INDICATIONS
HALAVEN IS INDICATED FOR THE TREATMENT OF PATIENTS WITH METASTATIC BREAST CANCER WHO HAVE PREVIOUSLY RECEIVED AT LEAST TWO CHEMOTHERAPEUTIC REGIMENS FOR THE TREATMENT OF METASTATIC DISEASE. PRIOR THERAPY SHOULD HAVE INCLUDED AN ANTHRACYCLINE AND A TAXANE IN EITHER THE ADJUVANT OR METASTATIC SETTING.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
HALAVEN (ERIBULIN MESYLATE) INJECTION, 1 MG/2 ML (0.5 MG/ML).
STORAGE AND HANDLING
NDC 62856-389-01 ERIBULIN MESYLATE INJECTION, 1 MG/2 ML, IN A SINGLE-USE VIAL. ONE VIAL PER CARTON. STORE AT 25°C (77°F); EXCURSIONS PERMITTED TO 15° – 30° C (59° -86° F). DO NOT FREEZE. STORE THE VIALS IN THEIR ORIGINAL CARTONS.
DISTRIBUTED BY: EISAI INC. WOODCLIFF LAKE, NJ 07677. REVISED AUGUST 2014
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSE
THE RECOMMENDED DOSE OF HALAVEN IS 1.4 MG/M² ADMINISTERED INTRAVENOUSLY OVER 2 TO 5 MINUTES ON DAYS 1 AND 8 OF A 21-DAY CYCLE.
THE RECOMMENDED DOSE OF HALAVEN IN PATIENTS WITH MILD HEPATIC IMPAIRMENT (CHILD-PUGH A) IS 1.1 MG/M² ADMINISTERED INTRAVENOUSLY OVER 2 TO 5 MINUTES ON DAYS 1 AND 8 OF A 21-DAY CYCLE [SEE USE IN SPECIFIC POPULATIONS].
THE RECOMMENDED DOSE OF HALAVEN IN PATIENTS WITH MODERATE HEPATIC IMPAIRMENT (CHILD-PUGH B) IS 0.7 MG/M² ADMINISTERED INTRAVENOUSLY OVER 2 TO 5 MINUTES ON DAYS 1 AND 8 OF A 21-DAY CYCLE [SEE USE IN SPECIFIC POPULATIONS].
THE RECOMMENDED DOSE OF HALAVEN IN PATIENTS WITH MODERATE RENAL IMPAIRMENT (CREATININE CLEARANCE OF 30-50 ML/MIN) IS 1.1 MG/M² ADMINISTERED INTRAVENOUSLY OVER 2 TO 5 MINUTES ON DAYS 1 AND 8 OF A 21-DAY CYCLE [SEE USE IN SPECIFIC POPULATIONS].
DOSE MODIFICATION
ASSESS FOR PERIPHERAL NEUROPATHY AND OBTAIN COMPLETE BLOOD CELL COUNTS PRIOR TO EACH DOSE.
RECOMMENDED DOSE DELAYS
DO NOT ADMINISTER HALAVEN ON DAY 1 OR DAY 8 FOR ANY OF THE FOLLOWING:
ANC < 1,000/MM³
PLATELETS < 75,000/MM³
GRADE 3 OR 4 NON-HEMATOLOGICAL TOXICITIES.
THE DAY 8 DOSE MAY BE DELAYED FOR A MAXIMUM OF 1 WEEK.
IF TOXICITIES DO NOT RESOLVE OR IMPROVE TO = GRADE 2 SEVERITY BY DAY 15, OMIT THE DOSE.
IF TOXICITIES RESOLVE OR IMPROVE TO = GRADE 2 SEVERITY BY DAY 15, ADMINISTER HALAVEN AT A REDUCED DOSE AND INITIATE THE NEXT CYCLE NO SOONER THAN 2 WEEKS LATER.
RECOMMENDED DOSE REDUCTIONS
IF A DOSE HAS BEEN DELAYED FOR TOXICITY AND TOXICITIES HAVE RECOVERED TO GRADE 2 SEVERITY OR LESS, RESUME HALAVEN AT A REDUCED DOSE AS SET OUT IN TABLE 1.
DO NOT RE-ESCALATE HALAVEN DOSE AFTER IT HAS BEEN REDUCED.
