BEVACIZUMAB
FOR INTRAVENOUS USE
WARNINGS
GASTROINTESTINAL PERFORATIONS
AVASTIN ADMINISTRATION CAN RESULT IN THE DEVELOPMENT OF GASTROINTESTINAL PERFORATION, IN SOME INSTANCES RESULTING IN FATALITY. GASTROINTESTINAL PERFORATION, SOMETIMES ASSOCIATED WITH INTRA-ABDOMINAL ABSCESS, OCCURRED THROUGHOUT TREATMENT WITH AVASTIN (I.E., WAS NOT CORRELATED TO DURATION OF EXPOSURE). THE INCIDENCE OF GASTROINTESTINAL PERFORATION (GASTROINTESTINAL PERFORATION, FISTULA FORMATION, AND/OR INTRA-ABDOMINAL ABSCESS) IN PATIENTS WITH COLORECTAL CANCER AND IN PATIENTS WITH NON-SMALL CELL LUNG CANCER (NSCLC) RECEIVING AVASTIN WAS 2.4% AND 0.9%, RESPECTIVELY. THE TYPICAL PRESENTATION WAS REPORTED AS ABDOMINAL PAIN ASSOCIATED WITH SYMPTOMS SUCH AS CONSTIPATION AND VOMITING. GASTROINTESTINAL PERFORATION SHOULD BE INCLUDED IN THE DIFFERENTIAL DIAGNOSIS OF PATIENTS PRESENTING WITH ABDOMINAL PAIN ON AVASTIN. AVASTIN THERAPY SHOULD BE PERMANENTLY DISCONTINUED IN PATIENTS WITH GASTROINTESTINAL PERFORATION. (SEE WARNINGS: GASTROINTESTINAL PERFORATIONS AND DOSAGE AND ADMINISTRATION: DOSE MODIFICATIONS.)
WOUND HEALING COMPLICATIONS
AVASTIN ADMINISTRATION CAN RESULT IN THE DEVELOPMENT OF WOUND DEHISCENCE, IN SOME INSTANCES RESULTING IN FATALITY. AVASTIN THERAPY SHOULD BE PERMANENTLY DISCONTINUED IN PATIENTS WITH WOUND DEHISCENCE REQUIRING MEDICAL INTERVENTION. THE APPROPRIATE INTERVAL BETWEEN TERMINATION OF AVASTIN AND SUBSEQUENT ELECTIVE SURGERY REQUIRED TO AVOID THE RISKS OF IMPAIRED WOUND HEALINGWOUND DEHISCENCE HAS NOT BEEN DETERMINED. (SEE WARNINGS: WOUND HEALING COMPLICATIONS AND DOSAGE AND ADMINISTRATION: DOSE MODIFICATIONS.)
HEMORRHAGE
FATAL PULMONARY HEMORRHAGE CAN OCCUR IN PATIENTS WITH NSCLC TREATED WITH CHEMOTHERAPY AND AVASTIN. THE INCIDENCE OF SEVERE OR FATAL HEMOPTYSIS WAS 3 1% IN PATIENTS WITH SQUAMOUS HISTOLOGY AND 2.3% IN PATIENTS WITH NSCLC EXCLUDING PREDOMINANT SQUAMOUS HISTOLOGY. PATIENTS WITH RECENT HEMOPTYSIS ( = 1/2 TSP OF RED BLOOD) SHOULD NOT RECEIVE AVASTIN. (SEE WARNINGS: HEMORRHAGE, ADVERSE REACTIONS: HEMORRHAGE, AND DOSAGE AND ADMINISTRATION: DOSE MODIFICATIONS.)
DRUG DESCRIPTION
AVASTIN® (BEVACIZUMAB) IS A RECOMBINANT HUMANIZED MONOCLONAL IGGL ANTIBODY THAT BINDS TO AND INHIBITS THE BIOLOGIC ACTIVITY OF HUMAN VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) IN IN VITRO AND IN VIVOASSAY SYSTEMS. BEVACIZUMAB CONTAINS HUMAN FRAMEWORK REGIONS AND THE COMPLEMENTARITY-DETERMINING REGIONS OF A MURINE ANTIBODY THAT BINDS TO VEGF (1). BEVACIZUMAB IS PRODUCED IN A CHINESE HAMSTER OVARY MAMMALIAN CELL EXPRESSION SYSTEM IN A NUTRIENT MEDIUM CONTAINING THE ANTIBIOTIC GENTAMICIN AND HAS A MOLECULAR WEIGHT OF APPROXIMATELY 149 KILODALTONS. AVASTIN IS A CLEAR TO SLIGHTLY OPALESCENT, COLORLESS TO PALE BROWN, STERILE, PH 6.2 SOLUTION FOR INTRAVENOUS (IV) INFUSION. AVASTIN IS SUPPLIED IN 100 MG AND 400 MG PRESERVATIVE-FREE, SINGLE-USE VIALS TO DELIVER 4 ML OR 16 ML OF AVASTIN (25 MG/ML). THE 100 MG PRODUCT IS FORMULATED IN 240 MG ?,?-TREHALOSE DIHYDRATE, 23.2 MG SODIUM PHOSPHATE (MONOBASIC, MONOHYDRATE), 4.8 MG SODIUM PHOSPHATE (DIBASIC, ANHYDROUS), 1.6 MG POLYSORBATE 20, AND WATER FOR INJECTION, USP. THE 400 MG PRODUCT IS FORMULATED IN 960 MG ?,?-TREHALOSE DIHYDRATE, 92.8 MG SODIUM PHOSPHATE (MONOBASIC, MONOHYDRATE), 19.2 MG SODIUM PHOSPHATE (DIBASIC, ANHYDROUS), 6.4 MG POLYSORBATE 20, AND WATER FOR INJECTION, USP.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
BEVACIZUMAB BINDS VEGF AND PREVENTS THE INTERACTION OF VEGF TO ITS RECEPTORS (FLT-1 AND KDR) ON THE SURFACE OF ENDOTHELIAL CELLS. .THE INTERACTION OF VEGF WITH ITS RECEPTORS LEADS TO ENDOTHELIAL CELL PROLIFERATION AND NEW BLOOD VESSEL FORMATION IN IN VITRO MODELS OF ANGIOGENESIS. ADMINISTRATION OF BEVACIZUMAB TO XENOTRANSPLANT MODELS OF COLON CANCER IN NUDE (ATHYMIC) MICE CAUSED REDUCTION OF MICROVASCULAR GROWTH AND INHIBITION OF METASTATIC DISEASE PROGRESSION.
PHARMACOKINETICS
THE PHARMACOKINETIC PROFILE OF BEVACIZUMAB WAS ASSESSED USING AN ASSAY THAT MEASURES TOTAL SERUM BEVACIZUMAB CONCENTRATIONS (I.E., THE ASSAY DID NOT DISTINGUISH BETWEEN FREE BEVACIZUMAB AND BEVACIZUMAB BOUND TO VEGF LIGAND). BASED ON A POPULATION PHARMACOKINETIC ANALYSIS OF 491 PATIENTS WHO RECEIVED 1 TO 20 MGLKG OF AVASTIN WEEKLY, EVERY 2 WEEKS, OR EVERY 3 WEEKS, THE ESTIMATED HALF-LIFE OF BEVACIZUMAB WAS APPROXIMATELY 20 DAYS (RANGE 11-50 DAYS). THE PREDICTED TIME TO REACH STEADY STATE WAS 100 DAYS. THE ACCUMULATION RATIO FOLLOWING A DOSE OF 10 MGLKG OF BEVACIZUMAB EVERY 2 WEEKS WAS 2.8.
