WARNING
NEPHROGENIC SYSTEMIC FIBROSIS (NSF)
GADOLINIUM-BASED CONTRAST AGENTS (GBCAS) INCREASE THE RISK FOR NSF AMONG PATIENTS WITH IMPAIRED ELIMINATION OF THE DRUGS. AVOID USE OF GBCAS IN THESE PATIENTS UNLESS THE DIAGNOSTIC INFORMATION IS ESSENTIAL AND NOT AVAILABLE WITH NON-CONTRASTED MRI OR OTHER MODALITIES. NSF MAY RESULT IN FATAL OR DEBILITATING FIBROSIS AFFECTING THE SKIN, MUSCLE AND INTERNAL ORGANS.
" THE RISK FOR NSF APPEARS HIGHEST AMONG PATIENTS WITH:
" CHRONIC, SEVERE KIDNEY DISEASE (GFR < 30 ML/MIN/1.73M²), OR
" ACUTE KIDNEY INJURY.
" SCREEN PATIENTS FOR ACUTE KIDNEY INJURY AND OTHER CONDITIONS THAT MAY REDUCE RENAL FUNCTION. FOR PATIENTS AT RISK FOR CHRONICALLY REDUCED RENAL FUNCTION (FOR EXAMPLE, AGE > 60 YEARS, HYPERTENSION OR DIABETES), ESTIMATE THE GLOMERULAR FILTRATION RATE (GFR) THROUGH LABORATORY TESTING.
" FOR PATIENTS AT HIGHEST RISK FOR NSF, DO NOT EXCEED THE RECOMMENDED GADAVIST DOSE AND ALLOW A SUFFICIENT PERIOD OF TIME FOR ELIMINATION OF THE DRUG FROM THE BODY PRIOR TO ANY RE-ADMINISTRATION [SEE WARNINGS AND PRECAUTIONS].
INDICATIONS
MAGNETIC RESONANCE IMAGING (MRI) OF THE CENTRAL NERVOUS SYSTEM (CNS)
GADAVIST IS INDICATED FOR USE WITH MAGNETIC RESONANCE IMAGING (MRI) IN ADULT AND PEDIATRIC PATIENTS (INCLUDING TERM NEONATES) TO DETECT AND VISUALIZE AREAS WITH DISRUPTED BLOOD BRAIN BARRIER (BBB) AND/OR ABNORMAL VASCULARITY OF THECENTRAL NERVOUS SYSTEM.
MRI OF THE BREAST
GADAVIST IS INDICATED FOR USE WITH MRI TO ASSESS THE PRESENCE AND EXTENT OFMALIGNANT BREAST DISEASE.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
GADAVIST IS A STERILE, CLEAR, AND COLORLESS TO PALE YELLOW SOLUTION FOR INJECTION CONTAINING 604.72 MG GADOBUTROL PER ML (EQUIVALENT TO 1 MMOL GADOBUTROL/ ML) SUPPLIED IN SINGLE-DOSE VIALS AND PRE-FILLED DISPOSABLE SYRINGES.
GADAVIST IS A STERILE, CLEAR AND COLORLESS TO PALE YELLOW SOLUTION CONTAINING 604.72 MG GADOBUTROL PER ML (EQUIVALENT TO 1 MMOL GADOBUTROL) PER ML. GADAVIST IS SUPPLIED IN THE FOLLOWING SIZES:
SINGLE-DOSE VIALS
2 ML SINGLE-DOSE VIALS, RUBBER STOPPERED IN CARTONS OF 3, BOXES OF 15 (NDC 50419-325-37)
7.5 ML SINGLE-DOSE VIALS, RUBBER STOPPERED IN CARTONS OF 10, BOXES OF 20 (NDC 50419-325-11)
10 ML SINGLE-DOSE VIALS, RUBBER STOPPERED, IN CARTONS OF 10, BOXES OF 20 (NDC 50419-325-12)
15 ML SINGLE-DOSE VIALS, RUBBER STOPPERED, IN CARTONS OF 10, BOXES OF 20 (NDC 50419-325-13)
SINGLE-DOSE PRE-FILLED SYRINGES
7.5 ML SINGLE-DOSE PRE-FILLED DISPOSABLE SYRINGES, BOXES OF 5 (NDC 50419-325-27)
10 ML SINGLE-DOSE PRE-FILLED DISPOSABLE SYRINGES, BOXES OF 5 (NDC 50419-325-28)
15 ML SINGLE-DOSE PRE-FILLED DISPOSABLE SYRINGES, BOXES OF 5 (NDC 50419-325-29)
STORAGE AND HANDLING
STORE AT 25°C (77°F); EXCURSIONS PERMITTED TO 15-30°C (59-86°F) [SEE USP CONTROLLED ROOM TEMPERATURE].
