LENVIMA IS A PRESCRIPTION MEDICINE THAT IS USED TO TREAT CERTAIN KINDS OF CANCER.
· LENVIMA IS USED BY ITSELF TO TREAT DIFFERENTIATED THYROID CANCER (DTC ), A TYPE OF THYROID CANCER THAT CAN NO LONGER BE TREATED WITH RADIOACTIVE IODINE AND IS PROGRESSING.
· LENVIMA IS USED ALONG WITH ANOTHER MEDICINE CALLED EVEROLIMUS TO TREAT ADVANCED RENAL CELL CARCINOMA (RCC), A TYPE OF KIDNEY CANCER , AFTER ONE COURSE OF TREATMENT WITH ANOTHER ANTICANCER MEDICINE.
· LENVIMA IS USED BY ITSELF AS THE FIRST TREATMENT FOR A TYPE OF LIVER CANCER CALLED HEPATOCELLULAR CARCINOMA (HCC) WHEN IT CANNOT BE REMOVED BY SURGERY.
· LENVIMA IS USED ALONG WITH ANOTHER MEDICINE CALLED PEMBROLIZUMAB TO TREAT ADVANCED ENDOMETRIAL CARCINOMA , A TYPE OF UTERINE CANCER :
o THAT IS NOT MICROSATELLITE INSTABILITY-HIGH (MSI-H) OR MISMATCH REPAIR DEFICIENT (DMMR), AND
o THAT HAS PROGRESSED AFTER TREATMENT WITH ANTI-CANCER MEDICINE, AND
o THAT CANNOT BE TREATED WITH SURGERY OR RADIATION .
IT IS NOT KNOWN IF LENVIMA IS SAFE AND EFFECTIVE IN CHILDREN.
WHAT ARE THE POSSIBLE SIDE EFFECTS OF LENVIMA?
LENVIMA MAY CAUSE SERIOUS SIDE EFFECTS, INCLUDING:
· HIGH BLOOD PRESSURE (HYPERTENSION). HIGH BLOOD PRESSURE IS A COMMON SIDE EFFECT OF LENVIMA AND CAN BE SERIOUS. YOUR BLOOD PRESSURE SHOULD BE WELL CONTROLLED BEFORE YOU START TAKING LENVIMA. YOUR HEALTHCARE PROVIDER SHOULD CHECK YOUR BLOOD PRESSURE REGULARLY DURING TREATMENT WITH LENVIMA. IF YOU DEVELOP BLOOD PRESSURE PROBLEMS, YOUR HEALTHCARE PROVIDER MAY PRESCRIBE MEDICINE TO TREAT YOUR HIGH BLOOD PRESSURE.
· HEART PROBLEMS. LENVIMA CAN CAUSE SERIOUS HEART PROBLEMS THAT MAY LEAD TO DEATH. CALL YOUR HEALTHCARE PROVIDER RIGHT AWAY IF YOU GET SYMPTOMS OF HEART PROBLEMS, SUCH AS SHORTNESS OF BREATH OR SWELLING OF YOUR ANKLES.
· PROBLEM WITH BLOOD CLOTS IN YOUR BLOOD VESSELS (ARTERIES). GET EMERGENCY MEDICAL HELP RIGHT AWAY IF YOU GET ANY OF THE FOLLOWING SYMPTOMS:
o SEVERE CHEST PAIN OR PRESSURE
o PAIN IN YOUR ARMS, BACK, NECK OR JAW
o SHORTNESS OF BREATH
o NUMBNESS OR WEAKNESS ON ONE SIDE OF YOUR BODY
o TROUBLE TALKING
o SUDDEN SEVERE HEADACHE
o SUDDEN VISION CHANGES
· LIVER PROBLEMS. LENVIMA MAY CAUSE LIVER PROBLEMS THAT MAY LEAD TO LIVER FAILURE AND DEATH. YOUR HEALTHCARE PROVIDER WILL CHECK YOUR LIVER FUNCTION BEFORE AND DURING TREATMENT WITH LENVIMA. TELL YOUR HEALTHCARE PROVIDER RIGHT AWAY IF YOU HAVE ANY OF THE FOLLOWING SYMPTOMS:
o YOUR SKIN OR THE WHITE PART OF YOUR EYES TURNS YELLOW (JAUNDICE )
o DARK “TEA COLORED” URINE
o LIGHT-COLORED BOWEL MOVEMENTS (STOOLS)
o FEELING DROWSY, CONFUSED OR LOSS OF CONSCIOUSNESS
· KIDNEY PROBLEMS. KIDNEY FAILURE, WHICH CAN LEAD TO DEATH, HAS HAPPENED WITH LENVIMA TREATMENT. YOUR HEALTHCARE PROVIDER SHOULD DO REGULAR BLOOD TESTS TO CHECK YOUR KIDNEYS.
· INCREASED PROTEIN IN YOUR URINE (PROTEINURIA). PROTEINURIA IS A COMMON SIDE EFFECT OF LENVIMA AND CAN BE SERIOUS. YOUR HEALTHCARE PROVIDER SHOULD CHECK YOUR URINE FOR PROTEIN BEFORE AND DURING YOUR TREATMENT WITH LENVIMA.
· DIARRHEA. DIARRHEA IS A COMMON SIDE EFFECT OF LENVIMA AND CAN BE SERIOUS. IF YOU GET DIARRHEA, ASK YOUR HEALTHCARE PROVIDER ABOUT WHAT MEDICINES YOU CAN TAKE TO TREAT YOUR DIARRHEA. IT IS IMPORTANT TO DRINK MORE WATER WHEN YOU GET DIARRHEA. TELL YOUR HEALTHCARE PROVIDER OR GO TO THE EMERGENCY ROOM, IF YOU ARE UNABLE TO DRINK ENOUGH LIQUIDS AND YOUR DIARRHEA IS NOT ABLE TO BE CONTROLLED.
· AN OPENING IN THE WALL OF YOUR STOMACH OR INTESTINES (PERFORATION) OR AN ABNORMALCONNECTION BETWEEN TWO OR MORE BODY PARTS (FISTULA). GET EMERGENCY MEDICAL HELP RIGHT AWAY IF YOU HAVE SEVERE STOMACH (ABDOMEN) PAIN.
· CHANGES IN THE ELECTRICAL ACTIVITY OF YOUR HEART CALLED QT PROLONGATION. QT PROLONGATION CAN CAUSE IRREGULAR HEARTBEATS THAT CAN BE LIFE THREATENING. YOUR HEALTHCARE PROVIDER WILL DO BLOOD TESTS BEFORE AND DURING YOUR TREATMENT WITH LENVIMA TO CHECK THE LEVELS OF POTASSIUM , MAGNESIUM, AND CALCIUM IN YOUR BLOOD, AND MAY CHECK THE ELECTRICAL ACTIVITY OF YOUR HEART WITH AN ECG .
· LOW LEVELS OF BLOOD CALCIUM (HYPOCALCEMIA). YOUR HEALTHCARE PROVIDER WILL CHECK YOUR BLOOD CALCIUM LEVELS DURING TREATMENT WITH LENVIMA AND MAY TELL YOU TO TAKE A CALCIUM SUPPLEMENT IF YOUR CALCIUM LEVELS ARE LOW.