THE CLEARANCE OF BEVACIZUMAB VARIED BY BODY WEIGHT, BY GENDER, AND BY TUMOR BURDEN. AFTER CORRECTING FOR BODY WEIGHT, MALES HAD A HIGHER BEVACIZUMAB CLEARANCE (0.262 L/DAY VS. 0.207 L/DAY) AND A LARGER VC, (3.25 L VS. 2.66 L) THAN FEMALES. PATIENTS WITH HIGHER TUMOR BURDEN (AT OR ABOVE MEDIAN VALUE OF TUMOR SURFACE AREA) HAD A HIGHER BEVACIZUMAB CLEARANCE (0.249 L/DAY VS. 0.199 L/DAY) THAN PATIENTS WITH TUMOR BURDENS BELOW THE MEDIAN. IN A RANDOMIZED STUDY OF 813 PATIENTS (STUDY I), THERE WAS NO EVIDENCE OF LESSER EFFICACY (HAZARD RATIO FOR OVERALL SURVIVAL) IN MALES OR PATIENTS WITH HIGHER TUMOR BURDEN TREATED WITH AVASTIN AS COMPARED TO FEMALES AND PATIENTS WITH LOW TUMOR BURDEN. THE RELATIONSHIP BETWEEN BEVACIZUMAB EXPOSURE AND CLINICAL OUTCOMES HAS NOT BEEN EXPLORED.
SPECIAL POPULATIONS
ANALYSES OF DEMOGRAPHIC DATA SUGGEST THAT NO DOSE ADJUSTMENTS ARE NECESSARY FOR AGE OR SEX.
PATIENTS WITH RENAL IMPAIRMENT. NO STUDIES HAVE BEEN CONDUCTED TO EXAMINE THE PHARMACOKINETICS OF BEVACIZUMAB IN PATIENTS WITH RENAL IMPAIRMENT.
PATIENTS WITH HEPATIC DYSFUNCTION. NO STUDIES HAVE BEEN CONDUCTED TO EXAMINE THE PHARMACOKINETICS OF BEVACIZUMAB IN PATIENTS WITH HEPATIC IMPAIRMENT.
CLINICAL STUDIES
AVASTIN® IN METASTATIC COLORECTAL CANCER (MCRC)
THE SAFETY AND EFFICACY OF AVASTIN IN THE TREATMENT OF PATIENTS WITH METASTATIC CARCINOMA OF THE COLON OR RECTUM WERE STUDIED IN THREE RANDOMIZED, CONTROLLED CLINICAL TRIALS IN COMBINATION WITH INTRAVENOUS 5-FLUOROURACIL-BASED CHEMOTHERAPY. THE ACTIVITY OF AVASTIN IN PATIENTS WITH METASTATIC COLORECTAL CANCER THAT PROGRESSED ON OR AFTER RECEIVING BOTH IRINOTECAN BASED- AND OXALIPLATIN BASED-CHEMOTHERAPY REGIMENS WAS EVALUATED IN AN OPEN-ACCESS TRIAL IN COMBINATION WITH INTRAVENOUS 5-FLUOROURACIL-BASED CHEMOTHERAPY.
AVASTIN IN COMBINATION WITH BOLUS-IFL
STUDY 1 WAS A RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLLED CLINICAL TRIAL EVALUATING AVASTIN AS FIRST-LINE TREATMENT OF METASTATIC CARCINOMA OF THE COLON OR RECTUM. PATIENTS WERE RANDOMIZED TO BOLUS-IFL (IRINOTECAN 125 MG/M2 IV, 5-FLUOROURACIL 500 MG/M2 N,AND LEUCOVORIN 20 MG/M2 IV GIVEN ONCE WEEKLY FOR 4 WEEKS EVERY 6 WEEKS) PLUS PLACEBO (ARM L), BOLUS-IFL PLUS AVASTIN (5 MG/KG EVERY 2 WEEKS) (ARM 2), OR 5-FU/LV PLUS AVASTIN (5 MGLKG EVERY 2 WEEKS) (ARM 3). ENROLLMENT IN ARM 3 WAS DISCONTINUED, AS PRE-SPECIFIED, WHEN THE TOXICITY OF AVASTIN IN COMBINATION WITH THE BOLUS-IFL REGIMEN WAS DEEMED ACCEPTABLE.
OF THE 813 PATIENTS RANDOMIZED TO ARMS 1 AND 2, THE MEDIAN AGE WAS 60, 40% WERE FEMALE, AND 79% WERE CAUCASIAN. FIFTY-SEVEN PERCENT HAD AN ECOG PERFORMANCE STATUS OF 0. TWENTY-ONE PERCENT HAD A RECTAL PRIMARY AND 28% RECEIVED PRIOR ADJUVANT CHEMOTHERAPY. IN THE MAJORITY OF PATIENTS, 56%, THE DOMINANT SITE OF DISEASE WAS EXTRA-ABDOMINAL, WHILE THE LIVER WAS THE DOMINANT SITE IN 38% OF PATIENTS. RESULTS ARE PRESENTED IN TABLE 1 AND FIGURE 1.
TABLE 1: STUDY 1 EFFICACY RESULTS
IFL+PLACEBO
IFL+ AVASTIN
5 MG/KG Q 2 WKS
NUMBER OF PATIENTS
411
402
OVERALL SURVIVALA
MEDIAN (MONTHS)
15.6
20.3
HAZARD RATIO
0.66
PROGRESSION-FIEE SURVIVALA
MEDIAN (MONTHS)
6.2
10.6
HAZARD RATIO
0.54
OVERALL RESPONSE RATEB
RATE (PERCENT)
35%
45%
DURATION OF RESPONSE
MEDIAN (MONTHS)
7.1
10.4
A P < 0.001 BY STRATIFIED LOGRANK TEST.
BP < 0.0L BY ?2 TEST.
FIGURE 1: DURATION OF SURVIVAL IN STUDY 1
ERROR BARS REPRESENT 95% CONFIDENCE INTERVALS.
THE CLINICAL BENEFIT OF AVASTIN, AS MEASURED BY SURVIVAL IN THE TWO PRINCIPAL ARMS, WAS SEEN IN THE SUBGROUPS DEFINED BY AGE ( < 65 YRS, = 65 YRS) AND GENDER.
AMONG THE 110 PATIENTS ENROLLED IN ARM 3, MEDIAN OVERALL SURVIVAL WAS 18.3 MONTHS, MEDIAN PROGRESSION-FREE SURVIVAL WAS 8.8 MONTHS, OVERALL RESPONSE RATE WAS 39%, AND MEDIAN DURATION OF RESPONSE WAS 8.5 MONTHS.
AVASTIN IN COMBINATION WITH 5-FUILV CHEMOTHERAPY
STUDY 2 WAS A RANDOMIZED, ACTIVE-CONTROLLED CLINICAL TRIAL TESTING AVASTIN IN COMBINATION WITH 5-FU/LV AS FIRST-LINE TREATMENT OF METASTATIC COLORECTAL CANCER. PATIENTS WERE RANDOMIZED TO RECEIVE 5-FU/LV (5-FLUOROURACIL 500 MG/M2, LEUCOVORIN 500 MG/M2 WEEKLY FOR 6 WEEKS EVERY 8 WEEKS) OR 5-FU/LV PLUS AVASTIN (5 MGKG EVERY 2 WEEKS) OR 5-FU/LV PLUS AVASTIN (10 MG/KG EVERY 2 WEEKS). THE PRIMARY ENDPOINTS OF THE TRIAL WERE OBJECTIVE RESPONSE RATE AND PROGRESSION-FREE SURVIVAL. RESULTS ARE PRESENTED IN TABLE 2.