SHOULD FREEZING OCCUR, GADAVIST SHOULD BE BROUGHT TO ROOM TEMPERATURE BEFORE USE. IF ALLOWED TO STAND AT ROOM TEMPERATURE, GADAVIST SHOULD RETURN TO A CLEAR AND COLORLESS TO PALE YELLOW SOLUTION. VISUALLY INSPECT GADAVIST FOR PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION. DO NOT USE THE SOLUTION IF IT IS DISCOLORED, IF PARTICULATE MATTER IS PRESENT OR IF THE CONTAINER APPEARS DAMAGED.
MANUFACTURED FOR: BAYER HEALTHCARE PHARMACEUTICALS INC. WHIPPANY, NJ 07981. REVISED: DECEMBER 2014
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSE
THE RECOMMENDED DOSE OF GADAVIST FOR ADULT AND PEDIATRIC PATIENTS (INCLUDING TERM NEONATES) IS 0.1 ML/KG BODY WEIGHT (0.1 MMOL/KG). REFER TO TABLE 1 TO DETERMINE THE VOLUME TO BE ADMINISTERED.
TABLE 1: VOLUME OF GADAVIST INJECTION BY BODY WEIGHT
BODY WEIGHT VOLUME TO BE ADMINISTERED, ML
LB KG
5.5 2.5 0.25
11 5 0.5
22 10 1
33 15 1.5
44 20 2
55 25 2.5
66 30 3
77 35 3.5
88 40 4
99 45 4.5
110 50 5
132 60 6
154 70 7
176 80 8
198 90 9
220 100 10
242 110 11
264 120 12
286 130 13
308 140 14
ADMINISTRATION GUIDELINES
" GADAVIST IS FORMULATED AT A HIGHER CONCENTRATION (1 MMOL/ML)COMPARED TO CERTAIN OTHER GADOLINIUM BASED CONTRAST AGENTS, RESULTING IN A LOWER VOLUME OF ADMINISTRATION. CLOSELY EXAMINE TABLE 1 TO DETERMINE THE VOLUME TO BE ADMINISTERED.
" USE STERILE TECHNIQUE WHEN PREPARING AND ADMINISTERING GADAVIST.
" ADMINISTER GADAVIST AS AN INTRAVENOUS BOLUS INJECTION, MANUALLY OR BY POWER INJECTOR, AT A FLOW RATE OF APPROXIMATELY 2 ML/SECOND.
" FOLLOW GADAVIST INJECTION WITH A NORMAL SALINE FLUSH TO ENSURE COMPLETE ADMINISTRATION OF THE CONTRAST.
" CONTRAST-ENHANCED MRI CAN COMMENCE IMMEDIATELY FOLLOWING CONTRAST ADMINISTRATION.
DRUG HANDLING
" VISUALLY INSPECT GADAVIST FOR PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION. DO NOT USE THE SOLUTION IF IT IS DISCOLORED, IF PARTICULATE MATTER IS PRESENT OR IF THE CONTAINER APPEARS DAMAGED.
" DO NOT MIX GADAVIST WITH OTHER MEDICATIONS AND DO NOT ADMINISTER GADAVIST IN THE SAME INTRAVENOUS LINE SIMULTANEOUSLY WITH OTHER MEDICATIONS BECAUSE OF THE POTENTIAL FOR CHEMICAL INCOMPATIBILITY.
VIALS
" DRAW GADAVIST INTO THE SYRINGE IMMEDIATELY BEFORE USE.
" DO NOT PIERCE THE RUBBER STOPPER MORE THAN ONCE. DISCARD ANY UNUSED VIAL CONTENTS.
PRE-FILLED SYRINGES
" REMOVE THE TIP CAP FROM THE PRE-FILLED SYRINGE IMMEDIATELY BEFORE USE. DISCARD ANY UNUSED SYRINGE CONTENTS.
SIDE EFFECTS
THE FOLLOWING SERIOUS ADVERSE REACTIONS ARE DISCUSSED ELSEWHERE IN LABELING:
" NEPHROGENIC SYSTEMIC FIBROSIS (NSF) [SEE BOXED WARNING ANDWARNINGS AND PRECAUTIONS].