TABLE 1 : RECOMMENDED DOSE REDUCTIONS
EVENT DESCRIPTION
RECOMMENDED HALAVEN DOSE
PERMANENTLY REDUCE THE 1.4 MG/M² HALAVEN DOSE FOR ANY OF THE FOLLOWING:
ANC < 500/MM³ FOR > 7 DAYS
ANC < 1,000 /MM³ WITH FEVER OR INFECTION
PLATELETS < 25,000/MM³
1.1 MG/M²
PLATELETS < 50,000/MM³ REQUIRING TRANSFUSION
NON-HEMATOLOGIC GRADE 3 OR 4 TOXICITIES
OMISSION OR DELAY OF DAY 8 HALAVEN DOSE IN PREVIOUS CYCLE FOR TOXICITY
OCCURRENCE OF ANY EVENT REQUIRING PERMANENT DOSE REDUCTION WHILE RECEIVING 1.1 MG/M²
0.7 MG/M²
OCCURRENCE OF ANY EVENT REQUIRING PERMANENT DOSE REDUCTION WHILE RECEIVING 0.7 MG/M²
DISCONTINUE HALAVEN
ANC = ABSOLUTE NEUTROPHIL COUNT.
TOXICITIES GRADED IN ACCORDANCE WITH NATIONAL CANCER INSTITUTE (NCI) COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) VERSION 3.0.
INSTRUCTIONS FOR PREPARATION AND ADMINISTRATION
ASEPTICALLY WITHDRAW THE REQUIRED AMOUNT OF HALAVEN FROM THE SINGLE-USE VIAL AND ADMINISTER UNDILUTED OR DILUTED IN 100 ML OF 0.9% SODIUM CHLORIDE INJECTION, USP.
DO NOT DILUTE IN OR ADMINISTER THROUGH AN INTRAVENOUS LINE CONTAINING SOLUTIONS WITH DEXTROSE. DO NOT ADMINISTER IN THE SAME INTRAVENOUS LINE CONCURRENT WITH THE OTHER MEDICINAL PRODUCTS.
STORE UNDILUTED HALAVEN IN THE SYRINGE FOR UP TO 4 HOURS AT ROOM TEMPERATURE OR FOR UP TO 24 HOURS UNDER REFRIGERATION (40°F OR/ 4°C). STORE DILUTED SOLUTIONS OF HALAVEN FOR UP TO 4 HOURS AT ROOM TEMPERATURE OR UP TO 24 HOURS UNDER REFRIGERATION.
DISCARD UNUSED PORTIONS OF THE VIAL.
SIDE EFFECTS
CLINICAL TRIALS EXPERIENCE
THE FOLLOWING ADVERSE REACTIONS ARE DISCUSSED IN DETAIL IN OTHER SECTIONS OF THE LABELING:
NEUTROPENIA [SEE WARNINGS AND PRECAUTIONS].
PERIPHERAL NEUROPATHY [SEE WARNINGS AND PRECAUTIONS].
QT INTERVAL PROLONGATION [SEE WARNINGS AND PRECAUTIONS].
THE MOST COMMON ADVERSE REACTIONS ( = 25%) REPORTED IN PATIENTS RECEIVING HALAVEN WERE NEUTROPENIA, ANEMIA, ASTHENIA/FATIGUE, ALOPECIA, PERIPHERAL NEUROPATHY, NAUSEA, AND CONSTIPATION. THE MOST COMMON SERIOUS ADVERSE REACTIONS REPORTED IN PATIENTS RECEIVING HALAVEN WERE FEBRILE NEUTROPENIA (4%) AND NEUTROPENIA (2%). THE MOST COMMON ADVERSE REACTION RESULTING IN DISCONTINUATION OF HALAVEN WAS PERIPHERAL NEUROPATHY (5%).
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, THE ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COMPARED TO RATES IN OTHER CLINICAL TRIALS AND MAY NOT REFLECT THE RATES OBSERVED IN CLINICAL PRACTICE.
IN CLINICAL TRIALS, HALAVEN HAS BEEN ADMINISTERED TO 1,222 PATIENTS WITH MULTIPLE TUMOR TYPES, INCLUDING 240 PATIENTS EXPOSED TO HALAVEN FOR 6 MONTHS OR LONGER. THE MAJORITY OF THE 1,222 PATIENTS WERE WOMEN (82%) WITH A MEDIAN AGE OF 58 YEARS (RANGE: 26 TO 91 YEARS). THE RACIAL AND ETHNIC DISTRIBUTION WAS CAUCASIAN (83%), BLACK (5%), ASIAN (2%), AND OTHER (5%).
