Julphar Bangladesh Ltd.
Levat 4 Capsule : Each capsule contains Lenvatinib Mesylate INN equivalent to Lenvatinib 4 mg.
Levat 10 Capsule : Each capsule contains Lenvatinib Mesylate INN equivalent to Lenvatinib 10 mg.
Mechanism of Action
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. The combination of Lenvatinib and Everolimus showed increased antiangiogenic and antitumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone.
Cardiac Electrophysiology: A single 32 mg dose (1.3 times the recommended daily dose) of Lenvatinib did not prolong the QT/QTc interval in a thorough QT study in healthy subjects. However, QT prolongation was observed in clinical studies.
Absorption: After oral administration of Lenvatinib, time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with food did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours. In patients with solid tumors administered single and multiple doses of Lenvatinib once daily, the maximum Lenvatinib plasma concentration (Cmax ) and the area under the concentration-time curve (AUC) increased proportionally over the dose range of 3.2 to 32 mg with a median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg).
Distribution: In vitro binding of Lenvatinib to human plasma proteins ranged from 98% to 99% (0.3 – 30 µg/mL). In vitro, the Lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608 (0.1 – 10 µg/mL). Based on in vitro data, Lenvatinib is a substrate of P-gp and BCRP but not a substrate for organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT)1, OCT2, or the bile salt export pump (BSEP). Metabolism: CYP3A is one of the main metabolic enzymes of Lenvatinib. The main metabolic pathways for Lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes.
Excretion: Ten days after a single administration of radiolabeled Lenvatinib to 6 patients with solid tumors, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.
Elimination: Plasma concentrations declined bi- exponentially following Cmax. The terminal elimination half-life of Lenvatinib was approximately 28 hours.
Levat is a kinase inhibitor that is indicated for:
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
Adverse Reaction CTCAE
Action Dose Reduce and Resume Lenvatinib
Hypertension Grade 31 Hold Resolves to Grade 0, 1, or 2
Grade 4 Discontinue Do Not Resume
Dysfunction Grade 31 Hold Resolves to Grade 0, 1, or baseline
Grade 4 Discontinue Do Not Resume
Arterial Thrombotic Event Any Grade Discontinue Do Not Resume
Grade 3 or 4 Hold OR Discontinue Consider resuming at reduced dose if resolves to Grade 0-1 or baseline
Hepatic Failure Grade 3 or 4 Discontinue Do Not Resume
Proteinuriaor Greater than equal to 2 gm/24 hours
Resolves to less than 2 gm/24 hours
Nephrotic Syndrome ——- Discontinue Do Not Resume
Nausea, Vomiting, & Diarrhea2
Resolves to Grade 0, 1, or baseline
Vomiting and Diarrhea2 Grade 4 Discontinue Do Not Resume
Renal Failure or Impairment Grade 3 or 4 Hold OR Discontinue Consider resuming at reduced dose if resolves to Grade 0-1 or baseline
GI Perforation Any Grade Discontinue Do Not Resume
Fistula Grade 3 or 4 Discontinue Do Not Resume
QTc Prolongation Greater than 500 ms Hold Resolves to less than 480 ms or baseline
RPLS Any Grade Hold OR Discontinue Consider resuming at reduced dose if resolves to Grade 0 to 1
Hemorrhage Grade 3 Hold Resolves to Grade 0 to 1
Grade 4 Discontinue Do Not Resume
1Grade 3 despite optimal anti-hypertensive therapy
2Initiate prompt medical management for nausea, vomiting or diarrhea. Permanently discontinue for Grade 4 vomiting and diarrhea despite medical management
Manage other adverse reactions according to the instructions in Table 2 for DTC or Table 3 for RCC.
Recommendations for Dose Modifications in DTC
Table 2: Dose Modifications for Lenvatinib for Persistent and Intolerable Grade 2 or Grade 3 Adverse Reactions or Grade 4 Laboratory Abnormalities in DTCa
Reaction Modification Adjusted Doseb
Hepatocellular Carcinoma (HCC): As first line therapy in patients with unresectable hepatocellular carcinoma.
Differentiated Thyroid Cancer (DTC): Single agent for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory DTC.
Renal Cell Cancer (RCC): Use in combination with Everolimus, for patients with advanced RCC following one prior anti-angiogenic therapy.