" HYPERSENSITIVITY REACTIONS [SEE CONTRAINDICATIONS AND 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 DIRECTLYCOMPARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REFLECT THE RATES OBSERVED IN CLINICAL PRACTICE.
THE ADVERSE REACTIONS DESCRIBED IN THIS SECTION REFLECT GADAVIST EXPOSURE IN 6,330 SUBJECTS (INCLUDING 184 PEDIATRIC PATIENTS, AGES 0 TO 17 YEARS) WITH THE MAJORITY RECEIVING THE RECOMMENDED DOSE. APPROXIMATELY 50% OF THE SUBJECTS WERE MALE AND THE ETHNIC DISTRIBUTION WAS 60% CAUCASIAN, 30% ASIAN, 6% HISPANIC, 2% BLACK, AND 3% PATIENTS OF OTHER ETHNIC GROUPS. THE AVERAGE AGE WAS 55 YEARS (RANGE FROM1 WEEK TO 93 YEARS).
OVERALL, APPROXIMATELY 4% OF SUBJECTS REPORTED ONE OR MORE ADVERSE REACTIONS DURING A FOLLOW-UP PERIOD THAT RANGED FROM 24 HOURS TO 7 DAYS AFTER GADAVIST ADMINISTRATION.
ADVERSE REACTIONS ASSOCIATED WITH THE USE OF GADAVIST WERE USUALLY MILD TO MODERATE IN SEVERITY AND TRANSIENT IN NATURE.
TABLE 2 LISTS ADVERSE REACTIONS THAT OCCURRED IN ? 0.1% SUBJECTS WHO RECEIVED GADAVIST.
TABLE 2: ADVERSE REACTIONS
REACTION RATE (%)
N=6330
HEADACHE 1.5
NAUSEA 1.2
DIZZINESS 0.5
DYSGEUSIA 0.4
FEELING HOT 0.4
INJECTION SITE REACTIONS 0.4
VOMITING 0.4
RASH (INCLUDES GENERALIZED, MACULAR, PAPULAR, PRURITIC) 0.3
PRURITUS (INCLUDES GENERALIZED) 0.2
ERYTHEMA 0.2
HYPERSENSITIVITY/ANAPHYLACTOID* 0.1
DYSPNEA 0.1
PARESTHESIA 0.1
*HYPERSENSITIVITY/ANAPHYLACTOID REACTION MAY OCCUR WITH ONE OR MORE OF THE FOLLOWING ADVERSE REACTIONS: FOR EXAMPLE, HYPOTENSION, URTICARIA, FACE EDEMA, EYELID EDEMA, FLUSHING
ADVERSE REACTIONS THAT OCCURRED WITH A FREQUENCY OF < 0.1% IN SUBJECTS WHO RECEIVED GADAVIST INCLUDE: LOSS OF CONSCIOUSNESS, CONVULSION, PAROSMIA,TACHYCARDIA, PALPITATION, DRY MOUTH, MALAISE AND FEELING COLD.
POSTMARKETING EXPERIENCE
THE FOLLOWING ADDITIONAL ADVERSE REACTIONS HAVE BEEN REPORTED DURING POSTMARKETING USE OF GADAVIST. BECAUSE THESE REACTIONS ARE REPORTED VOLUNTARILY FROM A POPULATION OF UNCERTAIN SIZE, IT IS NOT POSSIBLE TO RELIABLY ESTIMATE THEIR FREQUENCY OR ESTABLISH A CAUSAL RELATIONSHIP TO DRUG EXPOSURE.
" CARDIAC ARREST
" NEPHROGENIC SYSTEMIC FIBROSIS (NSF)
" HYPERSENSITIVITY REACTIONS (ANAPHYLACTIC SHOCK, CIRCULATORY COLLAPSE, RESPIRATORY ARREST, PULMONARY EDEMA, BRONCHOSPASM, CYANOSIS, OROPHARYNGEAL SWELLING, LARYNGEAL EDEMA,BLOOD PRESSURE INCREASED, CHEST PAIN, ANGIOEDEMA, CONJUNCTIVITIS, HYPERHIDROSIS, COUGH, SNEEZING, BURNING SENSATION, AND PALLOR) [SEE WARNINGS ANDPRECAUTIONS]
READ THE GADAVIST (GADOBUTROL) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
THE MAXIMUM DOSE OF GADAVIST TESTED IN HEALTHY VOLUNTEERS, 1.5 ML/KG BODY WEIGHT (1.5 MMOL/KG; 15 TIMES THE RECOMMENDED DOSE), WAS TOLERATED IN A MANNER SIMILAR TO LOWER DOSES. GADAVIST CAN BE REMOVED BY HEMODIALYSIS[SEE USE IN SPECIFIC POPULATIONS AND CLINICAL PHARMACOLOGY].