THE ADVERSE REACTIONS DESCRIBED IN TABLE 2 WERE IDENTIFIED IN 750 PATIENTS TREATED IN STUDY 1 [SEE CLINICAL STUDIES]. IN STUDY 1, PATIENTS WERE RANDOMIZED (2:1) TO RECEIVE EITHER HALAVEN (1.4 MG/M² ON DAYS 1 AND 8 OF A 21-DAY CYCLE) OR SINGLE AGENT TREATMENT CHOSEN BY THEIR PHYSICIAN (CONTROL GROUP). A TOTAL OF 503 PATIENTS RECEIVED HALAVEN, AND 247 PATIENTS IN THE CONTROL GROUP RECEIVED THERAPY CONSISTING OF CHEMOTHERAPY [TOTAL 97% (ANTHRACYCLINES 10%, CAPECITABINE 18%, GEMCITABINE 19%, TAXANES 15%, VINORELBINE 25%, OTHER CHEMOTHERAPIES 10%)] OR HORMONAL THERAPY (3%). THE MEDIAN DURATION OF EXPOSURE WAS 118 DAYS FOR PATIENTS RECEIVING HALAVEN AND 63 DAYS FOR PATIENTS RECEIVING CONTROL THERAPY. TABLE 2 REPORTS THE MOST COMMON ADVERSE REACTIONS OCCURRING IN AT LEAST 10% OF PATIENTS IN EITHER GROUP.
TABLE 2 : ADVERSE REACTIONS WITH A PER-PATIENT INCIDENCE OF AT LEAST 10% IN STUDY 1
MEDDRA VER 10.0
HALAVEN N=503
CONTROL GROUP N=247
ALL GRADES
= GRADE 3
ALL GRADES
= GRADE 3
BLOOD AND LYMPHATIC SYSTEM DISORDERSA
NEUTROPENIA
82%
57%
53%
23%
ANEMIA
58%
2%
55%
4%
NERVOUS SYSTEM DISORDERS
PERIPHERAL NEUROPATHYB
35%
8%
16%
2%
HEADACHE
19%
< 1%
12%
< 1%
GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS
ASTHENIA/FATIGUE
54%
10%
40%
11%
MUCOSAL INFLAMMATION
9%
1%
10%
2%
PYREXIA
21%
< 1%
13%
< 1%
GASTROINTESTINAL DISORDERS
CONSTIPATION
25%
1%
21%
1%
DIARRHEA
18%
0
18%
0
NAUSEA
35%
1%
28%
3%
VOMITING
18%
1%
18%
1%
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
ARTHRALGIA/MYALGIA
22%
< 1%
12%
1%
BACK PAIN
16%
1%
7%
2%
BONE PAIN
12%
2%
9%
2%
PAIN IN EXTREMITY
11%
1%
10%
1%
INVESTIGATIONS
WEIGHT DECREASED
21%
1%
14%
< 1%
METABOLISM AND NUTRITION DISORDERS
ANOREXIA
20%
1%
13%
1%
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS
COUGH
14%
0
9%
0
DYSPNEA
16%
4%
13%
4%
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
ALOPECIA
45%
NAC
10%
NAC
INFECTIONS AND INFESTATIONS
URINARY TRACT INFECTION
10%
1%
5%
0
ABASED UPON LABORATORY DATA.
BINCLUDES NEUROPATHY PERIPHERAL, NEUROPATHY, PERIPHERAL MOTOR NEUROPATHY, POLYNEUROPATHY, PERIPHERAL SENSORY NEUROPATHY, AND PARAESTHESIA.
CNOT APPLICABLE; (GRADING SYSTEM DOES NOT SPECIFY > GRADE 2 FOR ALOPECIA).