· A CONDITION CALLED REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME (RPLS). CALL YOUR HEALTHCARE PROVIDER RIGHT AWAY IF YOU GET SEVERE HEADACHE, SEIZURES, WEAKNESS, CONFUSION, OR BLINDNESS OR CHANGE IN VISION.
· BLEEDING. LENVIMA MAY CAUSE SERIOUS BLEEDING PROBLEMS THAT MAY LEAD TO DEATH. TELL YOUR HEALTHCARE PROVIDER IF YOU HAVE ANY SIGNS OR SYMPTOMS OF BLEEDING DURING TREATMENT WITH LENVIMA, INCLUDING:
o SEVERE AND PERSISTENT NOSE BLEEDS
o VOMITING BLOOD
o RED OR BLACK (LOOKS LIKE TAR) STOOLS
o BLOOD IN YOUR URINE
o COUGHING UP BLOOD OR BLOOD CLOTS
o HEAVY OR NEW ONSET VAGINAL BLEEDING
· CHANGE IN THYROID HORMONE LEVELS. YOUR HEALTHCARE PROVIDER SHOULD CHECK YOUR THYROID HORMONE LEVELS BEFORE STARTING AND EVERY MONTH DURING TREATMENT WITH LENVIMA.
· WOUND HEALING PROBLEMS. WOUND HEALING PROBLEMS HAVE HAPPENED IN SOME PEOPLE WHO TAKE LENVIMA. TELL YOUR HEALTHCARE PROVIDER IF YOU PLAN TO HAVE ANY SURGERY BEFORE OR DURING TREATMENT WITH LENVIMA.
o YOU SHOULD STOP TAKING LENVIMA AT LEAST 1 WEEK BEFORE PLANNED SURGERY.
o YOUR HEALTHCARE PROVIDER SHOULD TELL YOU WHEN YOU MAY START TAKING LENVIMA AGAIN AFTER SURGERY.
THE MOST COMMON SIDE EFFECTS OF LENVIMA IN PEOPLE TREATED FOR THYROID CANCER INCLUDE:
· TIREDNESS
· JOINT AND MUSCLE PAIN
· DECREASED APPETITE
· WEIGHT LOSS
· NAUSEA
· MOUTH SORES
· HEADACHE
· VOMITING
· RASH, REDNESS, ITCHING, OR PEELING OF YOUR SKIN ON YOUR HANDS AND FEET
· STOMACH (ABDOMEN) PAIN
· HOARSENESS
THE MOST COMMON SIDE EFFECTS OF LENVIMA IN PEOPLE TREATED FOR KIDNEY CANCER INCLUDE:
· TIREDNESS
· JOINT AND MUSCLE PAIN
· DECREASED APPETITE
· VOMITING
· NAUSEA
· MOUTH SORES
· SWELLING IN YOUR ARMS AND LEGS
· COUGH
· STOMACH (ABDOMEN) PAIN
· TROUBLE BREATHING
· RASH
· WEIGHT LOSS
· BLEEDING
THE MOST COMMON SIDE EFFECTS OF LENVIMA IN PEOPLE TREATED FOR LIVER CANCER INCLUDE:
· TIREDNESS
· DECREASED APPETITE
· JOINT AND MUSCLE PAIN
· WEIGHT LOSS
· STOMACH (ABDOMEN) PAIN
· RASH, REDNESS, ITCHING, OR PEELING OF YOUR SKIN ON YOUR HANDS AND FEET
· HOARSENESS
· BLEEDING
· CHANGE IN THYROID HORMONE LEVELS
· NAUSEA
THE MOST COMMON SIDE EFFECTS OF LENVIMA WHEN GIVEN WITH PEMBROLIZUMAB IN PEOPLETREATED FOR UTERINE CANCER INCLUDE:
· TIREDNESS
· JOINT AND MUSCLE PAIN
· DECREASED APPETITE
· CHANGE IN THYROID HORMONE LEVELS
· NAUSEA
· MOUTH SORES
· VOMITING
· WEIGHT LOSS
· STOMACH (ABDOMEN) PAIN
· HEADACHE
· CONSTIPATION
· URINARY TRACT INFECTION
· HOARSENESS
· BLEEDING
· LOW MAGNESIUM LEVEL
· RASH, REDNESS, ITCHING, OR PEELING OF YOUR SKIN ON YOUR HANDS AND FEET
· TROUBLE BREATHING
· COUGH
· RASH
LENVIMA MAY CAUSE FERTILITY PROBLEMS IN MALES AND FEMALES. TALK TO YOUR HEALTHCARE PROVIDER IF THIS IS A CONCERN FOR YOU.
THESE ARE NOT ALL THE POSSIBLE SIDE EFFECTS OF LENVIMA.
CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO FDA AT 1-800FDA-1088.
DESCRIPTION
LENVIMA, A KINASE INHIBITOR, IS THE MESYLATE SALT OF LENVATINIB. ITS CHEMICAL NAME IS 4-[3- CHLORO-4-(N'-CYCLOPROPYLUREIDO)PHENOXY]-7-METHOXYQUINOLINE-6-CARBOXAMIDE METHANESULFONATE. THE MOLECULAR FORMULA IS C21H19CLN4O4 • CH4O3S, AND THE MOLECULAR WEIGHT OF THE MESYLATE SALT IS 522.96.
LENVATINIB MESYLATE IS A WHITE TO PALE REDDISH YELLOW POWDER. IT IS SLIGHTLY SOLUBLE IN WATER AND PRACTICALLY INSOLUBLE IN ETHANOL (DEHYDRATED). THE DISSOCIATION CONSTANT (PKA VALUE) OF LENVATINIB MESYLATE IS 5.05 AT 25°C. THE PARTITION COEFFICIENT (LOG P VALUE) IS 3.3.
LENVIMA CAPSULES FOR ORAL ADMINISTRATION CONTAIN 4 MG OR 10 MG OF LENVATINIB, EQUIVALENT TO 4.90 MG OR 12.25 MG OF LENVATINIB MESYLATE, RESPECTIVELY. FOLLOWING ARE INACTIVE INGREDIENTS: CALCIUM CARBONATE, USP; MANNITOL, USP; MICROCRYSTALLINE CELLULOSE, NF; HYDROXYPROPYL CELLULOSE, NF; LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, NF; AND TALC, USP. THE HYPROMELLOSE CAPSULE SHELL CONTAINS TITANIUM DIOXIDE, FERRIC OXIDE YELLOW, AND FERRIC OXIDE RED. THE PRINTING INK CONTAINS SHELLAC, BLACK IRON OXIDE, POTASSIUM HYDROXIDE, AND PROPYLENE GLYCOL.
INDICATIONS
INDICATIONS
DIFFERENTIATED THYROID CANCER
LENVIMA IS INDICATED FOR THE TREATMENT OF PATIENTS WITH LOCALLY RECURRENT OR METASTATIC, PROGRESSIVE, RADIOACTIVE IODINE-REFRACTORY DIFFERENTIATED THYROID CANCER (DTC).
RENAL CELL CARCINOMA
LENVIMA IS INDICATED IN COMBINATION WITH EVEROLIMUS FOR THE TREATMENT OF PATIENTS WITH ADVANCED RENAL CELL CARCINOMA (RCC) FOLLOWING ONE PRIOR ANTI-ANGIOGENIC THERAPY.
HEPATOCELLULAR CARCINOMA
LENVIMA IS INDICATED FOR THE FIRST-LINE TREATMENT OF PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA (HCC).