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
IN MRI, VISUALIZATION OF NORMAL AND PATHOLOGICAL TISSUE DEPENDS IN PART ON VARIATIONS IN THE RADIOFREQUENCY SIGNAL INTENSITY THAT OCCURS WITH:
" DIFFERENCES IN PROTON DENSITY
" DIFFERENCES OF THE SPIN-LATTICE OR LONGITUDINAL RELAXATION TIMES (T1)
" DIFFERENCES IN THE SPIN-SPIN OR TRANSVERSE RELAXATION TIME (T2)
WHEN PLACED IN A MAGNETIC FIELD, GADAVIST SHORTENS THE T1 AND T2 RELAXATION TIMES. THE EXTENT OF DECREASE OF T1 AND T2 RELAXATION TIMES, AND THEREFORE THE AMOUNT OF SIGNAL ENHANCEMENT OBTAINED FROM GADAVIST, IS BASED UPON SEVERAL FACTORS INCLUDING THE CONCENTRATION OF GADAVIST IN THE TISSUE, THE FIELD STRENGTH OF THE MRI SYSTEM, AND THE RELATIVE RATIO OF THE LONGITUDINAL AND TRANSVERSE RELAXATION TIMES. AT THE RECOMMENDED DOSE, THE T1 SHORTENING EFFECT IS OBSERVED WITH GREATEST SENSITIVITY IN T1-WEIGHTED MAGNETIC RESONANCE SEQUENCES. IN T2*-WEIGHTED SEQUENCES THE INDUCTION OF LOCAL MAGNETIC FIELD INHOMOGENEITIES BY THE LARGE MAGNETIC MOMENT OF GADOLINIUM AND AT HIGH CONCENTRATIONS (DURING BOLUS INJECTION) LEADS TO A SIGNAL DECREASE.
PHARMACODYNAMICS
GADAVIST LEADS TO DISTINCT SHORTENING OF THE RELAXATION TIMES EVEN IN LOW CONCENTRATIONS. AT PH 7, 37°C AND 1.5 T, THE RELAXIVITY (R1) -DETERMINED FROM THE INFLUENCE ON THE RELAXATION TIMES (T1) OF PROTONS IN PLASMA -IS 5.2 L/(MMOL·SEC) AND THE RELAXIVITY (R2) -DETERMINED FROM THE INFLUENCE ON THE RELAXATION TIMES (T2) -IS 6.1 L/(MMOL·SEC). THESE RELAXIVITIES DISPLAY ONLY SLIGHT DEPENDENCE ON THE STRENGTH OF THE MAGNETIC FIELD. THE T1 SHORTENING EFFECT OF PARAMAGNETIC CONTRAST AGENTS IS DEPENDENT ON CONCENTRATION AND R1 RELAXIVITY (SEE TABLE 3). THIS MAY IMPROVE TISSUE VISUALIZATION.
TABLE 3: RELAXIVITY (R1) OF GADOLINIUM CHELATES AT 1.5 T
GADOLINIUM-CHELATE R1 (L-MMOL -1 -S-1)
GADOBENATE 6.3
GADOBUTROL 5.2
GADODIAMIDE 4.3
GADOFOSVESET 16
GADOPENTETATE 4.1
GADOTERATE 3.6
GADOTERIDOL 4.1
GADOVERSETAMIDE 4.7
GADOXETATE 6.9
R1 RELAXIVITY IN PLASMA AT 37°C
COMPARED TO 0.5 MOLAR GADOLINIUM-BASED CONTRAST AGENTS, THE HIGHER CONCENTRATION OF GADAVIST RESULTS IN HALF THE VOLUME OF ADMINISTRATION AND A MORE COMPACT CONTRAST BOLUS.
GADAVIST IS A HIGHLY WATER-SOLUBLE, EXTREMELY HYDROPHILIC COMPOUND WITH A PARTITION COEFFICIENT BETWEEN N-BUTANOL AND BUFFER AT PH 7.6 OF ABOUT 0.006.