TABLE 2: STUDY 2 EFFICACY RESULTS
5-FUILV
5-FU/LV+AVASTIN
5 MG/KG
5-FU/LV+AVASTIN
10 MG/KG
NUMBER OF PATIENTS
3 6
3 5
3 3
OVERALL SURVIVAL
MEDIAN (MONTHS)
13.6
17.7
15.2
PROGRESSION-FIEE SURVIVAL
MEDIAN (MONTHS)
5.2
9.0
7.2
OVERALL RESPONSE RATE
RATE (PERCENT)
17
40
24
PROGRESSION-FREE SURVIVAL WAS SIGNIFICANTLY LONGER IN PATIENTS RECEIVING 5-FU/LV PLUS AVASTIN AT 5 MGKG WHEN COMPARED TO THOSE NOT RECEIVING AVASTIN. HOWEVER, OVERALL SURVIVAL AND OVERALL RESPONSE RATE WERE NOT SIGNIFICANTLY DIFFERENT. OUTCOMES FOR PATIENTS RECEIVING 5-FU/LV PLUS AVASTIN AT 10 MG/KG WERE NOT SIGNIFICANTLY DIFFERENT THAN FOR PATIENTS WHO DID NOT RECEIVE AVASTIN.
AVASTIN IN COMBINATION WITH 5-FUILV AND OXALIPLATIN CHEMOTHERAPY
STUDY 3 WAS AN OPEN-LABEL, RANDOMIZED, 3-ARM, ACTIVE-CONTROLLED, MULTICENTER CLINICAL TRIAL EVALUATING AVASTIN ALONE, AVASTIN IN COMBINATION WITH 5-FU/LV AND OXALIPLATIN (FOLFOX4), AND FOLFOX4 ALONE IN THE SECOND-LINE TREATMENT OF METASTATIC CARCINOMA OF THE COLON OR RECTUM. PATIENTS WERE PREVIOUSLY TREATED WITH IRINOTECAN AND 5-FU FOR INITIAL THERAPY FOR METASTATIC DISEASE OR AS ADJUVANT THERAPY. PATIENTS WERE RANDOMIZED TO FOLFOX4 (DAY 1: OXALIPLATIN 85 MG/M2 AND LEUCOVORIN 200 MG/M2 CONCURRENTLY IV, THEN 5-FU 400 MG/M2 IV BOLUS FOLLOWED BY 600 MG/M2 CONTINUOUSLY IV; DAY 2: LEUCOVORIN 200 MG/M2 IV, THEN 5-FU 400 MG/M2 IV BOLUS FOLLOWED BY 600 MG/M2 CONTINUOUSLY IV; REPEATED EVERY 2 WEEKS), FOLFOX4 PLUS AVASTIN, OR AVASTIN MONOTHERAPY. AVASTIN WAS ADMINISTERED AT A DOSE OF 10 MG/KG EVERY 2 WEEKS AND FOR PATIENTS IN THE FOLFOX4 PLUS AVASTIN ARM, PRIOR TO THE FOLFOX4 CHEMOTHERAPY ON DAY 1.
OF THE 829 PATIENTS RANDOMIZED TO THE THREE ARMS, THE MEDIAN AGE WAS 61 YEARS, 40% WERE FEMALE, 87% WERE CAUCASIAN, AND 49% HAD AN ECOG PERFORMANCE STATUS OF 0. TWENTY-SIX PERCENT HAD RECEIVED PRIOR RADIATION THERAPY, AND 80% RECEIVED PRIOR ADJUVANT CHEMOTHERAPY. NINETY-NINE PERCENT RECEIVED PRIOR IRINOTECAN, WITH OR WITHOUT 5-FU FOR METASTATIC COLORECTAL CANCER, AND 1% RECEIVED PRIOR IRINOTECAN AND 5-FU AS ADJUVANT THERAPY.
THE AVASTIN MONOTHERAPY ARM OF STUDY 3 WAS CLOSED TO ACCRUAL AFTER ENROLLMENT OF 244 OF THE PLANNED 290 PATIENTS FOLLOWING A PLANNED INTERIM ANALYSIS BY THE DATA MONITORING COMMITTEE (DMC), BASED ON EVIDENCE OF DECREASED SURVIVAL IN THE AVASTIN ALONE ARM AS COMPARED TO THE FOLFOX4 ALONE ARM. IN THE TWO REMAINING STUDY ARMS, OVERALL SURVIVAL (OS) WAS SIGNIFICANTLY LONGER IN PATIENTS RECEIVING AVASTIN IN COMBINATION WITH FOLFOX4 AS COMPARED TO THOSE RECEIVING FOLFOX4 ALONE (MEDIAN OS 13.0 MOS VS. 10.8 MOS; HAZARD RATIO 0.75 [95% CI 0.63, 0.891, P=0.001 STRATIFIED LOG RANK TEST). IN ADDITION, PATIENTS TREATED WITH AVASTIN IN COMBINATION WITH FOLFOX4 WERE REPORTED TO HAVE SIGNIFICANTLY LONGER PROGRESSION-FREE SURVIVAL AND A HIGHER OVERALL RESPONSE RATE BASED ON INVESTIGATOR ASSESSMENT. THE CLINICAL BENEFIT OF AVASTIN, AS MEASURED BY SURVIVAL, WAS SEEN IN THE SUBGROUPS DEFINED BY AGE ( < 65 YRS, = 65 YRS) AND GENDER.
AVASTIN IN THIRD-LINE METASTATIC COLORECTAL CANCER
STUDY 4 WAS AN OPEN ACCESS, MULTICENTER, SINGLE ARM STUDY THAT EVALUATED THE ACTIVITY OF AVASTIN IN COMBINATION WITH BOLUS OR INFBSIONAL 5-FU/LV IN 339 PATIENTS WITH METASTATIC COLORECTAL CANCER WITH DISEASE PROGRESSION FOLLOWING BOTH IRINOTECAN- AND OXALIPLATIN-CONTAINING CHEMOTHERAPY REGIMENS. THE MAJORITY (73%) OF PATIENTS RECEIVED CONCURRENT 5-FU/LV ACCORDING TO A BOLUS REGIMEN.
THERE WAS ONE OBJECTIVE PARTIAL RESPONSE IN THE FIRST 100 EVALUABLE PATIENTS FOR AN OVERALL RESPONSE RATE OF 1% (95% CI 0-5.5%).
AVASTIN® IN UNRESECTABLE NON-SQUAMOUS, NON-SMALL CELL LUNG CANCER (NSCLC)
THE SAFETY AND EFFICACY OF AVASTIN AS FIRST-LINE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED, METASTATIC, OR RECURRENT NON SQUAMOUS, NSCLC WAS STUDIED IN A SINGLE, LARGE, RANDOMIZED, ACTIVE-CONTROLLED, OPEN-LABEL, MULTICENTER STUDY (STUDY 5, N= 878), SUPPORTED BY A RANDOMIZED, DOSE RANGING, ACTIVE CONTROLLED PHASE 2 STUDY (STUDY 6, N=98).