CYTOPENIAS: GRADE 3 NEUTROPENIA OCCURRED IN 28% (143/503) OF PATIENTS WHO RECEIVED HALAVEN IN STUDY 1, AND 29% (144/503) OF PATIENTS EXPERIENCED GRADE 4 NEUTROPENIA. FEBRILE NEUTROPENIA OCCURRED IN 5% (23/503) OF PATIENTS; TWO PATIENTS (0.4%) DIED FROM COMPLICATIONS OF FEBRILE NEUTROPENIA. DOSE REDUCTION DUE TO NEUTROPENIA WAS REQUIRED IN 12% (62/503) OF PATIENTS AND DISCONTINUATION WAS REQUIRED IN < 1% OF PATIENTS. THE MEAN TIME TO NADIR WAS 13 DAYS AND THE MEAN TIME TO RECOVERY FROM SEVERE NEUTROPENIA ( < 500/MM³) WAS 8 DAYS. GRADE 3 OR GREATER THROMBOCYTOPENIA OCCURRED IN 1% (7/503) OF PATIENTS. G-CSF (GRANULOCYTE COLONY-STIMULATING FACTOR) OR GM-CSF (GRANULOCYTE–MACROPHAGE COLONY-STIMULATING FACTOR) WAS USED IN 19% OF PATIENTS WHO RECEIVED HALAVEN.
PERIPHERAL NEUROPATHY: IN STUDY 1, 17 % OF ENROLLED PATIENTS HAD GRADE 1 PERIPHERAL NEUROPATHY AND 3% OF PATIENTS HAD GRADE 2 PERIPHERAL NEUROPATHY AT BASELINE. DOSE REDUCTION DUE TO PERIPHERAL NEUROPATHY WAS REQUIRED BY 3% (14/503) OF PATIENTS WHO RECEIVED HALAVEN. FOUR PERCENT (20/503) OF PATIENTS EXPERIENCED PERIPHERAL MOTOR NEUROPATHY OF ANY GRADE AND 2% (8/503) OF PATIENTS DEVELOPED GRADE 3 PERIPHERAL MOTOR NEUROPATHY.
LIVER FUNCTION TEST ABNORMALITIES: AMONG PATIENTS WITH GRADE 0 OR 1 ALT LEVELS AT BASELINE, 18% OF HALAVEN-TREATED PATIENTS EXPERIENCED GRADE 2 OR GREATER ALT ELEVATION. ONE HALAVEN-TREATED PATIENT WITHOUT DOCUMENTED LIVER METASTASES HAD CONCOMITANT GRADE 2 ELEVATIONS IN BILIRUBIN AND ALT; THESE ABNORMALITIES RESOLVED AND DID NOT RECUR WITH RE-EXPOSURE TO HALAVEN.
LESS COMMON ADVERSE REACTIONS: THE FOLLOWING ADDITIONAL ADVERSE REACTIONS WERE REPORTED IN = 5% TO < 10% OF THE HALAVEN-TREATED GROUP:
EYE DISORDERS: INCREASED LACRIMATION
GASTROINTESTINAL DISORDERS: DYSPEPSIA, ABDOMINAL PAIN, STOMATITIS, DRY MOUTH
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: PERIPHERAL EDEMA
INFECTIONS AND INFESTATIONS: UPPER RESPIRATORY TRACT INFECTION
METABOLISM AND NUTRITION DISORDERS: HYPOKALEMIA
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: MUSCLE SPASMS, MUSCULAR WEAKNESS
NERVOUS SYSTEM DISORDERS: DYSGEUSIA, DIZZINESS
PSYCHIATRIC DISORDERS: INSOMNIA, DEPRESSION
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: RASH
POSTMARKETING EXPERIENCE
THE FOLLOWING ADVERSE DRUG REACTIONS HAVE BEEN IDENTIFIED DURING POST-APPROVAL OF HALAVEN. BECAUSE THESE REACTIONS ARE REPORTED VOLUNTARILY FROM A POPULATION OF UNCERTAIN SIZE, IT IS NOT ALWAYS POSSIBLE TO RELIABLY ESTIMATE THEIR FREQUENCY OR ESTABLISH A CAUSAL RELATIONSHIP TO DRUG EXPOSURE.