PHARMACOKINETICS
DISTRIBUTION
AFTER INTRAVENOUS ADMINISTRATION, GADOBUTROL IS RAPIDLY DISTRIBUTED IN THEEXTRACELLULAR SPACE. AFTER A GADOBUTROL DOSE OF 0.1 MMOL/KG BODY WEIGHT, AN AVERAGE LEVEL OF 0.59 MMOL GADOBUTROL/L WAS MEASURED IN PLASMA 2 MINUTES AFTER THE INJECTION AND 0.3 MMOL GADOBUTROL/L 60 MINUTES AFTER THE INJECTION. GADOBUTROL DOES NOT DISPLAY ANY PARTICULAR PROTEIN BINDING. IN RATS, GADOBUTROL DOES NOT PENETRATE THE INTACT BLOOD-BRAIN BARRIER.
METABOLISM
GADOBUTROL IS NOT METABOLIZED.
ELIMINATION
VALUES FOR AUC, BODY WEIGHT NORMALIZED PLASMA CLEARANCE AND HALF-LIFE ARE GIVEN IN TABLE 4, BELOW.
GADOBUTROL IS EXCRETED IN AN UNCHANGED FORM VIA THE KIDNEYS. IN HEALTHY SUBJECTS, RENAL CLEARANCE OF GADOBUTROL IS 1.1 TO 1.7 ML/(MINoKG) AND THUSCOMPARABLE TO THE RENAL CLEARANCE OF INULIN, CONFIRMING THAT GADOBUTROL IS ELIMINATED BY GLOMERULAR FILTRATION.
WITHIN TWO HOURS AFTER INTRAVENOUS ADMINISTRATION MORE THAN 50% AND WITHIN 12 HOURS MORE THAN 90% OF THE GIVEN DOSE IS ELIMINATED VIA THE URINE. EXTRA-RENAL ELIMINATION IS NEGLIGIBLE.
SPECIFIC POPULATIONS
GENDER
GENDER HAS NO CLINICALLY RELEVANT EFFECT ON THE PHARMACOKINETICS OF GADOBUTROL.
GERIATRIC
A SINGLE IV DOSE OF 0.1 MMOL/KG GADAVIST WAS ADMINISTERED TO 15 ELDERLY AND 16 NON-ELDERLY SUBJECTS. AUC WAS SLIGHTLY HIGHER AND CLEARANCE SLIGHTLY LOWER IN ELDERLY SUBJECTS ASCOMPARED TO NON-ELDERLY SUBJECTS [SEE USE IN SPECIFIC POPULATIONS].
PEDIATRIC
THE PHARMACOKINETICS OF GADOBUTROL WERE EVALUATED IN TWO STUDIES IN A TOTAL OF 130 PATIENTS AGE 2 TO LESS THAN 18 YEARS AND IN 43 PATIENTS LESS THAN 2 YEARS OF AGE (INCLUDING TERM NEONATES). PATIENTS RECEIVED A SINGLE INTRAVENOUS DOSE OF 0.1 MMOL/KG OF GADAVIST. THE PHARMACOKINETIC PROFILE OF GADOBUTROL IN PEDIATRIC PATIENTS IS SIMILAR TO THAT IN ADULTS, RESULTING IN SIMILAR VALUES FOR AUC, BODY WEIGHT NORMALIZED PLASMA CLEARANCE, AS WELL AS ELIMINATION HALF-LIFE. APPROXIMATELY 99% (MEDIAN VALUE) OF THE DOSE WAS RECOVERED IN URINE WITHIN 6 HOURS (THIS INFORMATION WAS DERIVED FROM THE 2 TO LESS THAN 18 YEAR OLD AGE GROUP).
TABLE 4: PHARMACOKINETICS BY AGE GROUP (MEDIAN [RANGE])
0 TO < 2 YEARS
N=43 2 TO 6 YEARS
N=45 7 TO 11 YEARS
N=39 12 TO < 18 YEARS
N=46 ADULTS
N=93
AUC (?MOLXH/L) 781
[513, 1891] 846
[412, 1331] 1025
[623, 2285] 1237
[946, 2211] 1072
[667, 1992]
CL (L/H/KG) 0.128
[0.053, 0.195] 0.119
[0.080, 0.215] 0.099
[0.043, 0.165] 0.081
[0.046, 0.103] 0.094
[0.051, 0.150]
T½ (H) 2.91
[1.60, 12.4] 1.91
[1.04, 2.70] 1.66
[0.91, 2.71] 1.68
[1.31, 2.48] 1.80
[1.20, 6.55]
C20 (?MOL/L) 367
[280, 427] 421
[369, 673] 462
[392, 760] 511
[387, 1077] 441
[281, 829]
RENAL IMPAIRMENT
IN PATIENTS WITH IMPAIRED RENAL FUNCTION, THE SERUM HALF-LIFE OF GADOBUTROL IS PROLONGED AND CORRELATED WITH THE REDUCTION IN CREATININE CLEARANCE.