IN STUDY 5, CHEMOTHERAPY-NAIVE PATIENTS WITH LOCALLY ADVANCED, METASTATIC OR RECURRENT NON-SQUAMOUS NSCLC WERE RANDOMIZED (1:1) TO RECEIVE SIX CYCLES OF PACLITAXEL200 MG/M2 AND CARBOPLATIN AUC= 6.0, BOTH BY IV INFUSION ON DAY 1 (PC) OR PC IN COMBINATION WITH AVASTIN AT A DOSE OF 15 MGLKG BY IV INFUSION ON DAY 1 (PC PLUS AVASTIN). AFTER COMPLETION OR UPON DISCONTINUATION OF CHEMOTHERAPY, PATIENTS IN THE PC PLUS AVASTIN ARM CONTINUED TO RECEIVE AVASTIN ALONE UNTIL DISEASE PROGRESSION OR UNTIL UNACCEPTABLE TOXICITY. CYCLES WERE REPEATED EVERY 21 DAYS. PATIENTS WITH PREDOMINANT SQUAMOUS HISTOLOGY (MIXED CELL TYPE TUMORS ONLY), CENTRAL NERVOUS SYSTEM (CNS) METASTASIS, GROSS HEMOPTYSIS ( = 1/2 TSP OF RED BLOOD), OR UNSTABLE ANGINA AND THOSE RECEIVING THERAPEUTIC ANTICOAGULATION WERE EXCLUDED. THE MAIN OUTCOME MEASURE OF THE STUDY WAS DURATION OF SURVIVAL.
AMONG THE 878 PATIENTS RANDOMIZED TO THE TWO TREATMENT ARMS, THE MEDIAN AGE WAS 63, 46% WERE FEMALE, 43% WERE = AGE 65, AND 28% HAD = 5% WEIGHT LOSS AT STUDY ENTRY. ELEVEN PERCENT HAD RECURRENT DISEASE AND OF THE REMAINING 89% WITH NEWLY DIAGNOSED NSCLC, 12% HAD STAGE IIIB WITH MALIGNANT PLEURAL EFFUSION AND 76% HAD STAGE IV DISEASE. THE SURVIVAL CURVES ARE PRESENTED IN FIGURE 2. OVERALL SURVIVAL WAS STATISTICALLY SIGNIFICANTLY HIGHER AMONG PATIENTS RECEIVING PC PLUS AVASTIN COMPARED WITH THOSE RECEIVING PC ALONE; MEDIAN OS WAS 12.3 MOS VS. 10.3 MOS (HAZARD RATIO 0.80 [REPEATED 95% CI 0.68, 0.941, FINAL P-VALUE 0.013, STRATIFIED LOG-RANK TEST). BASED ON INVESTIGATOR ASSESSMENT WHICH WAS NOT INDEPENDENTLY VERIFIED, PATIENTS WERE REPORTED TO HAVE LONGER PROGRESSION-FREE SURVIVAL WITH AVASTIN IN COMBINATION WITH PC COMPARED TO PC ALONE.
FIGURE 2: DURATION OF SURVIVAL IN STUDY 5
IN AN EXPLORATORY ANALYSES ACROSS PATIENT SUBGROUPS, THE IMPACT OF AVASTIN ON OVERALL SURVIVAL WAS LESS ROBUST IN THE FOLLOWING: WOMEN [HR=0.99 (95% CI: 0.79, 1.25)], AGE = 65 YEARS [HR=0.91 (95% CI: 0.72, 1.14)] AND PATIENTS WITH = 5% WEIGHT LOSS AT STUDY ENTRY [HR=0.96 (95% CI: 0.73, 1.26)].
AVASTIN IN METASTATIC BREAST CANCER
THE EFFICACY AND SAFETY OF AVASTIN AS FIRST-LINE TREATMENT OF PATIENTS WITH METASTATIC BREAST CANCER WAS STUDIED IN A SINGLE, OPEN-LABEL, RANDOMIZED, MULTICENTER STUDY (STUDY 7, N=722). THE EFFICACY AND SAFETY OF AVASTIN AS SECOND- AND THIRD-LINE TREATMENT OF PATIENTS WITH METASTATIC BREAST CANCER WAS STUDIED IN A SINGLE OPEN-LABEL RANDOMIZED STUDY (STUDY 8, N= 462).
STUDY 7
IN STUDY 7, PATIENTS WHO HAD NOT RECEIVED CHEMOTHERAPY FOR LOCALLY RECURRENT OR METASTATIC BREAST CANCER WERE RANDOMIZED (1:1) TO RECEIVE PACLITAXEL(90 MG/M2 IV ONCE WEEKLY FOR 3 OUT OF 4 WEEKS) ALONE OR IN COMBINATION WITH AVASTIN (10 MGKG IV INHSION EVERY 2 WEEKS). PATIENTS WERE TREATED UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY. IN SITUATIONS WHERE PACLITAXEL WAS DISCONTINUED OR HELD, TREATMENT WITH AVASTIN ALONE COULD BE CONTINUED UNTIL DISEASE PROGRESSION. PATIENTS WITH BREAST CANCER OVEREXPRESSING HER2 WERE NOT ELIGIBLE UNLESS THEY HAD RECEIVED PRIOR THERAPY WITH HERCEPTIN®. PRIOR HORMONAL THERAPY FOR THE TREATMENT OF METASTATIC DISEASE WAS ALLOWED, AS WAS PRIOR ADJUVANT CHEMO OR HORMONAL THERAPY. ADJUVANT TAXANE THERAPY, IF RECEIVED, MUST HAVE BEEN COMPLETED 12 OR MORE MONTHS PRIOR TO STUDY ENTRY. PATIENTS WITH CENTRAL NERVOUS SYSTEM METASTASIS WERE EXCLUDED. THE MAIN OUTCOME MEASURE OF THE STUDY WAS PROGRESSION-FREE SURVIVAL (PFS), AS ASSESSED BY AN INDEPENDENT REVIEW FACILITY (IRF). SECONDARY OUTCOME MEASURES WERE OVERALL SURVIVAL AND OBJECTIVE RESPONSE RATE.
OF THE 722 PATIENTS RANDOMIZED TO THE TWO TREATMENT ARMS, THE MEDIAN AGE WAS 55 YEARS (RANGE 27 - 85), 76% WERE WHITE, 55.3% WERE POSTMENOPAUSAL, AND 64% WERE ER AND/OR PR POSITIVE. THE PATIENT CHARACTERISTICS WERE SIMILAR ACROSS THE TREATMENT ARMS. THIRTY-SIX PERCENT HAD RECEIVED PRIOR HORMONAL THERAPY FOR ADVANCED DISEASE, AND 66% HAD RECEIVED ADJUVANT CHEMOTHERAPY, INCLUDING 20% WITH PRIOR TAXANE USE AND 50% WITH PRIOR ANTHRACYCLINE USE. EFFICACY RESULTS ARE SUMMARIZED IN TABLE 3.
TABLE 3: AVASTIN EFFICACY RESULTS FROM STUDY 7
P-VALUEHR
(95% CI)PROGRESSION-FREE SURVIVAL [MEDIAN, MONTHS (95% CI)]11.3
(10.5, 13.3)5.8
(5.4, 8.2)<0.00010.48
(0.39, 0.61)OVERALL SURVIVAL [MEDIAN, MONTHS (95% CI)]26.5
(23.7,29.2)24.8
(2 1.4,27.4)0.140.87
(0.72, 1.05)PARTIAL RESPONSE RATEL (PR)48.9%222.2%<0.001 1INCLUDES ONLY PATIENTS WITH MEASURABLE DISEASE
2THE DIFFERENCE IN PARTIAL RESPONSERATES IS 26.7% WITH A 95% CI (18.4%, 35.0%).EFFICACY PARAMETER
AVASTIN + PACLITAXEL
(N=368)PACLITAXEL ALONE
(N=354)THE ADDITION OF AVASTIN TO PACLITAXEL RESULTED IN AN IMPROVEMENT IN PFS WITH NO SIGNIFICANT IMPROVEMENT IN OVERALL SURVIVAL. PARTIAL RESPONSE RATES IN PATIENTS WITH MEASURABLE DISEASE WERE HIGHER WITH AVASTIN PLUS PACLITAXEL. NO COMPLETE RESPONSES WERE OBSERVED.