BLOOD AND LYMPHATIC SYSTEM DISORDERS: LYMPHOPENIA
GASTROINTESTINAL DISORDERS: PANCREATITIS
HEPATOBILIARY DISORDERS: HEPATOTOXICITY
IMMUNE SYSTEM DISORDERS: DRUG HYPERSENSITIVITY
INFECTIONS AND INFESTATIONS: PNEUMONIA, SEPSIS/NEUTROPENIC SEPSIS
METABOLISM AND NUTRITION DISORDERS: HYPOMAGNESEMIA, DEHYDRATION
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: INTERSTITIAL LUNG DISEASE
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: PRURITUS
READ THE HALAVEN (ERIBULIN MESYLATE) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
OVERDOSAGE OF HALAVEN HAS BEEN REPORTED AT APPROXIMATELY 4 TIMES THE RECOMMENDED DOSE, WHICH RESULTED IN GRADE 3 NEUTROPENIA LASTING SEVEN DAYS AND A GRADE 3 HYPERSENSITIVITY REACTION LASTING ONE DAY.
THERE IS NO KNOWN ANTIDOTE FOR HALAVEN OVERDOSE.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
ERIBULIN INHIBITS THE GROWTH PHASE OF MICROTUBULES WITHOUT AFFECTING THE SHORTENING PHASE AND SEQUESTERS TUBULIN INTO NONPRODUCTIVE AGGREGATES. ERIBULIN EXERTS ITS EFFECTS VIA A TUBULIN-BASED ANTIMITOTIC MECHANISM LEADING TO G 2/M CELL-CYCLE BLOCK, DISRUPTION OF MITOTIC SPINDLES, AND, ULTIMATELY, APOPTOTIC CELL DEATH AFTER PROLONGED MITOTIC BLOCKAGE.
PHARMACOKINETICS
THE PHARMACOKINETICS (PK) OF ERIBULIN IS LINEAR WITH A MEAN ELIMINATION HALF-LIFE OF APPROXIMATELY 40 HOURS, A MEAN VOLUME OF DISTRIBUTION OF 43 L/M² TO 114 L/M² AND MEAN CLEARANCE OF 1.16 L/HR/M² TO 2.42 L/HR/M² OVER THE DOSE RANGE OF 0.25 MG/M² TO 4.0 MG/M². THE HUMAN PLASMA PROTEIN BINDING OF ERIBULIN AT CONCENTRATIONS OF 100 NG/ML TO 1,000 NG/ML RANGES FROM 49% TO 65% ERIBULIN EXPOSURE AFTER MULTIPLE DOSING IS COMPARABLE TO THAT FOLLOWING A SINGLE DOSE. NO ACCUMULATION OF ERIBULIN IS OBSERVED WITH WEEKLY ADMINISTRATION.
METABOLISM
UNCHANGED ERIBULIN WAS THE MAJOR CIRCULATING SPECIES IN PLASMA FOLLOWING ADMINISTRATION OF 14C-ERIBULIN TO PATIENTS. METABOLITE CONCENTRATIONS REPRESENTED < 0.6% OF PARENT COMPOUND, CONFIRMING THAT THERE ARE NO MAJOR HUMAN METABOLITES OF ERIBULIN. CYTOCHROME P450 3A4 (CYP3A4) NEGLIGIBLY METABOLIZES ERIBULIN IN VITRO.
ELIMINATION
ERIBULIN IS ELIMINATED PRIMARILY IN FECES UNCHANGED. AFTER ADMINISTRATION OF 14C-ERIBULIN TO PATIENTS, APPROXIMATELY 82% OF THE DOSE WAS ELIMINATED IN FECES AND 9% IN URINE. UNCHANGED ERIBULIN ACCOUNTED FOR APPROXIMATELY 88% AND 91% OF THE DOSE IN FECES AND URINE, RESPECTIVELY.
EFFECTS OF AGE, GENDER, AND RACE
BASED ON A POPULATION PHARMACOKINETIC ANALYSIS WITH DATA COLLECTED FROM 340 PATIENTS, GENDER, RACE, AND AGE DO NOT HAVE A CLINICALLY MEANINGFUL EFFECT ON THE PK OF ERIBULIN.
DRUG INTERACTIONS
EFFECT OF OTHER DRUGS ON HALAVEN
THE EFFECT OF A STRONG CYP3A4 INHIBITOR AND A P-GP INHIBITOR, KETOCONAZOLE, ON THE PK OF ERIBULIN WAS STUDIED IN A CROSSOVER TRIAL OF 12 PATIENTS WITH ADVANCED SOLID TUMORS. NO CLINICALLY RELEVANT PK INTERACTION WAS OBSERVED WHEN HALAVEN WAS ADMINISTERED WITH OR WITHOUT KETOCONAZOLE (THE GEOMETRIC MEAN RATIO OF THE AUC: 0.97; 90%CI: 0.83, 1.12).
