis and differentiation, and in pathogenic angiogenesis, lymphogenesis, tumour growth and cancer progression. In particular, VEGF has been identified as a crucial regulator of both physiologic and pathologic angiogenesis and increased expression of VEGF is associated with a poor prognosis in many types of cancers. Lenvatinib is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer. Most patients with thyroid cancer have a very good prognosis with treatment (98% 5 year survival rate) involving surgery and hormone therapy. However, for patients with RAI-refractory thyroid cancer, treatment options are limited and the prognosis is poor, leading to a push for the development of more targeted therapies such as Lenvatinib.