ENDOMETRIAL CARCINOMA
LENVIMA, IN COMBINATION WITH PEMBROLIZUMAB, IS INDICATED FOR THE TREATMENT OF PATIENTS WITH ADVANCED ENDOMETRIAL CARCINOMA THAT IS NOT MICROSATELLITE INSTABILITY-HIGH (MSI-H) OR MISMATCH REPAIR DEFICIENT (DMMR), WHO HAVE DISEASE PROGRESSION FOLLOWING PRIOR SYSTEMIC THERAPY AND ARE NOT CANDIDATES FOR CURATIVE SURGERY OR RADIATION.
THIS INDICATION IS APPROVED UNDER ACCELERATED APPROVAL BASED ON TUMOR RESPONSE RATE AND DURABILITY OF RESPONSE [SEE CLINICAL STUDIES ]. CONTINUED APPROVAL FOR THIS INDICATION MAY BE CONTINGENT UPON VERIFICATION AND DESCRIPTION OF CLINICAL BENEFIT IN THE CONFIRMATORY TRIAL.
DOSAGE
DOSAGE AND ADMINISTRATION
IMPORTANT DOSAGE INFORMATION
· REDUCE THE DOSE FOR CERTAIN PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT [SEE DOSAGE AND ADMINISTRATION].
· TAKE LENVIMA ONCE DAILY, WITH OR WITHOUT FOOD, AT THE SAME TIME EACH DAY [SEE CLINICAL PHARMACOLOGY ]. 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 DOSAGE FOR DIFFERENTIATED THYROID CANCER (DTC)
THE RECOMMENDED DOSAGE OF LENVIMA IS 24 MG ORALLY ONCE DAILY UNTIL DISEASE PROGRESSION OR UNTIL UNACCEPTABLE TOXICITY.
RECOMMENDED DOSAGE FOR RENAL CELL CARCINOMA (RCC)
THE RECOMMENDED DOSAGE OF LENVIMA IS 18 MG IN COMBINATION WITH 5 MG EVEROLIMUS ORALLY ONCE DAILY UNTIL DISEASE PROGRESSION OR UNTIL UNACCEPTABLE TOXICITY.
REFER TO EVEROLIMUS PRESCRIBING INFORMATION FOR RECOMMENDED EVEROLIMUS DOSING INFORMATION.
RECOMMENDED DOSAGE FOR HEPATOCELLULAR CARCINOMA (HCC)
THE RECOMMENDED DOSAGE OF LENVIMA IS BASED ON ACTUAL BODY WEIGHT:
· 12 MG FOR PATIENTS GREATER THAN OR EQUAL TO 60 KG OR
· 8 MG FOR PATIENTS LESS THAN 60 KG.
TAKE LENVIMA ORALLY ONCE DAILY UNTIL DISEASE PROGRESSION OR UNTIL UNACCEPTABLE TOXICITY.
RECOMMENDED DOSAGE FOR ENDOMETRIAL CARCINOMA
THE RECOMMENDED DOSAGE OF LENVIMA IS 20 MG ORALLY ONCE DAILY, IN COMBINATION WITH PEMBROLIZUMAB 200 MG ADMINISTERED AS AN INTRAVENOUS INFUSION OVER 30 MINUTES EVERY 3 WEEKS, UNTIL UNACCEPTABLE TOXICITY OR DISEASE PROGRESSION.
REFER TO THE PEMBROLIZUMAB PRESCRIBING INFORMATION FOR RECOMMENDED PEMBROLIZUMAB DOSING INFORMATION.
DOSAGE MODIFICATIONS FOR ADVERSE REACTIONS
RECOMMENDATIONS FOR LENVIMA DOSE INTERRUPTION, REDUCTION AND DISCONTINUATION FOR ADVERSE REACTIONS ARE LISTED IN TABLE 1. TABLE 2 LISTS THE RECOMMENDED DOSAGE REDUCTIONS OF LENVIMA FOR ADVERSE REACTIONS.
TABLE 1: RECOMMENDED DOSAGE MODIFICATIONS FOR LENVIMA FOR ADVERSE REACTIONS
ADVERSE REACTION SEVERITYA DOSAGE MODIFICATIONS FOR LENVIMA
HYPERTENSION [SEE WARNINGS AND PRECAUTIONS ]GRADE 3· WITHHOLD FOR GRADE 3 THAT PERSISTS DESPITE OPTIMAL ANTIHYPERTENSIVE THERAPY. · RESUME AT REDUCED DOSE WHEN HYPERTENSION IS CONTROLLED AT LESS THAN OR EQUAL TO GRADE 2.
GRADE 4 · PERMANENTLY DISCONTINUE.
CARDIAC DYSFUNCTION [SEE WARNINGS AND PRECAUTIONS ]GRADE 3· WITHHOLD UNTIL IMPROVES TO GRADE 0 TO 1 OR BASELINE. · RESUME AT A REDUCED DOSE OR DISCONTINUE DEPENDING ON THE SEVERITY AND PERSISTENCE OF ADVERSE REACTION.
GRADE 4 · PERMANENTLY DISCONTINUE.
ARTERIAL THROMBOEMBOLIC EVENT [SEE WARNINGS AND PRECAUTIONS ]ANY GRADE· PERMANENTLY DISCONTINUE.
HEPATOTOXICITY [SEE WARNINGS AND PRECAUTIONS ]GRADE 3 OR 4· WITHHOLD UNTIL IMPROVES TO GRADE 0 TO 1 OR BASELINE. · EITHER RESUME AT A REDUCED DOSE OR DISCONTINUE DEPENDING ON SEVERITY AND PERSISTENCE OF HEPATOTOXICITY. · PERMANENTLY DISCONTINUE FOR HEPATIC FAILURE.
RENAL FAILURE OR IMPAIRMENT [SEE WARNINGS AND PRECAUTIONS ]GRADE 3 OR 4· WITHHOLD UNTIL IMPROVES TO GRADE 0 TO 1 OR BASELINE. · RESUME AT A REDUCED DOSE OR DISCONTINUE DEPENDING ON SEVERITY AND PERSISTENCE OF RENAL IMPAIRMENT.
PROTEINURIA [SEE WARNINGS AND PRECAUTIONS ]2 G OR GREATER PROTEINURIA IN 24 HOURS· WITHHOLD UNTIL LESS THAN OR EQUAL TO 2 GRAMS OF PROTEINURIA PER 24 HOURS. · RESUME AT A REDUCED DOSE. · PERMANENTLY DISCONTINUE FOR NEPHROTIC SYNDROME.
GASTROINTESTINAL PERFORATION [SEE WARNINGS AND PRECAUTIONS ]ANY GRADE· PERMANENTLY DISCONTINUE.
FISTULA FORMATION [SEE WARNINGS AND PRECAUTIONS ]GRADE 3 OR 4· PERMANENTLY DISCONTINUE.
QT PROLONGATION [SEE WARNINGS AND PRECAUTIONS ]GREATER THAN 500 MS OR GREATER THAN 60 MS INCREASE FROM BASELINE· WITHHOLD UNTIL IMPROVES TO LESS THAN OR EQUAL TO 480 MS OR BASELINE. · RESUME AT A REDUCED DOSE.
REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME [SEE WARNINGS AND PRECAUTIONS ]ANY GRADEWITHHOLD UNTIL FULLY RESOLVED. RESUME AT A REDUCED DOSE OR DISCONTINUE DEPENDING ON SEVERITY AND PERSISTENCE OF NEUROLOGIC SYMPTOMS.
OTHER ADVERSE REACTIONS [SEE WARNINGS AND PRECAUTIONS ]PERSISTENT OR INTOLERABLE GRADE 2 OR 3 ADVERSE REACTION GRADE 4 LABORATORY ABNORMALITY· WITHHOLD UNTIL IMPROVES TO GRADE 0 TO 1 OR BASELINE. · RESUME AT REDUCED DOSE.
GRADE 4 ADVERSE REACTION · PERMANENTLY DISCONTINUE.
A NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS, VERSION 4.0.
TABLE 2: RECOMMENDED DOSAGE REDUCTIONS OF LENVIMA FOR ADVERSE REACTIONS
INDICATION FIRST DOSAGE REDUCTION TO SECOND DOSAGE REDUCTION TO THIRD DOSAGE REDUCTION TO
DTC 20 MG ONCE DAILY 14 MG ONCE DAILY 10 MG ONCE DAILY
RCC 14 MG ONCE DAILY 10 MG ONCE DAILY 8 MG ONCE DAILY
ENDOMETRIAL CARCINOMA 14 MG ONCE DAILY 10 MG ONCE DAILY 8 MG ONCE DAILY
HCC
· ACTUAL WEIGHT 60 KG OR GREATER 8 MG ONCE DAILY 4 MG ONCE DAILY 4 MG EVERY OTHER DAY
· ACTUAL WEIGHT LESS THAN 60 KG 4 MG ONCE DAILY 4 MG EVERY OTHER DAY DISCONTINUE
WHEN ADMINISTERING LENVIMA IN COMBINATION WITH EVEROLIMUS FOR THE TREATMENT OF RENAL CELL CARCINOMA, REDUCE THE LENVIMA DOSE FIRST AND THEN THE EVEROLIMUS DOSE FOR ADVERSE REACTIONS OF BOTH LENVIMA AND EVEROLIMUS. REFER TO THE EVEROLIMUS PRESCRIBING INFORMATION FOR ADDITIONAL DOSE MODIFICATION INFORMATION.
WHEN ADMINISTERING LENVIMA IN COMBINATION WITH PEMBROLIZUMAB FOR THE TREATMENT OF ENDOMETRIAL CARCINOMA, INTERRUPT ONE OR BOTH DRUGS OR DOSE REDUCE LENVIMA AS APPROPRIATE. NO DOSE REDUCTIONS ARE RECOMMENDED FOR PEMBROLIZUMAB. WITHHOLD OR DISCONTINUE PEMBROLIZUMAB IN ACCORDANCE WITH THE INSTRUCTIONS IN THE PEMBROLIZUMAB PRESCRIBING INFORMATION.
DOSAGE MODIFICATIONS FOR SEVERE RENAL IMPAIRMENT
THE RECOMMENDED DOSAGE OF LENVIMA FOR PATIENTS WITH DTC, RCC, OR ENDOMETRIAL CARCINOMA AND SEVERE RENAL IMPAIRMENT (CREATININE CLEARANCE LESS THAN 30 ML/MIN CALCULATED BY COCKCROFT-GAULT EQUATION USING ACTUAL BODY WEIGHT) IS [SEE WARNINGS AND PRECAUTIONS , USE IN SPECIFIC POPULATIONS ]:
· DIFFERENTIATED THYROID CANCER: 14 MG ORALLY ONCE DAILY
· RENAL CELL CARCINOMA: 10 MG ORALLY ONCE DAILY
· ENDOMETRIAL CARCINOMA: 10 MG ORALLY ONCE DAILY
DOSAGE MODIFICATIONS FOR SEVERE HEPATIC IMPAIRMENT
THE RECOMMENDED DOSAGE OF LENVIMA FOR PATIENTS WITH DTC, RCC, OR ENDOMETRIAL CARCINOMA AND SEVERE HEPATIC IMPAIRMENT (CHILD-PUGH C) IS [SEE WARNINGS AND PRECAUTIONS , USE IN SPECIFIC POPULATIONS ]:
· DIFFERENTIATED THYROID CANCER: 14 MG TAKEN ORALLY ONCE DAILY
· RENAL CELL CARCINOMA: 10 MG TAKEN ORALLY ONCE DAILY
· ENDOMETRIAL CARCINOMA: 10 MG ORALLY ONCE DAILY
PREPARATION AND ADMINISTRATION
LENVIMA CAPSULES CAN BE SWALLOWED WHOLE OR DISSOLVED IN A SMALL GLASS OF LIQUID. TO DISSOLVE IN LIQUID, PUT CAPSULES INTO 1 TABLESPOON OF WATER OR APPLE JUICE WITHOUT BREAKING OR CRUSHING THE CAPSULES. LEAVE THE CAPSULES IN THE WATER OR APPLE JUICE FOR AT LEAST 10 MINUTES. STIR FOR AT LEAST 3 MINUTES. AFTER DRINKING THE MIXTURE, ADD 1 TABLESPOON OF WATER OR APPLE JUICE TO THE GLASS, SWIRL THE CONTENTS A FEW TIMES AND SWALLOW THE WATER OR APPLE JUICE.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
CAPSULES
· 4 MG: YELLOWISH-RED BODY AND YELLOWISH-RED CAP, MARKED IN BLACK INK WITH “?” ON CAP AND “LENV 4 MG” ON BODY.
· 10 MG: YELLOW BODY AND YELLOWISH-RED CAP, MARKED IN BLACK INK WITH “?” ON CAP AND “LENV 10 MG” ON BODY.
STORAGE AND HANDLING
LENVIMA 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.
LENVIMA 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.
LENVIMA 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 62856-712-30: 12 MG, CARTON WITH 6 CARDS NDC 62856-712-05 (FIFTEEN 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).
NDC 62856-704-30: 4 MG, CARTON WITH 6 CARDS NDC 62856-704-05 (FIVE 4 MG CAPSULES PER CARD).
STORE AT 25°C (77°F); EXCURSIONS PERMITTED TO 15 €“ 30°C (59 €“ 86°F) [SEE USP CONTROLLED ROOM TEMPERATURE].