THE EFFECT OF A CYP3A4 INDUCER, RIFAMPIN, ON THE PK OF ERIBULIN WAS STUDIED IN A CROSSOVER TRIAL OF 14 PATIENTS WITH ADVANCED SOLID TUMORS. NO CLINICALLY RELEVANT PK INTERACTION WAS OBSERVED WHEN HALAVEN WAS ADMINISTERED WITH OR WITHOUT RIFAMPIN (THE GEOMETRIC MEAN RATIO OF THE AUC: 1.10; 90CI%: 0.91, 1.34).
EFFECT OF HALAVEN ON OTHER DRUGS
ERIBULIN SHOWS NO INDUCTION POTENTIAL FOR CYP1A, CYP2C9, CYP2C19, AND CYP3A IN PRIMARY HUMAN HEPATOCYTES. ERIBULIN INHIBITS CYP3A4 ACTIVITY IN HUMAN LIVER MICROSOMES, BUT IT IS UNLIKELY THAT ERIBULIN WILL SUBSTANTIALLY INCREASE THE PLASMA LEVELS OF CYP3A4 SUBSTRATES. NO SIGNIFICANT INHIBITION OF CYP1A2, CYP2C9, CYP2C19, CYP2D6, OR CYP2E1 WAS DETECTED WITH ERIBULIN CONCENTRATIONS UP TO 5 ?M IN POOLED HUMAN LIVER MICROSOMES. IN VITRO DRUG INTERACTION STUDIES INDICATE THAT ERIBULIN DOES NOT INHIBIT DRUGS THAT ARE SUBSTRATES OF THESE ENZYMES AND IT IS UNLIKELY THAT ERIBULIN WILL AFFECT PLASMA LEVELS OF DRUGS THAT ARE SUBSTRATES OF CYP ENZYMES. ERIBULIN IS A SUBSTRATE AND A WEAK INHIBITOR OF THE DRUG EFFLUX TRANSPORTER P-GP IN VITRO.
SPECIFIC POPULATIONS
HEPATIC IMPAIRMENT
A STUDY EVALUATED THE PK OF ERIBULIN IN PATIENTS WITH MILD (CHILD-PUGH A; N=7) AND MODERATE (CHILD-PUGH B; N=5) HEPATIC IMPAIRMENT. COMPARED TO PATIENTS WITH NORMAL HEPATIC FUNCTION (N=6), ERIBULIN EXPOSURE INCREASED 1.8-FOLD AND 2.5-FOLD IN PATIENTS WITH MILD AND MODERATE HEPATIC IMPAIRMENT, RESPECTIVELY. ADMINISTRATION OF HALAVEN AT A DOSE OF 1.1 MG/M² TO PATIENTS WITH MILD HEPATIC IMPAIRMENT AND 0.7 MG/M² TO PATIENTS WITH MODERATE HEPATIC IMPAIRMENT RESULTED IN SIMILAR EXPOSURE TO ERIBULIN AS A DOSE OF 1.4 MG/M² TO PATIENTS WITH NORMAL HEPATIC FUNCTION. [SEE DOSAGE AND ADMINISTRATION, USE IN SPECIFIC POPULATIONS]
RENAL IMPAIRMENT
NO FORMAL PK TRIALS WERE CONDUCTED WITH HALAVEN IN PATIENTS WITH RENAL IMPAIRMENT. AVAILABLE DATA SUGGESTS THAT GEOMETRIC MEAN DOSE-NORMALIZED SYSTEMIC EXPOSURE IS SIMILAR FOR PATIENTS WITH MILD RENAL IMPAIRMENT (CRCL 50-80 ML/MIN) RELATIVE TO PATIENTS WITH NORMAL RENAL FUNCTION. HOWEVER, FOR PATIENTS WITH MODERATE RENAL IMPAIRMENT (CRCL 30-50 ML/MIN), THE GEOMETRIC MEAN DOSE-NORMALIZED SYSTEMIC EXPOSURE INCREASED 2-FOLD COMPARED TO PATIENTS WITH NORMAL RENAL FUNCTION [SEE DOSAGE AND ADMINISTRATION, USE IN SPECIFIC POPULATIONS].