AFTER INTRAVENOUS INJECTION OF 0.1 MMOL GADOBUTROL/KG BODY WEIGHT, THE ELIMINATION HALF-LIFE WAS 5.8 ± 2.4 HOURS IN MILD TO MODERATELY IMPAIRED PATIENTS (80 > CLCR > 30 ML/MIN) AND 17.6 ± 6.2 HOURS IN SEVERELY IMPAIRED PATIENTS NOT ON DIALYSIS (CLCR < 30 ML/MIN). THE MEAN AUC OF GADOBUTROL IN PATIENTS WITH NORMAL RENAL FUNCTION WAS 1.1 ± 0.1 MMOLoH/L,COMPARED TO 4.0 ± 1.8 MMOLoH/L IN PATIENTS WITH MILD TO MODERATE RENAL IMPAIRMENT AND 11.5 ± 4.3 MMOLoH/L IN PATIENTS WITH SEVERE RENAL IMPAIRMENT.
COMPLETE RECOVERY IN THE URINE WAS SEEN IN PATIENTS WITH MILD OR MODERATE RENAL IMPAIRMENT WITHIN 72 HOURS. IN PATIENTS WITH SEVERELY IMPAIRED RENAL FUNCTION ABOUT 80% OF THE ADMINISTERED DOSE WAS RECOVERED IN THE URINE WITHIN 5 DAYS.
FOR PATIENTS RECEIVING HEMODIALYSIS, PHYSICIANS MAY CONSIDER THE PROMPT INITIATION OF HEMODIALYSIS FOLLOWING THE ADMINISTRATION OF GADAVIST IN ORDER TO ENHANCE THE CONTRAST AGENT'S ELIMINATION. SIXTY-EIGHT PERCENT (68%) OF GADOBUTROL IS REMOVED FROM THE BODY AFTER THE FIRST DIALYSIS, 94% AFTER THE SECOND DIALYSIS, AND 98% AFTER THE THIRD DIALYSIS SESSION. [SEE WARNINGS AND PRECAUTIONS AND USE IN SPECIFIC POPULATIONS].
ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY
LOCAL INTOLERANCE REACTIONS, INCLUDING MODERATE IRRITATION ASSOCIATED WITH INFILTRATION OF INFLAMMATORY CELLS WAS OBSERVED AFTER PARAVENOUS ADMINISTRATION TO RABBITS, SUGGESTING THE POSSIBILITY OF OCCURRENCE OF LOCAL IRRITATION IF THE CONTRAST MEDIUM LEAKS AROUND VEINS IN A CLINICAL SETTING [SEEWARNINGS AND PRECAUTIONS].
CLINICAL STUDIES
MRI OF THE CNS
PATIENTS REFERRED FOR MRI OF THE CENTRAL NERVOUS SYSTEM WITH CONTRAST WERE ENROLLED IN TWO CLINICAL TRIALS THAT EVALUATED THE VISUALIZATION CHARACTERISTICS OF LESIONS. IN BOTH STUDIES, PATIENTS UNDERWENT A BASELINE, PRE-CONTRAST MRI PRIOR TO ADMINISTRATION OF GADAVIST AT A DOSE OF 0.1 MMOL/KG, FOLLOWED BY A POST-CONTRAST MRI. IN STUDY A, PATIENTS ALSO UNDERWENT AN MRI BEFORE AND AFTER THE ADMINISTRATION OF GADOTERIDOL. THE STUDIES WERE DESIGNED TO DEMONSTRATE SUPERIORITY OF GADAVIST MRI TO NON-CONTRAST MRI FOR LESIONVISUALIZATION. FOR BOTH STUDIES, PRE-CONTRAST AND PRE-PLUS-POST CONTRAST IMAGES (PAIRED IMAGES) WERE INDEPENDENTLY EVALUATED BY THREE READERS FOR CONTRAST ENHANCEMENT AND BORDER DELINEATION USING A SCALE OF 1 TO 4, AND FOR INTERNAL MORPHOLOGY USING A SCALE OF 1 TO 3 (TABLE 5). LESION COUNTING WAS ALSO PERFORMED TO DEMONSTRATE NON-INFERIORITY OF PAIRED GADAVIST IMAGE SETS TO PRE-CONTRAST MRI. READERS WERE BLINDED TO CLINICAL INFORMATION.