DISTRIBUTED BY: EISAI INC. WOODCLIFF LAKE, NJ 07677. REVISED: SEP 2019
SIDE EFFECTS & DRUG INTERACTIONS
SIDE EFFECTS
THE FOLLOWING ADVERSE REACTIONS ARE DISCUSSED ELSEWHERE IN THE LABELING:
· HYPERTENSION [SEE WARNINGS AND PRECAUTIONS ]
· CARDIAC DYSFUNCTION [SEE WARNINGS AND PRECAUTIONS ]
· ARTERIAL THROMBOEMBOLIC EVENTS [SEE WARNINGS AND PRECAUTIONS ]
· HEPATOTOXICITY [SEE WARNINGS AND PRECAUTIONS ]
· RENAL FAILURE AND IMPAIRMENT [SEE WARNINGS AND PRECAUTIONS ]
· PROTEINURIA [SEE WARNINGS AND PRECAUTIONS ]
· DIARRHEA [SEE WARNINGS AND PRECAUTIONS ]
· FISTULA FORMATION AND GASTROINTESTINAL PERFORATION [SEE WARNINGS AND PRECAUTIONS ]
· QT INTERVAL PROLONGATION [SEE WARNINGS AND PRECAUTIONS ]
· HYPOCALCEMIA [SEE WARNINGS AND PRECAUTIONS ]
· REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME [SEE WARNINGS AND PRECAUTIONS ]
· HEMORRHAGIC EVENTS [SEE WARNINGS AND PRECAUTIONS ]
· IMPAIRMENT OF THYROID STIMULATING HORMONE SUPPRESSION/THYROID DYSFUNCTION [SEE WARNINGS AND PRECAUTIONS ]
· WOUND HEALING COMPLICATIONS [SEE WARNINGS AND PRECAUTIONS ]
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 REFLECT EXPOSURE TO LENVIMA AS A SINGLE AGENT IN 261 PATIENTS WITH DTC (SELECT) AND 476 PATIENTS WITH HCC (REFLECT), LENVIMA WITH PEMBROLIZUMAB IN 94 PATIENTS WITH ENDOMETRIAL CARCINOMA (STUDY 111), AND LENVIMA WITH EVEROLIMUS IN 62 PATIENTS WITH RCC (STUDY 205). SAFETY DATA OBTAINED IN 1823 PATIENTS WITH ADVANCED SOLID TUMORS WHO RECEIVED LENVIMA AS A SINGLE AGENT ACROSS MULTIPLE CLINICAL STUDIES WAS USED TO FURTHER CHARACTERIZE THE RISKS OF SERIOUS ADVERSE REACTIONS. AMONG THE 1823 PATIENTS WHO RECEIVED LENVIMA AS A SINGLE AGENT, THE MEDIAN AGE WAS 61 YEARS (20 TO 89 YEARS), THE DOSE RANGE WAS 0.2 MG TO 32 MG DAILY, AND THE MEDIAN DURATION OF EXPOSURE WAS 5.6 MONTHS.
THE DATA BELOW REFLECT EXPOSURE TO LENVIMA IN 893 PATIENTS ENROLLED IN THE RANDOMIZED, ACTIVE-CONTROLLED TRIALS (REFLECT; STUDY 205), A RANDOMIZED, PLACEBO-CONTROLLED TRIAL (SELECT) AND A SINGLE ARM TRIAL (STUDY 111). THE MEDIAN DURATION OF EXPOSURE TO LENVIMA ACROSS THESE FOUR STUDIES RANGED FROM 6 TO 16 MONTHS. THE DEMOGRAPHIC AND EXPOSURE DATA FOR EACH CLINICAL TRIAL POPULATION ARE DESCRIBED IN THE SUBSECTIONS BELOW.
DIFFERENTIATED THYROID CANCER
THE SAFETY OF LENVIMA WAS EVALUATED IN SELECT, IN WHICH PATIENTS WITH RADIOACTIVE IODINE-REFRACTORY DIFFERENTIATED THYROID CANCER WERE RANDOMIZED (2:1) TO LENVIMA (N=261) OR PLACEBO (N=131) [SEE CLINICAL STUDIES]. THE MEDIAN TREATMENT DURATION WAS 16.1 MONTHS FOR LENVIMA. AMONG 261 PATIENTS WHO RECEIVED LENVIMA, MEDIAN AGE WAS 64 YEARS, 52% WERE FEMALES, 80% WERE WHITE, 18% WERE ASIAN, AND 2% WERE BLACK; AND 4% WERE HISPANIC/LATINO.
THE MOST COMMON ADVERSE REACTIONS OBSERVED IN LENVIMA-TREATED PATIENTS (?30%) WERE, IN ORDER OF DECREASING FREQUENCY, HYPERTENSION, FATIGUE, DIARRHEA, ARTHRALGIA/MYALGIA, DECREASED APPETITE, DECREASED WEIGHT, 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 LENVIMA; 18% OF PATIENTS DISCONTINUED LENVIMA FOR ADVERSE REACTIONS. THE MOST COMMON ADVERSE REACTIONS (AT LEAST 10%) RESULTING IN DOSE REDUCTIONS OF LENVIMA WERE HYPERTENSION (13%), PROTEINURIA (11%), DECREASED APPETITE (10%), AND DIARRHEA (10%); THE MOST COMMON ADVERSE REACTIONS (AT LEAST 1%) RESULTING IN DISCONTINUATION OF LENVIMA WERE HYPERTENSION (1%) AND ASTHENIA (1%).
TABLE 3 PRESENTS ADVERSE REACTIONS OCCURRING AT A HIGHER RATE IN LENVIMA-TREATED PATIENTS THAN PATIENTS RECEIVING PLACEBO IN THE DOUBLE-BLIND PHASE OF THE STUDY.
TABLE 3: ADVERSE REACTIONS OCCURRING IN PATIENTS WITH A BETWEEN-GROUP DIFFERENCE OF ?5% IN ALL GRADES OR ?2% IN GRADES 3 AND 4 IN SELECT (DTC)
ADVERSE REACTION LENVIMA 24 MG N=261 PLACEBO N=131
ALL GRADES (%) GRADES 3-4 (%) ALL GRADES (%) GRADES 3-4 (%)
VASCULAR
HYPERTENSIONA 73 44 16 4
HYPOTENSION 9 2 2 0
GASTROINTESTINAL
DIARRHEA 67 9 17 0
NAUSEA 47 2 25 1
STOMATITISB 41 5 8 0
VOMITING 36 2 15 0
ABDOMINAL PAINC 31 2 11 1
CONSTIPATION 29 0.4 15 1
ORAL PAIND 25 1 2 0
DRY MOUTH 17 0.4 8 0
DYSPEPSIA 13 0.4 4 0
GENERAL
FATIGUEE 67 11 35 4
EDEMA PERIPHERAL 21 0.4 8 0
MUSCULOSKELETAL AND CONNECTIVE TISSUE
ARTHRALGIA/MYALGIAF 62 5 28 3
METABOLISM AND NUTRITION
DECREASED APPETITE 54 7 18 1
DECREASED WEIGHT 51 13 15 1
DEHYDRATION 9 2 2 1
NERVOUS SYSTEM
HEADACHE 38 3 11 1
DYSGEUSIA 18 0 3 0
DIZZINESS 15 0.4 9 0
RENAL AND URINARY
PROTEINURIA 34 11 3 0
SKIN AND SUBCUTANEOUS TISSUE
PALMAR-PLANTAR ERYTHRODYSESTHESIA 32 3 1 0
RASHG 21 0.4 3 0
ALOPECIA 12 0 5 0
HYPERKERATOSIS 7 0 2 0
RESPIRATORY, THORACIC AND MEDIASTINAL
DYSPHONIA 31 1 5 0
COUGH 24 0 18 0
EPISTAXIS 12 0 1 0
PSYCHIATRIC
INSOMNIA. 12 0 3 0
INFECTIONS
URINARY TRACT INFECTION 11 1 5 0
DENTAL AND ORAL INFECTIONSH 10 1 1 0
CARDIAC
ELECTROCARDIOGRAM QT PROLONGED 9 2 2 0
A INCLUDES HYPERTENSION, HYPERTENSIVE CRISIS, INCREASED BLOOD PRESSURE DIASTOLIC, AND INCREASED BLOOD PRESSURE B INCLUDES APHTHOUS STOMATITIS, STOMATITIS, GLOSSITIS, MOUTH ULCERATION, AND MUCOSAL INFLAMMATION C INCLUDES ABDOMINAL DISCOMFORT, ABDOMINAL PAIN, LOWER ABDOMINAL PAIN, UPPER ABDOMINAL PAIN, ABDOMINAL TENDERNESS, EPIGASTRIC DISCOMFORT, AND GASTROINTESTINAL PAIN D INCLUDES ORAL PAIN, GLOSSODYNIA, AND OROPHARYNGEAL PAIN E INCLUDES ASTHENIA, FATIGUE, AND MALAISE F INCLUDES MUSCULOSKELETAL PAIN, BACK PAIN, PAIN IN EXTREMITY, ARTHRALGIA, AND MYALGIA G INCLUDES MACULAR RASH, MACULO-PAPULAR RASH, GENERALIZED RASH, AND RASH H INCLUDES GINGIVITIS, ORAL INFECTION, PAROTITIS, PERICORONITIS, PERIODONTITIS, SIALOADENITIS, TOOTH ABSCESS, AND TOOTH INFECTION
A CLINICALLY IMPORTANT ADVERSE REACTION OCCURRING MORE FREQUENTLY IN LENVIMA-TREATED PATIENTS THAN PATIENTS RECEIVING PLACEBO, BUT WITH AN INCIDENCE OF <5% WAS PULMONARY EMBOLISM (3%, INCLUDING FATAL REPORTS VS 2%, RESPECTIVELY).