CARDIAC ELECTROPHYSIOLOGY
THE EFFECT OF HALAVEN ON THE QTC INTERVAL WAS ASSESSED IN AN OPEN-LABEL, UNCONTROLLED, MULTICENTER, SINGLE-ARM DEDICATED QT TRIAL. A TOTAL OF 26 PATIENTS WITH SOLID TUMORS RECEIVED 1.4 MG/M² OF HALAVEN ON DAYS 1 AND 8 OF A 21-DAY CYCLE. A DELAYED QTC PROLONGATION WAS OBSERVED ON DAY 8, WITH NO PROLONGATION OBSERVED ON DAY 1. THE MAXIMUM MEAN QTCF CHANGE FROM BASELINE (95% UPPER CONFIDENCE INTERVAL) WAS 11.4 (19.5) MS.
CLINICAL STUDIES
STUDY 1 WAS AN OPEN-LABEL, RANDOMIZED, MULTICENTER TRIAL OF 762 PATIENTS WITH METASTATIC BREAST CANCER WHO RECEIVED AT LEAST TWO CHEMOTHERAPEUTIC REGIMENS FOR THE TREATMENT OF METASTATIC DISEASE AND EXPERIENCED DISEASE PROGRESSION WITHIN 6 MONTHS OF THEIR LAST CHEMOTHERAPEUTIC REGIMEN. PATIENTS WERE REQUIRED TO RECEIVE PRIOR ANTHRACYCLINE-AND TAXANE-BASED CHEMOTHERAPY FOR ADJUVANT OR METASTATIC DISEASE. PATIENTS WERE RANDOMIZED (2:1) TO RECEIVE HALAVEN (N=508) OR A SINGLE AGENT THERAPY SELECTED PRIOR TO RANDOMIZATION (CONTROL ARM, N=254). RANDOMIZATION WAS STRATIFIED BY GEOGRAPHIC REGION, HER2/NEU STATUS, AND PRIOR CAPECITABINE EXPOSURE. HALAVEN WAS ADMINISTERED AT A DOSE OF 1.4 MG/M² ON DAYS 1 AND 8 OF A 21-DAY CYCLE. HALAVEN-TREATED PATIENTS RECEIVED A MEDIAN OF 5 CYCLES (RANGE: 1 TO 23 CYCLES) OF THERAPY. CONTROL ARM THERAPY CONSISTED OF 97% CHEMOTHERAPY (26% VINORELBINE, 18% GEMCITABINE, 18% CAPECITABINE, 16% TAXANE, 9% ANTHRACYCLINE, 10% OTHER CHEMOTHERAPY), AND 3% HORMONAL THERAPY. THE MAIN EFFICACY OUTCOME WAS OVERALL SURVIVAL.
PATIENT DEMOGRAPHIC AND BASELINE CHARACTERISTICS WERE COMPARABLE BETWEEN THE TREATMENT ARMS. THE MEDIAN AGE WAS 55 (RANGE: 27 TO 85 YEARS) AND 92% WERE WHITE. SIXTY-FOUR PERCENT OF PATIENTS WERE ENROLLED IN NORTH AMERICA/WESTERN EUROPE/AUSTRALIA, 25% IN EASTERN EUROPE/RUSSIA, AND 11% IN LATIN AMERICA/SOUTH AFRICA. NINETY-ONE PERCENT OF PATIENTS HAD A BASELINE ECOG PERFORMANCE STATUS OF 0 OR 1. TUMOR PROGNOSTIC CHARACTERISTICS, INCLUDING ESTROGEN RECEPTOR STATUS (POSITIVE: 67%, NEGATIVE: 28%), PROGESTERONE RECEPTOR STATUS (POSITIVE: 49%, NEGATIVE: 39%), HER2/NEU RECEPTOR STATUS (POSITIVE: 16%, NEGATIVE: 74%), TRIPLE NEGATIVE STATUS (ER-, PR-, HER2/NEU -: 19%), PRESENCE OF VISCERAL DISEASE (82%, INCLUDING 60% LIVER AND 38% LUNG) AND BONE DISEASE (61%), AND NUMBER OF SITES OF METASTASES (GREATER THAN TWO: 50%), WERE ALSO SIMILAR IN THE HALAVEN AND CONTROL ARMS. PATIENTS RECEIVED A MEDIAN OF FOUR PRIOR CHEMOTHERAPY REGIMENS IN BOTH ARMS.