TABLE 5: PRIMARY ENDPOINT VISUALIZATION SCORING SYSTEM
SCORE VISUALIZATION CHARACTERISTICS
CONTRAST ENHANCEMENT BORDER DELINEATION INTERNAL MORPHOLOGY
1 NONE NONE POORLY VISIBLE
2 WEAK MODERATE MODERATELY VISIBLE
3 CLEAR CLEAR BUT INCOMPLETE SUFFICIENTLY VISIBLE
4 CLEAR AND BRIGHT CLEAR AND COMPLETE N/A
EFFICACY WAS DETERMINED IN 657 SUBJECTS. THE AVERAGE AGE WAS 49 YEARS (RANGE 18 TO 85 YEARS) AND 42% WERE MALE. THE ETHNIC REPRESENTATIONS WERE 39% CAUCASIAN, 4% BLACK, 16% HISPANIC, 38% ASIAN, AND 3% OF OTHER ETHNIC GROUPS.
TABLE 6 SHOWS A COMPARISON OF VISUALIZATION RESULTS BETWEEN PAIRED IMAGES AND PRE-CONTRAST IMAGES. GADAVIST PROVIDED A STATISTICALLY SIGNIFICANT IMPROVEMENT FOR EACH OF THE THREE LESION VISUALIZATION PARAMETERS WHEN AVERAGED ACROSS THREE INDEPENDENT READERS FOR EACH STUDY.
TABLE 6: VISUALIZATION ENDPOINT RESULTS OF CENTRAL NERVOUS SYSTEM ADULT MRI STUDIES WITH 0.1 MMOL/KG GADAVIST
ENDPOINT STUDY A N=336 STUDY B N=321
PRE-CONTRAST PAIRED DIFFERENCE* PRE-CONTRAST PAIRED DIFFERENCE
CONTRAST ENHANCEMENT 0.97 2.26 1.29^ 0.93 2.86 1.94 ^
BORDER DELINEATION 1.98 2.58 0.60^ 1.92 2.94 1.02^
INTERNAL MORPHOLOGY 1.32 1.93 0.60^ 1.57 2.35 0.78^
AVERAGE # LESIONS DETECTED 8.08 8.25 0.17** 2.65 2.97 0.32^^
* DIFFERENCE OF MEANS = (PAIRED MEAN) - (PRE-CONTRAST MEAN)
^ P < 0.001
^^ MET NONINFERIORITY MARGIN OF -0.35
** DID NOT MEET NONINFERIORITY MARGIN OF -0.35
PERFORMANCES OF GADAVIST AND GADOTERIDOL FOR VISUALIZATION PARAMETERS WERE SIMILAR. REGARDING THE NUMBER OF LESIONS DETECTED, STUDY B MET THE PRESPECIFIED NONINFERIORITY MARGIN OF -0.35 FOR PAIRED READ VERSUS PRE-CONTRAST READ WHILE IN STUDY A, GADAVIST AND GADOTERIDOL DID NOT.
FOR THE VISUALIZATION ENDPOINTS CONTRAST ENHANCEMENT, BORDER DELINEATION, AND INTERNAL MORPHOLOGY, THE PERCENTAGE OF PATIENTS SCORING HIGHER FOR PAIRED IMAGESCOMPARED TO PRE-CONTRAST IMAGES RANGED FROM 93% TO 99% FOR STUDY A, AND 95% TO 97% FOR STUDY B. FOR BOTH STUDIES, THE MEAN NUMBER OF LESIONS DETECTED ON PAIRED IMAGES EXCEEDED THAT OF THE PRE-CONTRAST IMAGES; 37% FOR STUDY A AND 24% FOR STUDY B. THERE WERE 29% AND 11% OF SUBJECTS IN WHICH THE PRE-CONTRAST IMAGES DETECTED MORE LESIONS FOR STUDY A AND STUDY B, RESPECTIVELY.
THE PERCENTAGE OF PATIENTS WHOSE AVERAGE READER MEAN SCORE CHANGED BY ? 0, UP TO 1, UP TO 2, AND ? 2 SCORING CATEGORIES PRESENTED IN TABLE 5 IS SHOWN IN TABLE 7. THE CATEGORICAL IMPROVEMENT OF ( ? 0) REPRESENTS HIGHER ( < 0) OR IDENTICAL (= 0) SCORES FOR THE PRE-CONTRAST READ, THE CATEGORIES WITH SCORES > 0 REPRESENT THE MAGNITUDE OF IMPROVEMENT SEEN FOR THE PAIRED READ.