THIRTY-FOUR PERCENT OF THE PATIENTS HAD INCOMPLETE FOLLOW-UP FOR DISEASE PROGRESSION, THEREFORE, AN EXPLORATORY ANALYSIS WAS PERFORMED PROVIDING A HAZARD RATIO OF 0.57.
STUDY 8
IN STUDY 8, PATIENTS WHO HAD RECEIVED PRIOR ANTHRACYCLINE AND TAXANE THERAPY IN THE ADJUVANT SETTING OR FOR THEIR METASTATIC BREAST CANCER WERE RANDOMIZED, (1:1) TO RECEIVE CAPECITABINE ALONE OR IN COMBINATION WITH AVASTIN. THE STUDY ENROLLED 462 PATIENTS. THE MEDIAN AGE WAS 51 YEARS (RANGE 29 -78), 80.5% WERE WHITE, AND 50% WERE ER AND 40% WERE PR POSITIVE. THE PATIENT CHARACTERISTICS WERE SIMILAR ACROSS THE TREATMENT ARMS. THE STUDY FAILED TO DEMONSTRATE A STATISTICALLY SIGNIFICANT EFFECT ON PFS OR OVERALL SURVIVAL. THE MEDIAN PFS WAS 4.2 MONTHS IN THE CAPECITABINE ARM AND 4.9 MONTHS IN THE CAPECITABINE PLUS AVASTIN ARM (LOG-RANK P-VALUE = 0.86, HAZARD RATIO 0.98). THE MEDIAN OVERALL SURVIVAL WAS 14.5 MONTHS IN THE CAPECITABINE ARM AND 15.1 MONTHS IN THE CAPECITABINE PLUS AVASTIN ARM (HAZARD RATIO OF 1.08).
INDICATIONS
AVASTIN®, IN COMBINATION WITH INTRAVENOUS 5-FLUOROURACIL-BASED CHEMOTHERAPY, IS INDICATED FOR FIRST- OR SECOND-LINE TREATMENT OF PATIENTS WITH METASTATIC CARCINOMA OF THE COLON OR RECTUM.
AVASTIN®, IN COMBINATION WITH CARBOPLATIN AND PACLITAXEL, IS INDICATED FOR FIRST-LINE TREATMENT OF PATIENTS WITH UNRESECTABLE, LOCALLY ADVANCED, RECURRENT OR METASTATIC NON-SQUAMOUS, NON-SMALL CELL LUNG CANCER.
AVASTIN®, IN COMBINATION WITH PACLITAXEL IS INDICATED FOR THE TREATMENT OF PATIENTS WHO HAVE NOT RECEIVED CHEMOTHERAPY FOR METASTATIC HER2 NEGATIVE BREAST CANCER.
THE EFFECTIVENESS OF AVASTIN IN METASTATIC BREAST CANCER IS BASED ON AN IMPROVEMENT IN PROGRESSION FREE SURVIVAL. AVASTIN IS NOT INDICATED FOR PATIENTS WITH BREAST CANCER THAT HAS PROGRESSED FOLLOWING ANTHRACYCLINE AND TAXANE CHEMOTHERAPY ADMINISTERED FOR METASTATIC DISEASE.
CURRENTLY, NO DATA ARE AVAILABLE THAT DEMONSTRATE AN IMPROVEMENT IN DISEASE-RELATED SYMPTOMS OR INCREASED SURVIVAL WITH AVASTIN IN BREAST CANCER. (SEE CLINICAL STUDIES.)
DOSAGE AND ADMINISTRATION
DO NOT INITIATE AVASTIN UNTIL AT LEAST 28 DAYS FOLLOWING MAJOR SURGERY. THE SURGICAL INCISION SHOULD BE FULLY HEALED PRIOR TO INITIATION OF AVASTIN.
METASTATIC CARCINOMA OF THE COLON OR RECTUM
AVASTIN, USED IN COMBINATION WITH INTRAVENOUS 5-FU-BASED CHEMOTHERAPY, IS ADMINISTERED AS AN INTRAVENOUS INFUSION (5 MG/KG OR 10 MG/KG) EVERY 1 4 DAYS.
THE RECOMMENDED DOSE OF AVASTIN, WHEN USED IN COMBINATION WITH BOLUS-IFL, IS 5 MG/KG.
THE RECOMMENDED DOSE OF AVASTIN, WHEN USED IN COMBINATION WITH FOLFOX4, IS 10 MG/KG.
NON-SQUAMOUS, NON-SMALL CELL LUNG CANCER
THE RECOMMENDED DOSE OF AVASTIN IS 15 MG/KG, AS AN IV INFUSION EVERY 3 WEEKS.
METASTATIC BREAST CANCER
THE RECOMMENDED DOSE OF AVASTIN IS 10 MG/KG, AS AN IV INFUSION EVERY 14 DAYS.
DOSE MODIFICATIONS
THERE ARE NO RECOMMENDED DOSE REDUCTIONS FOR THE USE OF AVASTIN. IF NEEDED, AVASTIN SHOULD BE EITHER DISCONTINUED OR TEMPORARILY SUSPENDED AS DESCRIBED BELOW.
AVASTIN SHOULD BE PERMANENTLY DISCONTINUED IN PATIENTS WHO DEVELOP GASTROINTESTINAL PERFORATION (GASTROINTESTINAL PERFORATION, FISTULA FORMATION IN THE GASTROINTESTINAL TRACT, INTRA-ABDOMINAL ABSCESS), FISTULA FORMATION INVOLVING AN INTERNAL ORGAN, WOUND DEHISCENCE REQUIRING MEDICAL INTERVENTION, SERIOUS BLEEDING, A SEVERE ARTERIAL THROMBOEMBOLIC EVENT, NEPHROTIC SYNDROME, HYPERTENSIVE CRISIS OR HYPERTENSIVE ENCEPHALOPATHY. IN PATIENTS DEVELOPING RPLS, DISCONTINUE AVASTIN AND INITIATE TREATMENT OF HYPERTENSION, IF PRESENT. (SEE WARNINGS: REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME.)
TEMPORARY SUSPENSION OF AVASTIN IS RECOMMENDED IN PATIENTS WITH EVIDENCE OF MODERATE TO SEVERE PROTEINURIA PENDING FURTHER EVALUATION AND IN PATIENTS WITH SEVERE HYPERTENSION THAT IS NOT CONTROLLED WITH MEDICAL MANAGEMENT. THE RISK OF CONTINUATION OR TEMPORARY SUSPENSION OF AVASTIN IN PATIENTS WITH MODERATE TO SEVERE PROTEINURIA IS UNKNOWN.
AVASTIN SHOULD BE SUSPENDED AT LEAST SEVERAL WEEKS PRIOR TO ELECTIVE SURGERY. (SEE WARNINGS: GASTROINTESTINAL PERFORATION AND WOUND HEALING COMPLICATIONS AND PRECAUTIONS: SURGERY.)
AVASTIN SHOULD NOT BE RESUMED UNTIL THE SURGICAL INCISION IS FULLY HEALED.