IN STUDY 1, A STATISTICALLY SIGNIFICANT IMPROVEMENT IN OVERALL SURVIVAL WAS OBSERVED IN PATIENTS RANDOMIZED TO THE HALAVEN ARM COMPARED TO THE CONTROL ARM (SEE TABLE 3). AN UPDATED, UNPLANNED SURVIVAL ANALYSIS, CONDUCTED WHEN 77% OF EVENTS HAD BEEN OBSERVED (SEE FIGURE 1), WAS CONSISTENT WITH THE PRIMARY ANALYSIS. IN PATIENTS RANDOMIZED TO HALAVEN, THE OBJECTIVE RESPONSE RATE BY THE RECIST CRITERIA WAS 11% (95% CI: 8.6%, 14.3%) AND THE MEDIAN RESPONSE DURATION WAS 4.2 MONTHS (95% CI: 3.8, 5.0 MONTHS).
TABLE 3 : COMPARISON OF OVERALL SURVIVAL IN HALAVEN AND CONTROL ARM -STUDY 1
OVERALL SURVIVAL
HALAVEN
(N=508)
CONTROL ARM
(N=254)
PRIMARY SURVIVAL ANALYSIS
NUMBER OF DEATHS
274
148
MEDIAN, MONTHS (95% CI)
13.1 (11.8, 14.3)
10.6 (9.3, 12.5)
HAZARD RATIO (95% CI)A
0.81 (0.66, 0.99)
P VALUEB
0.041
UPDATED SURVIVAL ANALYSIS
NUMBER OF DEATHS
386
203
MEDIAN, MONTHS (95% CI)
13.2 (12.1, 14.4)
10.6 (9.2, 12.0)
CI = CONFIDENCE INTERVAL
ABASED ON COX PROPORTIONAL HAZARDS MODEL STRATIFIED BY GEOGRAPHIC REGION, HER2 STATUS, AND PRIOR CAPECITABINE THERAPY.
BBASED ON A LOG-RANK TEST STRATIFIED BY GEOGRAPHIC REGION, HER2 STATUS, AND PRIOR CAPECITABINE THERAPY.
FIGURE 1 : UPDATED OVERALL SURVIVAL ANALYSIS FOR STUDY 1
HALAVEN CONSUMER
IMPORTANT: HOW TO USE THIS INFORMATION: THIS IS A SUMMARY AND DOES NOT HAVE ALL POSSIBLE INFORMATION ABOUT THIS PRODUCT. THIS INFORMATION DOES NOT ASSURE THAT THIS PRODUCT IS SAFE, EFFECTIVE, OR APPROPRIATE FOR YOU. THIS INFORMATION IS NOT INDIVIDUAL MEDICAL ADVICE AND DOES NOT SUBSTITUTE FOR THE ADVICE OF YOUR HEALTH CARE PROFESSIONAL. ALWAYS ASK YOUR HEALTH CARE PROFESSIONAL FOR COMPLETE INFORMATION ABOUT THIS PRODUCT AND YOUR SPECIFIC HEALTH NEEDS.
ERIBULIN - INJECTION
(ER-I-BUE-LIN)
COMMON BRAND NAME(S): HALAVEN
USES: ERIBULIN IS USED TO TREAT BREAST CANCER THAT HAS SPREAD TO OTHER PARTS OF THE BODY. IT WORKS BY SLOWING OR STOPPING THE GROWTH OF CANCER CELLS.
HOW TO USE: READ THE PATIENT INFORMATION LEAFLET IF AVAILABLE FROM YOUR PHARMACIST BEFORE YOU START USING ERIBULIN AND EACH TIME YOU GET A REFILL. IF YOU HAVE ANY QUESTIONS, ASK YOUR DOCTOR OR PHARMACIST.
THIS MEDICATION IS GIVEN BY INJECTION INTO A VEIN BY A HEALTH CARE PROFESSIONAL. IT IS GIVEN ON A SCHEDULE AS DIRECTED BY YOUR DOCTOR. DOSAGE IS BASED ON YOUR MEDICAL CONDITION, BODY SIZE, AND RESPONSE TO TREATMENT.