LABORATORY ABNORMALITIES WITH A DIFFERENCE OF ?2% IN GRADE 3 - 4 EVENTS AND AT A HIGHER INCIDENCE IN THE LENVIMA ARM ARE PRESENTED IN TABLE 4.
TABLE 4: LABORATORY ABNORMALITIES WITH A DIFFERENCE OF ?2% IN GRADE 3 -4 EVENTS AND AT A HIGHER INCIDENCE IN THE LENVIMA ARMA,B IN SELECT (DTC)
LABORATORY ABNORMALITY LENVIMA 24 MG PLACEBO
GRADES 3-4 (%) GRADES 3-4 (%)
CHEMISTRY
HYPOCALCEMIA 9 2
HYPOKALEMIA 6 1
INCREASED ASPARTATE AMINOTRANSFERASE (AST) 5 0
INCREASED ALANINE AMINOTRANSFERASE (ALT) 4 0
INCREASED LIPASE 4 1
INCREASED CREATININE 3 0
HEMATOLOGY
THROMBOCYTOPENIA 2 0
A WITH AT LEAST 1 GRADE INCREASE FROM BASELINE B LABORATORY ABNORMALITY PERCENTAGE IS BASED ON THE NUMBER OF PATIENTS WHO HAD BOTH BASELINE AND AT LEAST ONE POST BASELINE LABORATORY MEASUREMENT FOR EACH PARAMETER. LENVIMA (N = 253 TO 258), PLACEBO (N = 129 TO 131)
THE FOLLOWING LABORATORY ABNORMALITIES (ALL GRADES) OCCURRED IN >5% OF LENVIMA-TREATED PATIENTS AND AT A RATE THAT WAS TWO-FOLD OR HIGHER THAN IN PATIENTS WHO RECEIVED PLACEBO: HYPOALBUMINEMIA, INCREASED ALKALINE PHOSPHATASE, HYPOMAGNESEMIA, HYPOGLYCEMIA, HYPERBILIRUBINEMIA, HYPERCALCEMIA, HYPERCHOLESTEROLEMIA, INCREASED SERUM AMYLASE, AND HYPERKALEMIA.
RENAL CELL CARCINOMA
THE SAFETY OF LENVIMA WAS EVALUATED IN STUDY 205, IN WHICH PATIENTS WITH UNRESECTABLE ADVANCED OR METASTATIC RENAL CELL CARCINOMA (RCC) WERE RANDOMIZED (1:1:1) TO LENVIMA 18 MG ORALLY ONCE DAILY WITH EVEROLIMUS 5 MG ORALLY ONCE DAILY (N=51), LENVIMA 24 MG ORALLY ONCE DAILY (N=52), OR EVEROLIMUS 10 MG ORALLY ONCE DAILY (N=50) [SEE CLINICAL STUDIES ]. THIS DATA ALSO INCLUDES PATIENTS ON THE DOSE ESCALATION PORTION OF THE STUDY WHO RECEIVED LENVIMA WITH EVEROLIMUS (N=11). THE MEDIAN TREATMENT DURATION WAS 8.1 MONTHS FOR LENVIMA WITH EVEROLIMUS. AMONG 62 PATIENTS WHO RECEIVED LENVIMA WITH EVEROLIMUS, THE MEDIAN AGE WAS 61 YEARS, 71% WERE MEN, AND 98% WERE WHITE.
THE MOST COMMON ADVERSE REACTIONS OBSERVED IN THE LENVIMA WITH EVEROLIMUS-TREATED GROUP (?30%) WERE, IN ORDER OF DECREASING FREQUENCY, DIARRHEA, FATIGUE, ARTHRALGIA/MYALGIA, DECREASED APPETITE, VOMITING, NAUSEA, STOMATITIS/ORAL INFLAMMATION, HYPERTENSION, PERIPHERAL EDEMA, COUGH, ABDOMINAL PAIN, DYSPNEA, RASH, DECREASED WEIGHT, HEMORRHAGIC EVENTS, AND PROTEINURIA. THE MOST COMMON SERIOUS ADVERSE REACTIONS (?5%) WERE RENAL FAILURE (11%), DEHYDRATION (10%), ANEMIA (6%), THROMBOCYTOPENIA (5%), DIARRHEA (5%), VOMITING (5%), AND DYSPNEA (5%).
ADVERSE REACTIONS LED TO DOSE REDUCTIONS OR INTERRUPTION IN 89% OF PATIENTS RECEIVING LENVIMA WITH EVEROLIMUS. THE MOST COMMON ADVERSE REACTIONS (?5%) RESULTING IN DOSE REDUCTIONS IN THE LENVIMA WITH EVEROLIMUS-TREATED GROUP WERE DIARRHEA (21%), FATIGUE (8%), THROMBOCYTOPENIA (6%), VOMITING (6%), NAUSEA (5%), AND PROTEINURIA (5%).
TREATMENT DISCONTINUATION DUE TO AN ADVERSE REACTION OCCURRED IN 29% OF PATIENTS IN THE LENVIMA WITH EVEROLIMUS-TREATED GROUP.
TABLE 5 PRESENTS THE ADVERSE REACTIONS IN >15% OF PATIENTS IN THE LENVIMA WITH EVEROLIMUS ARM. STUDY 205 WAS NOT DESIGNED TO DEMONSTRATE A STATISTICALLY SIGNIFICANT DIFFERENCE IN ADVERSE REACTION RATES FOR LENVIMA IN COMBINATION WITH EVEROLIMUS, AS COMPARED TO EVEROLIMUS FOR ANY SPECIFIC ADVERSE REACTION LISTED IN TABLE 5.