PREPARATION FOR ADMINISTRATION
AVASTIN SHOULD BE DILUTED FOR INFUSION BY A HEALTHCARE PROFESSIONAL USING ASEPTIC TECHNIQUE. WITHDRAW THE NECESSARY AMOUNT OF AVASTIN TO OBTAIN THE REQUIRED DOSE AND DILUTE IN A TOTAL VOLUME OF 100 ML OF 0.9% SODIUM CHLORIDE INJECTION, USP. DISCARD ANY UNUSED PORTION LEFT IN A VIAL, AS THE PRODUCT CONTAINS NO PRESERVATIVES. PARENTERAL DRUG PRODUCTS SHOULD BE INSPECTED VISUALLY FOR PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION.
DILUTED AVASTIN SOLUTIONS FOR INFUSION MAY BE STORED AT 2°C-8°C (36°F-46°F) FOR UP TO 8 HOURS. NO INCOMPATIBILITIES BETWEEN AVASTIN AND POLYVINYLCHLORIDE OR POLYOLEFIN BAGS HAVE BEEN OBSERVED.
AVASTIN INFUSIONS SHOULD NOT BE ADMINISTERED OR MIXED WITH DEXTROSE SOLUTIONS.
ADMINISTRATION
DO NOT ADMINISTER AS AN IV PUSH OR BOLUS. THE INITIAL AVASTIN DOSE SHOULD BE DELIVERED OVER 90 MINUTES AS AN IV INFUSION FOLLOWING CHEMOTHERAPY. IF THE FIRST INFUSION IS WELL TOLERATED, THE SECOND INFUSION MAY'BE ADMINISTERED OVER 60 MINUTES. IF THE 60-MINUTE INFUSION IS WELL TOLERATED, ALL SUBSEQUENT INFUSIONS MAY BE ADMINISTERED OVER 30 MINUTES.
STABILITY AND STORAGE
AVASTIN VIALS MUST BE REFRIGERATED AT 2-8°C (36-46°F). AVASTINVIALS SHOULD BE PROTECTED FIOM LIGHT. STORE IN THE ORIGINAL CARTON UNTIL TIME OF USE. DO NOT FREEZE. DO NOT SHAKE.
SIDE EFFECTS
THE MOST SERIOUS ADVERSE REACTIONS IN PATIENTS RECEIVING AVASTIN WERE:
GASTROINTESTINAL PERFORATIONS (SEE WARNINGS)
NON GASTROINTESTINAL FISTULA FORMATION (SEE WARNINGS)
WOUND HEALING COMPLICATIONS (SEE WARNINGS)
HEMORRHAGE (SEE WARNINGS)
ARTERIAL THROMBOEMBOLIC EVENTS (SEE WARNINGS)
HYPERTENSIVE CRISES (SEE WARNINGS: HYPERTENSION)
REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME (SEE WARNINGS)
NEUTROPENIA AND INFECTION (SEE WARNINGS)
NEPHROTIC SYNDROME (SEE WARNINGS : PROTEINURIA)
CONGESTIVE HEART FAILURE (SEE WARNINGS)
ADVERSE REACTIONS IN CLINICAL TRIALS
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 ADVERSE REACTION INFORMATION FI-OM CLINICAL TRIALS DOES, HOWEVER, PROVIDE A BASIS FOR IDENTIFYING THE ADVERSE EVENTS THAT APPEAR TO BE RELATED TO DRUG USE AND FOR APPROXIMATING RATES.
THE DATA DESCRIBED BELOW REFLECT EXPOSURE TO AVASTIN IN 1529 PATIENTS, INCLUDING 665 RECEIVING AVASTIN FOR AT LEAST 6 MONTHS AND 199 RECEIVING AVASTIN FOR AT LEAST ONE YEAR. AVASTIN WAS STUDIED PRIMARILY IN PLACEBO- AND ACTIVE-CONTROLLED TRIALS (N= 501, AND N= 1028, RESPECTIVELY).
GASTROINTESTINAL PERFORATION
THE INCIDENCE OF GASTROINTESTINAL PERFORATION ACROSS ALL STUDIES RANGED FI-OM 0-3.7%. THE INCIDENCE OF GASTROINTESTINAL PERFORATION, IN SOME CASES FATAL, IN PATIENTS WITH MCRC RECEIVING AVASTIN ALONE OR IN COMBINATION WITH CHEMOTHERAPY WAS 2.4% COMPARED TO 0.3% IN PATIENTS RECEIVING ONLY CHEMOTHERAPY. THE INCIDENCE OF GASTROINTESTINAL PERFORATION IN NSCLC PATIENTS RECEIVING AVASTIN WAS 0.9% COMPARED TO 0% IN PATIENTS RECEIVING ONLY CHEMOTHERAPY. (SEE WARNINGS: GASTROINTESTINAL PERFORATIONS AND DOSAGE AND ADMINISTRATION: DOSE MODIFICATIONS.)
NON-GASTROINTESTINAL FISTULA FORMATION
(SEE WARNINGS: NON-GASTROINTESTINAL FISTULA FORMATION, DOSAGE AND ADMINISTRATION: DOSE MODIFICATIONS.)
WOUND HEALING COMPLICATIONS
THE INCIDENCE OF POST-OPERATIVE WOUND HEALING AND/OR BLEEDING COMPLICATIONS WAS INCREASED IN PATIENTS WITH MCRC RECEIVING AVASTIN AS COMPARED TO PATIENTS RECEIVING ONLY CHEMOTHERAPY. AMONG PATIENTS REQUIRING SURGERY ON OR WITHIN 60 DAYS OF RECEIVING STUDY TREATMENT, WOUND HEALING ANDLOR BLEEDING COMPLICATIONS OCCURRED IN 15% (6139) OF PATIENTS RECEIVING BOLUS-IFL PLUS AVASTIN AS COMPARED TO 4% (1125) OF PATIENTS WHO RECEIVED BOLUS-IFL ALONE. IN THE SAME STUDY, THE INCIDENCE OF WOUND DEHISCENCE WAS ALSO HIGHER IN THE AVASTIN-TREATED PATIENTS (1% VS. 0.5%).
HEMORRHAGE
SEVERE OR FATAL HEMORRHAGES, INCLUDING HEMOPTYSIS, GASTROINTESTINAL BLEEDING, HEMATEMESIS, CNS HEMORRHAGE, EPISTAXIS, AND VAGINAL BLEEDING OCCURRED UP TO FIVE-FOLD MORE FREQUENTLY IN AVASTIN-TREATED PATIENTS COMPARED TO PATIENTS TREATED WITH CHEMOTHERAPY ALONE. NCI-CTC GRADE 3-5 HEMORRHAGIC EVENTS OCCURRED IN 4.7% OF NSCLC PATIENTS AND 5.2% OF MCRC PATIENTS RECEIVING AVASTIN COMPARED TO 1.1% AND 0.7% FOR THE CONTROL GROUPS RESPECTIVELY. (SEE WARNINGS: HEMORRHAGE.)
THE INCIDENCE OF EPISTAXIS WAS HIGHER (35% VS. 10%) IN PATIENTS WITH MCRC RECEIVING BOLUS-IFL PLUS AVASTIN COMPARED WITH PATIENTS RECEIVING BOLUS-IFL PLUS PLACEBO. THESE EVENTS WERE GENERALLY MILD IN SEVERITY (NCI-CTC GRADE 1) AND RESOLVED WITHOUT MEDICAL INTERVENTION. ADDITIONAL MILD TO MODERATE HEMORRHAGIC EVENTS REPORTED MORE FREQUENTLY IN PATIENTS RECEIVING BOLUS-IFL PLUS AVASTIN WHEN COMPARED TO THOSE RECEIVING BOLUS-IFL PLUS PLACEBO INCLUDED GASTROINTESTINAL HEMORRHAGE (24% VS. 6%), MINOR GUM BLEEDING (2% VS. O), AND VAGINAL HEMORRHAGE (4% VS. 2%). (SEE WARNINGS: HEMORRHAGE AND DOSAGE AND ADMINISTRATION: DOSE MODIFICATIONS.)