Dosage And Administration:
Recommended dose (HCC): 12 mg orally, once daily (for adults weighing
resolved to Grade 0-1 or baseline
Interrupt until resolved to Grade 0-1 or baseline
Interrupt until resolved to Grade 0-1 or baseline
20 mg (two 10 mg capsules) orally once daily
14 mg (two 10 mg capsules one 4 mg capsule)
orally once daily
10 mg (one 10 mg capsule) orally once daily
>60 Kg). 8 mg orally, once daily for adults weighing <60 Kg). Recommended dose (DTC): 24 mg orally, once daily. Recommended dose (RCC): 18 mg Lenvatinib + 5 mg Everolimus, orally, once daily 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 aInitiate medical management for nausea, vomiting, or diarrhea prior to interruption or dose reduction of Lenvatinib bReduce dose in succession based on the previous dose level (24 mg, 20 mg, or 14 mg per day) cRefers to the same or a different adverse reaction that requires dose modification Severe Renal or Hepatic Impairment in DTC For patients with DTC, the recommended dose of Lenvatinib is 14 mg taken orally once daily in patients with severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min calculated by the Cockcroft-Gault equation) or severe hepatic impairment (Child- Pugh C) Recommendations for Dose Modifications in RCC Table 3: Dose Modifications for Lenvatinib for Persistent and Intolerable Grade 2 or Grade 3 Adverse Reactions or Grade 4 Laboratory Abnormalities in RCCa Adverse Reaction Modification Adjusted Doseb Interrupt until Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and Precautions: Hypertension: Control blood pressure prior to treatment with Lenvatinib. Withhold Lenvatinib for Grade 3 hypertension despite optimal antihypertensive therapy. Discontinue for life-threatening hypertension. Cardiac Failure First occurrence Second occurrence Third occurrence resolved to Grade 0-1 or baseline Interrupt until resolved to Grade 0-1 or baseline Interrupt until resolved to Grade 0-1 or baseline 14 mg (one 10 mg capsule One) 4 mg capsule ) orally once daily 10 mg (one 10 mg capsule) orally once daily 8 mg (Two 4 mg capsules) orally once daily Monitor for clinical symptoms or signs of cardiac decompensation. Withhold Lenvatinib for Grade 3 cardiac dysfunction. Discontinue for Grade 4 cardiac dysfunction. Arterial Thromboembolic Events Discontinue Lenvatinib following an arterial thromboembolic event. Hepatotoxicity Monitor liver function tests before initiation of Lenvatinib and periodically throughout treatment. Withhold Lenvatinib for Grade 3 or greater liver impairment. Discontinue for hepatic failure. aInitiate medical management for nausea, vomiting, or diarrhea prior to interruption or dose reduction of Lenvatinib bReduce dose in succession based on the previous dose level (18 mg, 14 mg, 10 mg, or 8 mg per day) cRefers to the same or a different adverse reaction that requires dose modification Chronic hepatitis. 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). In patients with severe renal or hepatic impairment, the dose is 14 mg, once daily in DTC and 10 mg once daily in RCC Special Populations: Pregnancy Lenvatinib can cause fetal harm when administered to pregnant woman. Lactation Risk Summary: It is not known whether Lenvatinib is present in human milk. However, Lenvatinib and its metabolites are excreted in rat milk at concentrations higher than in maternal. Because of the potential for serious adverse reactions in nursing infants from Lenvatinib, advise women to discontinue breastfeeding during treatment with Lenvatinib. Females and Males of Reproductive Potential: Contraception Based on its mechanism of action, Lenvatinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Lenvatinib and for at least 2 weeks following completion of therapy. Infertility Females: Lenvatinib may result in reduced fertility in females of reproductive potential. Males: Lenvatinib may result in damage to male reproductive tissues leading to reduced fertility of unknown duration. Pediatric Use The safety and effectiveness of Lenvatinib in pediatric patients have not been established. Geriatric Use Conclusions are limited due to the small sample size, but there appeared to be no overall differences in safety or effectiveness between subjects and younger subjects. Renal Impairment No dose adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended dose is 14 mg in the treatment of DTC and 10 mg in the treatment of RCC, either taken orally once daily. Patients with end stage renal disease were not studied. Hepatic Impairment No dose adjustment is recommended in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the recommended dose is 14 mg in the treatment of DTC and 10 mg in the treatment of RCC, either taken orally once daily. Proteinuria Monitor for proteinuria before initiation of, and periodically throughout, treatment with Lenvatinib. Withhold Lenvatinib for 2 grams of proteinuria for 24 hours. Discontinue for nephrotic syndrome. Diarrhea May be severe and recurrent. Use standard anti-diarrheal therapy. Withhold Lenvatinib for Grade 3 and discontinue for Grade 4 diarrhea. Renal Failure and Impairment Withhold Lenvatinib for Grade 3 or 4 renal failure/impairment. Gastrointestinal Perforation and Fistula Formation Discontinue Lenvatinib in patients who develop gastrointestinal perforation or lifethreatening fistula. QT Interval Prolongation Monitor and correct electrolyte abnormalities in all patients. Withhold Lenvatinib for the development of Grade 3 or greater QT interval prolongation. Hypocalcemia Monitor blood calcium levels at least monthly and replace calcium as necessary. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) Withhold Lenvatinib for RPLS until fully resolved. Hemorrhagic Events Withhold Lenvatinib for Grade 3 hemorrhage. Discontinue for Grade 4 hemorrhage. Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction Monitor TSH levels monthly and use thyroid replacement medication as needed. Embryofetal Toxicity Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. Adverse Reactions: In DTC, the most common adverse reactions (incidence greater than or equal to 30%) for Lenvatinib are hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, and dysphonia. In RCC, the most common adverse reactions (greater than 30%) for Lenvatinib + Everolimus are diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, weight decreased, hemorrhagic events, and proteinuria. Drug Interactions: Effect of Other Drugs on Lenvatinib No dose adjustment of Lenvatinib is recommended when co-administered with CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors and CYP3A and P-gp inducers. Pharmaceutical Information: Storage Condition Store in a cool and dry place below 30 C, protect from light. Keep out of the reach of children. How Supplied Levat 4 Capsule: Each box contains 30 capsules and one packet silica gel in a sealed plastic container. Levat 10 Capsule: Each box contains 30 capsules and one packet silica gel in a sealed plastic container. Manufactured by: Julphar Bangladesh Ltd.