TABLE 5: ADVERSE REACTIONS OCCURRING IN >15% OF PATIENTS IN THE LENVIMA WITH EVEROLIMUS ARM IN STUDY 205 (RCC)
ADVERSE REACTIONS LENVIMA 18 MG WITH EVEROLIMUS 5 MG N=62 EVEROLIMUS 10 MG N=50
GRADE 1-4 (%) GRADE 3-4 (%) GRADE 1-4 (%) GRADE 3-4 (%)
ENDOCRINE
HYPOTHYROIDISM 24 0 2 0
GASTROINTESTINAL
DIARRHEA 81 19 34 2
VOMITING 48 7 12 0
NAUSEA 45 5 16 0
STOMATITIS/ORAL INFLAMMATIONA 44 2 50 4
ABDOMINAL PAINB 37 3 8 0
ORAL PAINC 23 2 4 0
DYSPEPSIA/GASTRO-ESOPHAGEAL REFLUX 21 0 12 0
CONSTIPATION 16 0 18 0
GENERAL
FATIGUED 73 18 40 2
PERIPHERAL EDEMA 42 2 20 0
PYREXIA/INCREASED BODY TEMPERATURE 21 2 10 2
METABOLISM AND NUTRITION
DECREASED APPETITE 53 5 18 0
DECREASED WEIGHT 34 3 8 0
MUSCULOSKELETAL AND CONNECTIVE TISSUE
ARTHRALGIA/MYALGIAE 55 5 32 0
MUSCULOSKELETAL CHEST PAIN 18 2 4 0
NERVOUS SYSTEM
HEADACHE 19 2 10 2
PSYCHIATRIC
INSOMNIA 16 2 2 0
RENAL AND URINARY
PROTEINURIA/URINE PROTEIN PRESENT 31 8 14 2
RENAL FAILURE EVENTF 18 10 12 2
RESPIRATORY, THORACIC AND MEDIASTINAL
COUGH 37 0 30 0
DYSPNEA/EXERTIONAL DYSPNEA 35 5 28 8
DYSPHONIA 18 0 4 0
SKIN AND SUBCUTANEOUS TISSUE
RASHG 35 0 40 0
VASCULAR
HYPERTENSION/INCREASED BLOOD PRESSURE 42 13 10 2
HEMORRHAGIC EVENTSH 32 6 26 2
A INCLUDES APHTHOUS STOMATITIS, GINGIVAL INFLAMMATION, GLOSSITIS, AND MOUTH ULCERATION B INCLUDES ABDOMINAL DISCOMFORT, GASTROINTESTINAL PAIN, LOWER ABDOMINAL PAIN, AND UPPER ABDOMINAL PAIN C INCLUDES GINGIVAL PAIN, GLOSSODYNIA, AND OROPHARYNGEAL PAIN D INCLUDES ASTHENIA, FATIGUE, LETHARGY AND MALAISE E INCLUDES ARTHRALGIA, BACK PAIN, EXTREMITY PAIN, MUSCULOSKELETAL PAIN, AND MYALGIA F INCLUDES BLOOD CREATININE INCREASED, BLOOD UREA INCREASED, CREATININE RENAL CLEARANCE DECREASED, NEPHROPATHY TOXIC, RENAL FAILURE, RENAL FAILURE ACUTE, AND RENAL IMPAIRMENT G INCLUDES ERYTHEMA, ERYTHEMATOUS RASH, GENITAL RASH, MACULAR RASH, MACULO-PAPULAR RASH, PAPULAR RASH, PRURITIC RASH, PUSTULAR RASH, AND SEPTIC RASH H INCLUDES HEMORRHAGIC DIARRHEA, EPISTAXIS, GASTRIC HEMORRHAGE, HEMARTHROSIS, HEMATOMA, HEMATURIA, HEMOPTYSIS, LIP HEMORRHAGE, RENAL HEMATOMA, AND SCROTAL HEMATOCELE
IN TABLE 6, GRADE 3-4 LABORATORY ABNORMALITIES OCCURRING IN ?3% OF PATIENTS IN THE LENVIMA WITH EVEROLIMUS ARM ARE PRESENTED.
TABLE 6: GRADE 3-4 LABORATORY ABNORMALITIES OCCURRING IN ?3% OF PATIENTS IN THE LENVIMA WITH EVEROLIMUS ARMA,B IN STUDY 205 (RCC)
LABORATORY ABNORMALITY LENVIMA 18 MG WITH EVEROLIMUS 5 MG EVEROLIMUS 10 MG
GRADES 3-4 (%) GRADES 3-4 (%)
CHEMISTRY
HYPERTRIGLYCERIDEMIA 18 18
INCREASED LIPASE 13 12
HYPERCHOLESTEROLEMIA 11 0
HYPONATREMIA 11 6
HYPOPHOSPHATEMIA 11 6
HYPERKALEMIA 6 2
HYPOCALCEMIA 6 2
HYPOKALEMIA 6 2
INCREASED ASPARTATE AMINOTRANSFERASE (AST) 3 0
INCREASED ALANINE AMINOTRANSFERASE (ALT) 3 2
INCREASED ALKALINE PHOSPHATASE 3 0
HYPERGLYCEMIA 3 16
INCREASED CREATINE KINASE 3 4
HEMATOLOGY
LYMPHOPENIA 10 20
ANEMIA 8 16
THROMBOCYTOPENIA 5 0
A WITH AT LEAST 1 GRADE INCREASE FROM BASELINE B LABORATORY ABNORMALITY PERCENTAGE IS BASED ON THE NUMBER OF PATIENTS WHO HAD BOTH BASELINE AND AT LEAST ONE POST BASELINE LABORATORY MEASUREMENT FOR EACH PARAMETER. LENVIMA WITH EVEROLIMUS (N = 62), EVEROLIMUS (N = 50).
HEPATOCELLULAR CARCINOMA
THE SAFETY OF LENVIMA WAS EVALUATED IN REFLECT, WHICH RANDOMIZED (1:1) PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA (HCC) TO LENVIMA (N=476) OR SORAFENIB (N=475) [SEE CLINICAL STUDIES ]. THE DOSE OF LENVIMA WAS 12 MG ORALLY ONCE DAILY FOR PATIENTS WITH A BASELINE BODY WEIGHT OF ?60 KG AND 8 MG ORALLY ONCE DAILY FOR PATIENTS WITH A BASELINE BODY WEIGHT OF <60 KG. THE DOSE OF SORAFENIB WAS 400 MG ORALLY TWICE DAILY. DURATION OF TREATMENT WAS ?6 MONTHS IN 49% AND 32% OF PATIENTS IN THE LENVIMA AND SORAFENIB GROUPS, RESPECTIVELY. AMONG THE 476 PATIENTS WHO RECEIVED LENVIMA IN REFLECT, THE MEDIAN AGE WAS 63 YEARS, 85% WERE MEN, 28% WERE WHITE AND 70% WERE ASIAN.
THE MOST COMMON ADVERSE REACTIONS OBSERVED IN THE LENVIMA-TREATED PATIENTS (?20%) WERE, IN ORDER OF DECREASING FREQUENCY, HYPERTENSION, FATIGUE, DIARRHEA, DECREASED APPETITE, ARTHRALGIA/MYALGIA, DECREASED WEIGHT, ABDOMINAL PAIN, PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME, PROTEINURIA, DYSPHONIA, HEMORRHAGIC EVENTS, HYPOTHYROIDISM, AND NAUSEA.