ARTERIAL THROMBOEMBOLIC EVENTS
THE INCIDENCE OF ARTERIAL THROMBOEMBOLIC EVENTS WAS INCREASED IN NSCLC PATIENTS RECEIVING PC PLUS AVASTIN (3.0%) COMPARED WITH PATIENTS RECEIVING PC ALONE (1.4%). FIVE EVENTS WERE FATAL IN THE PC PLUS AVASTIN ARM, COMPARED WITH 1 EVENT IN THE PC ALONE ARM. THIS INCREASED RISK IS CONSISTENT WITH THAT OBSERVED IN PATIENTS WITH MCRC. (SEE WARNINGS: ARTERIAL THROMBOEMBOLIC EVENTS, DOSAGE AND ADMINISTRATION: DOSE MODIFICATIONS, AND PRECAUTIONS: GERIATRIC USE.)
VENOUS THROMBOEMBOLIC EVENTS
THE INCIDENCE OF NCI-CTC GRADE 3-4 VENOUS THROMBOEMBOLIC EVENTS WAS HIGHER IN PATIENTS WITH MCRC OR NSCLC RECEIVING AVASTIN WITH CHEMOTHERAPY AS COMPARED TO THOSE RECEIVING CHEMOTHERAPY ALONE. IN ADDITION, IN PATIENTS WITH MCRC THE RISK OF DEVELOPING A SECOND SUBSEQUENT THROMBOEMBOLIC EVENT IN PATIENTS RECEIVING AVASTIN AND CHEMOTHERAPY IS INCREASED COMPARED TO PATIENTS RECEIVING CHEMOTHERAPY ALONE. IN STUDY 1,53 PATIENTS (14%) ON THE BOLUS-IFL PLUS AVASTIN ARM AND 30 PATIENTS (8%) ON THE BOLUS-IFL PLUS PLACEBO ARM RECEIVED FULL DOSE WARFARIN FOLLOWING A VENOUS THROMBOEMBOLIC EVENT. AMONG THESE PATIENTS, AN ADDITIONAL THROMBOEMBOLIC EVENT OCCURRED'IN 21% (1 1/53) OF PATIENTS RECEIVING BOLUS-IFL PLUS AVASTIN AND 3% (1130) OF PATIENTS RECEIVING BOLUS-IFL ALONE.
THE OVERALL INCIDENCE OF NCI-CTC GRADE 3-4 VENOUS THROMBOEMBOLIC EVENTS IN STUDY 1 WAS 15.1% IN PATIENTS RECEIVING BOLUS-IFL PLUS AVASTIN AND 13.6% IN PATIENTS RECEIVING BOLUS-IFL PLUS PLACEBO. IN STUDY 1, THE INCIDENCE OF THE FOLLOWING NCI-CTC GRADE 3 AND 4 VENOUS THROMBOEMBOLIC EVENTS WAS HIGHER IN PATIENTS RECEIVING BOLUS-IFL PLUS AVASTIN AS COMPARED TO PATIENTS RECEIVING BOLUS-IFL PLUS PLACEBO: DEEP VENOUS THROMBOSIS (34 VS. 19 PATIENTS) AND INTRA-ABDOMINAL VENOUS THROMBOSIS (10 VS. 5 PATIENTS).
HYPERTENSION
FATAL CNS HEMORRHAGE COMPLICATING AVASTIN INDUCED HYPERTENSION CAN OCCUR.
IN STUDY 1, THE INCIDENCES OF HYPERTENSION AND OF SEVERE HYPERTENSION WERE INCREASED IN PATIENTS WITH MCRC RECEIVING AVASTINCOMPARED TO THOSE RECEIVING CHEMOTHERAPY ALONE (SEE TABLE 3).
TABLE 4: INCIDENCE OF HYPERTENSION AND SEVERE HYPERTENSION IN STUDY 1
ARM1 IFL + PLACEBO
(N= 394)
ARM 2 IFL + AVASTIN
(N=392)
ARM 3 5-FUILV + AVASTIN
(N= 109)
HYPERTENSIONA
(> 1501100 MMHG)
43%
60%
67%
SEVERE HYPERTENSIONA (>200/110 MMHG)
2%
7%
10%
A THIS INCLUDES PATIENTS WITH EITHER A SYSTOLIC OR DIASTOLIC READING GREATER THAN THE CUTOFF VALUE ON ONE OR MORE OCCASIONS.
AMONG PATIENTS WITH SEVERE HYPERTENSION IN THE AVASTIN ARMS, SLIGHTLY OVER HALF THE PATIENTS (51%) HAD A DIASTOLIC READING GREATER THAN 1 10 RNMHG ASSOCIATED WITH A SYSTOLIC READING LESS THAN 200 MMHG.
SIMILAR RESULTS WERE SEEN IN PATIENTS RECEIVING AVASTIN ALONE OR IN COMBINATION WITH FOLFOX4 OR CARBOPLATIN AND PACLITAXEL. (SEE WARNINGS: HYPERTENSION AND DOSAGE AND ADMINISTRATION: DOSE MODIFICATIONS.)
NEUTROPENIA AND INFECTION
AN INCREASED INCIDENCE OF NEUTROPENIA HAS BEEN REPORTED'IN PATIENTS RECEIVING AVASTINAND CHEMOTHERAPY COMPARED TO CHEMOTHERAPY ALONE. IN STUDY 1, THE INCIDENCE OF NCI-CTC GRADE 3 OR 4 NEUTROPENIA WAS INCREASED IN PATIENTS WITH MCRC RECEIVING IFL+ AVASTIN (21%) COMPARED TO PATIENTS RECEIVING IFL ALONE (14%). IN STUDY 5, THE INCIDENCE OF NCI-CTC GRADE 4 NEUTROPENIA WAS INCREASED IN PATIENTS WITH NSCLC RECEIVING PC PLUS AVASTIN (26.2%) COMPARED WITH PATIENTS RECEIVING PC ALONE (17.2%). FEBRILE NEUTROPENIA WAS ALSO INCREASED (5.4% FOR PC PLUS AVASTIN VS. 1.8% FOR PC ALONE). THERE WERE 19 (4.5%) INFECTIONS WITH NCI-CTC GRADE 3 OR 4 NEUTROPENIA IN THE PC PLUS AVASTIN ARM OF WHICH 3 WERE FATAL COMPARED TO 9 (2%) NEUTROPENIC INFECTIONS IN PATIENTS RECEIVING PC ALONE, OF WHICH NONE WERE FATAL. DURING THE FIRST 6 CYCLES OF TREATMENT THE INCIDENCE OF SERIOUS INFECTIONS INCLUDING PNEUMONIA, FEBRILE NEUTROPENIA, CATHETER INFECTIONS AND WOUND INFECTIONS WAS INCREASED IN THE PC PLUS AVASTIN ARM [58 PATIENTS (1 3.6%)] COMPARED TO THE PC ALONE ARM [29 PATIENTS (6.6%)].
PROTEINURIA
(SEE WARNINGS: PROTEINURIA, DOSAGE AND ADMINISTRATION: DOSE MODIFICATIONS, AND PRECAUTIONS: GERIATRIC USE.)