THE MOST COMMON SERIOUS ADVERSE REACTIONS (?2%) IN LENVIMA-TREATED PATIENTS WERE HEPATIC ENCEPHALOPATHY (5%), HEPATIC FAILURE (3%), ASCITES (3%), AND DECREASED APPETITE (2%).
ADVERSE REACTIONS LED TO DOSE REDUCTION OR INTERRUPTION IN 62% OF PATIENTS RECEIVING LENVIMA. THE MOST COMMON ADVERSE REACTIONS (?5%) RESULTING IN DOSE REDUCTION OR INTERRUPTION OF LENVIMA WERE FATIGUE (9%), DECREASED APPETITE (8%), DIARRHEA (8%), PROTEINURIA (7%), HYPERTENSION (6%), AND PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME (5%).
TREATMENT DISCONTINUATION DUE TO ADVERSE REACTIONS OCCURRED IN 20% OF PATIENTS IN THE LENVIMA-TREATED GROUP. THE MOST COMMON ADVERSE REACTIONS (?1%) RESULTING IN DISCONTINUATION OF LENVIMA WERE FATIGUE (1%), HEPATIC ENCEPHALOPATHY (2%), HYPERBILIRUBINEMIA (1%), AND HEPATIC FAILURE (1%).
TABLE 7 SUMMARIZES THE ADVERSE REACTIONS THAT OCCURRED IN ?10% OF PATIENTS RECEIVING LENVIMA IN REFLECT. REFLECT WAS NOT DESIGNED TO DEMONSTRATE A STATISTICALLY SIGNIFICANT REDUCTION IN ADVERSE REACTION RATES FOR LENVIMA, AS COMPARED TO SORAFENIB, FOR ANY SPECIFIED ADVERSE REACTION LISTED IN TABLE 7.
TABLE 7: ADVERSE REACTIONS OCCURRING IN ?10% OF PATIENTS IN THE LENVIMA ARM IN REFLECT (HCC)
ADVERSE REACTION LENVIMA 8 MG/12 MG N=476 SORAFENIB 800 MG N=475
GRADE 1-4 (%) GRADE 3-4 (%) GRADE 1-4 (%) GRADE 3-4 (%)
ENDOCRINE
HYPOTHYROIDISMA 21 0 3 0
GASTROINTESTINAL
DIARRHEA 39 4 46 4
ABDOMINAL PAINB 30 3 28 4
NAUSEA 20 1 14 1
VOMITING 16 1 8 1
CONSTIPATION 16 1 11 0
ASCITESC 15 4 11 3
STOMATITISD 11 0.4 14 1
GENERAL
FATIGUEE 44 7 36 6
PYREXIAF 15 0 14 0.2
PERIPHERAL EDEMA 14 1 7 0.2
METABOLISM AND NUTRITION
DECREASED APPETITE 34 5 27 1
DECREASED WEIGHT 31 8 22 3
MUSCULOSKELETAL AND CONNECTIVE TISSUE
ARTHRALGIA/MYALGIAG 31 1 20 2
NERVOUS SYSTEM
HEADACHE 10 1 8 0
RENAL AND URINARY
PROTEINURIAH 26 6 12 2
RESPIRATORY, THORACIC AND MEDIASTINAL
DYSPHONIA 24 0.2 12 0
SKIN AND SUBCUTANEOUS TISSUE
PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME 27 3 52 11
RASHI 14 0 24 2
VASCULAR
HYPERTENSIONK 45 24 31 15
HEMORRHAGIC EVENTSK 23 4 15 4
A INCLUDES HYPOTHYROIDISM, BLOOD THYROID STIMULATING HORMONE INCREASED. B INCLUDES ABDOMINAL DISCOMFORT, ABDOMINAL PAIN, ABDOMINAL TENDERNESS, EPIGASTRIC DISCOMFORT, GASTROINTESTINAL PAIN, LOWER ABDOMINAL PAIN, AND UPPER ABDOMINAL PAIN C INCLUDES ASCITES AND MALIGNANT ASCITES D INCLUDES APHTHOUS ULCER, GINGIVAL EROSION, GINGIVAL ULCERATION, GLOSSITIS, MOUTH ULCERATION, ORAL MUCOSAL BLISTERING, AND STOMATITIS E INCLUDES ASTHENIA, FATIGUE, LETHARGY AND MALAISE F INCLUDES INCREASED BODY TEMPERATURE, PYREXIA G INCLUDES ARTHRALGIA, BACK PAIN, EXTREMITY PAIN, MUSCULOSKELETAL CHEST PAIN, MUSCULOSKELETAL DISCOMFORT, MUSCULOSKELETAL PAIN, AND MYALGIA H INCLUDES PROTEINURIA, INCREASED URINE PROTEIN, PROTEIN URINE PRESENT I INCLUDES ERYTHEMA, ERYTHEMATOUS RASH, EXFOLIATIVE RASH, GENITAL RASH, MACULAR RASH, MACULO-PAPULAR RASH, PAPULAR RASH, PRURITIC RASH, PUSTULAR RASH AND RASH J INCLUDES INCREASED DIASTOLIC BLOOD PRESSURE, INCREASED BLOOD PRESSURE, HYPERTENSION AND ORTHOSTATIC HYPERTENSION K INCLUDES ALL HEMORRHAGE TERMS. HEMORRHAGE TERMS THAT OCCURRED IN 5 OR MORE SUBJECTS IN EITHER TREATMENT GROUP INCLUDE: EPISTAXIS, HEMATURIA, GINGIVAL BLEEDING, HEMOPTYSIS, ESOPHAGEAL VARICES HEMORRHAGE, HEMORRHOIDAL HEMORRHAGE, MOUTH HEMORRHAGE, RECTAL HEMORRHAGE AND UPPER GASTROINTESTINAL HEMORRHAGE
IN TABLE 8, GRADE 3-4 LABORATORY ABNORMALITIES OCCURRING IN ?2% OF PATIENTS IN THE LENVIMA ARM IN REFLECT (HCC) ARE PRESENTED.
TABLE 8: GRADE 3-4 LABORATORY ABNORMALITIES OCCURRING IN ?2% OF PATIENTS IN THE LENVIMA ARMA,B IN REFLECT (HCC)
LABORATORY ABNORMALITY LENVATINIB (%) SORAFENIB (%)
CHEMISTRY
INCREASED GGT 17 20
HYPONATREMIA 15 9
HYPERBILIRUBINEMIA 13 10
INCREASED ASPARTATE AMINOTRANSFERASE (AST) 12 18
INCREASED ALANINE AMINOTRANSFERASE (ALT) 8 9
INCREASED ALKALINE PHOSPHATASE 7 5
INCREASED LIPASE 6 17
HYPOKALEMIA 3 4
HYPERKALEMIA 3 2
DECREASED ALBUMIN 3 1
INCREASED CREATININE 2 2
HEMATOLOGY
THROMBOCYTOPENIA 10 8
LYMPHOPENIA 8 9
NEUTROPENIA 7 3
ANEMIA 4 5
A WITH AT LEAST 1 GRADE INCREASE FROM BASELINE B LABORATORY ABNORMALITY PERCENTAGE IS BASED ON THE NUMBER OF PATIENTS WHO HAD BOTH BASELINE AND AT LEAST ONE POST BASELINE LABORATORY MEASUREMENT FOR EACH PARAMETER. LENVIMA (N=278 TO 470) AND SORAFENIB (N=260 TO 473)