IMMUNOGENICITY
AS WITH ALL THERAPEUTIC PROTEINS, THERE IS A POTENTIAL FOR IMMUNOGENICITY. THE INCIDENCE OF ANTIBODY DEVELOPMENT IN PATIENTS RECEIVING AVASTIN HAS NOT BEEN ADEQUATELY DETERMINED BECAUSE THE ASSAY SENSITIVITY WAS INADEQUATE TO RELIABLY DETECT LOWER TITERS. ENZYME-LINKED IMMUNOSORBENT ASSAYS (ELISAS) WERE PERFORMED ON SERA FROM APPROXIMATELY 500 PATIENTS TREATED WITH AVASTIN, PRIMARILY IN COMBINATION WITH CHEMOTHERAPY. HIGH TITER HUMAN ANTI-AVASTIN ANTIBODIES WERE NOT DETECTED.
IMMUNOGENICITY DATA ARE HIGHLY DEPENDENT ON THE SENSITIVITY AND SPECIFICITY OF THE ASSAY. ADDITIONALLY, THE OBSERVED INCIDENCE OF ANTIBODY POSITIVITY IN AN ASSAY MAY BE INFLUENCED BY SEVERAL FACTORS, INCLUDING SAMPLE HANDLING, TIMING OF SAMPLE COLLECTION, CONCOMITANT MEDICATIONS, AND UNDERLYING DISEASE. FOR THESE REASONS, COMPARISON OF THE INCIDENCE OF ANTIBODIES TO AVASTIN WITH THE INCIDENCE OF ANTIBODIES TO OTHER PRODUCTS MAY BE MISLEADING.
METASTATIC CARCINOMA OF THE COLON AND RECTUM
THE DATA IN TABLES 5 AND 6 WERE OBTAINED IN STUDY 1. ALL NCI-CTC GRADE 3 AND 4 ADVERSE EVENTS AND SELECTED NCI-CTC GRADE 1 AND 2 ADVERSE EVENTS (HYPERTENSION, PROTEINURIA, THROMBOEMBOLIC EVENTS) WERE REPORTED FOR THE OVERALL STUDY POPULATION. THE MEDIAN AGE WAS 60,60% WERE MALE, 79% WERE CAUCASIAN, 78% HAD A COLON PRIMARY LESION, 56% HAD EXTRA-ABDOMINAL DISEASE, 29% HAD PRIOR ADJUVANT OR NEOADJUVANT CHEMOTHERAPY, AND 57% HAD ECOG PERFORMANCE STATUS OF 0. THE MEDIAN DURATION OF EXPOSURE TO AVASTIN WAS 8 MONTHS IN ARM 2 AND 7 MONTHS IN ARM 3. SEVERE AND LIFE-THREATENING (NCI-CTC GRADE 3 AND 4) ADVERSE EVENTS, WHICH OCCURRED AT A HIGHER INCIDENCE ( = 2%) IN PATIENTS RECEIVING BOLUS-IFL PLUS AVASTIN AS COMPARED TO BOLUS-IFL PLUS PLACEBO, ARE PRESENTED IN TABLE 5.
TABLE 5: NCI-CTC GRADE 3 AND 4 ADVERSE EVENTS IN STUDY 1 (OCCURRING AT HIGHER INCIDENCE ( = 2%) AVASTIN VS. CONTROL)
ARM 1 IFL+PLACEBO
(N= 396)
ARM 2 IFL+AVASTIN
(N=392)
NCI-CTC GRADE 3-4 EVENTS
295 (74%)
340 (87%)
BODY AS A WHOLE
ASTHENIA
28 (7%)
38 (10%)
ABDOMINAL PAIN
20 (5%)
32 (8%)
30 (8%)
PAIN
CARDIOVASCULAR21(5%)
HYPERTENSION
10 (2%)
46 (12%)
DEEP VEIN THROMBOSIS
19 (5%)
34 (9%)
INTRA-ABDOMINAL THROMBOSIS
5 (1%)
13 (3%)
SYNCOPE
4 (1%)
11 (3%)
DIGESTIVE
DIARRHEA
99 (25%)
133 (34%)
CONSTIPATION
9 (2%)
14 (4%)
HEMIC/LVMVHATIC
LEUKOPENIA
122 (31%)
145 (37%)
58 (21%)
NEUTROPENIAA
ACENTRAL LABORATORIES WERE COLLECTED ON DAYS 1 AND 21 OF EACH CYCLE. NEUTROPHIL COUNTS ARE AVAILABLE IN 303 PATIENTS IN ARM 1 AND 276 IN ARM 2.41 (14%)
NCI-CTC GRADE 1-4 ADVERSE EVENTS WHICH OCCURRED AT A HIGHER INCIDENCE ( = 5%) IN PATIENTS RECEIVING BOLUS-IFL PLUS AVASTIN AS COMPARED TO THE BOLUS-IFL PLUS PLACEBO ARM, ARE PRESENTED IN TABLE 6.
TABLE 6: NCI-CTC GRADE 1-4 ADVERSE EVENTS IN STUDY 1 (OCCURRING AT HIGHER INCIDENCE ( = 5%) IN IFL+AVASTIN VS. IFL)
ARM1 IFL+PLACEBO
(N=98)
ARM 2 IFL+AVASTIN
(N= 102)
ARM 3 5-FU/LV+AVASTIN
(N=109)
BODY AS A WHOLE
PAIN
54 (55%)
62 (61%)
67 (62%)
ABDOMINAL PAIN
54 (55%)
62 (61%)
55 (50%)
HEADACHE
19 (19%)
27 (26%)
30 (26%)
CARDIOVASCULAR
HYPERTENSION
14 (14%)
23 (23%)
37 (34%)
HYPOTENSION
7 (7%)
15 (15%)
8 (7%)
DEEP VEIN THROMBOSIS
3 (3%)
9 (9%)
6 (6%)
DIGESTIVE
VOMITING
46 (47%)
53 (52%)
51 (47%)
ANOREXIA
29 (30%)
44 (43%)
38 (35%)
CONSTIPATION
28 (29%)
41 (40%)
32 (29%)
STOMATITIS
18 (18%)
33 (32%)
33 (30%)
DYSPEPSIA
15 (15%)
25 (24%)
19 (17%)
GI HEMORRHAGE
6 (6%)
25 (24%)
21 (19%)
WEIGHT LOSS
10 (10%)
15 (15%)
18 (16%)
DRY MOUTH
2 (2%)
7 (7%)
4 (4%)
COLITIS
1 (1%)
6 (6%)
1 (1%)
HEMICILYMVHATIC
THROMBOCYTOPENIA
0
5 (5%)
5 (5%)
NERVOUS
DIZZINESS
20 (20%)
27 (26%)
21 (19%)
RESPIRATORY
UPPER RESPIRATORY INFECTION
38 (39%)
48 (47%)
44 (40%)
EPISTAXIS
10 (10%)
36 (35%)
35 (32%)
DYSPNEA
15 (15%)
26 (26%)
27 (25%)
VOICE ALTERATION
2 (2%)
9 (9%)
6 (6%)
SKIN/APPENDAGES
ALOPECIA
25 (26%)
33(32%)
6 (6%)
SKIN ULCER
1 (1%)
6 (6%)
7 (6%)
SPECIAL SENSES
TASTE DISORDER
9 (9%)
14 (14%)
23 (21%)
UROGENITAL
PROTEINURIA
24 (24%)
37 (36%)
39 (36%)