TABLE 7: PRIMARY ENDPOINT VISUALIZATION CATEGORICAL IMPROVEMENT FOR AVERAGE READER
ENDPOINT STUDY A
N=336 STUDY B
N=321
CATEGORICAL IMPROVEMENT (PAIRED - PRE-CONTRAST) % CATEGORICAL IMPROVEMENT (PAIRED - PRE-CONTRAST) %
? 0 > 0 - < 1 1 - < 2 ? 2 ? 0 > 0 - < 1 1 - < 2 ? 2
CONTRAST ENHANCEMENT 1 30 55 13 3 6 34 57
BORDER DELINEATION 7 73 18 1 5 38 51 5
INTERNAL MORPHOLOGY 4 79 17 0 5 61 33 1
FOR BOTH STUDIES, THE IMPROVEMENT OF VISUALIZATION ENDPOINTS IN PAIRED GADAVIST IMAGESCOMPARED TO PRE-CONTRAST IMAGES RESULTED IN IMPROVED ASSESSMENT OF NORMAL AND ABNORMAL CNS ANATOMY.
PEDIATRIC PATIENTS
TWO STUDIES IN 44 PEDIATRICS PATIENTS AGE YOUNGER THAN 2 YEARS AND 135 PEDIATRIC PATIENTS AGE 2 TO LESS THAN18 YEARS WITH CNS AND NON-CNS LESIONS SUPPORTED EXTRAPOLATION OF ADULT CNS EFFICACY FINDINGS. FOR EXAMPLE,COMPARING PRE VS PAIRED PRE-AND POST-CONTRAST IMAGES, INVESTIGATORS SELECTED THE BEST OF FOUR DESCRIPTORS UNDER THE HEADING, "VISUALIZATION OF LESION-INTERNAL MORPHOLOGY (LESION CHARACTERIZATION) OR HOMOGENEITY OF VESSEL ENHANCEMENT" FOR 27/44 (62% = PRE) VS 43/44 (98% = PAIRED) MR IMAGES FROM PATIENTS AGE 0 TO LESS THAN 2 YEARS AND 106/135 (78% = PRE) VS 108/135 (80% = PAIRED) MR IMAGES FROM PATIENTS AGE 2 TO LESS THAN 18 YEARS.
MRI OF THE BREAST
PATIENTS WITH RECENTLY DIAGNOSED BREAST CANCER WERE ENROLLED IN TWO IDENTICAL CLINICAL TRIALS TO EVALUATE THE ABILITY OF GADAVIST TO ASSESS THE PRESENCE AND EXTENT OF MALIGNANT BREAST DISEASE PRIOR TO SURGERY. PATIENTS UNDERWENT NON-CONTRAST BREAST MRI (BMR) PRIOR TO GADAVIST (0.1 MMOL/KG) BREAST MRI. BMR IMAGES AND GADAVIST BMR (COMBINED CONTRAST PLUS NON-CONTRAST) IMAGES WERE INDEPENDENTLY EVALUATED IN EACH STUDY BY THREE READERS BLINDED TO CLINICAL INFORMATION. IN SEPARATE READING SESSIONS THE BMR IMAGES AND GADAVIST BMR IMAGES WERE ALSO INTERPRETED TOGETHER WITH X-RAYMAMMOGRAPHY IMAGES (XRM).
THE STUDIES EVALUATED 787 PATIENTS: STUDY 1 ENROLLED 390 WOMEN WITH AN AVERAGE AGE OF 56 YEARS, 74% WERE WHITE, 25% ASIAN, 0.5% BLACK, AND 0.5% OTHER; STUDY 2 ENROLLED 396 WOMEN AND 1 MAN WITH AN AVERAGE AGE OF 57 YEARS, 71% WERE WHITE, 24% ASIAN, 3% BLACK, AND 2% OTHER.
THE READERS ASSESSED 5 REGIONS PER BREAST FOR THE PRESENCE OF MALIGNANCYUSING EACH READING MODALITY. THE READINGS WERECOMPARED TO AN INDEPENDENT STANDARD OF TRUTH (SOT) CONSISTING OF HISTOPATHOLOGY FOR ALL REGIONS WHERE EXCISIONS WERE MADE AND TISSUE EVALUATED. XRM PLUS ULTRASOUND WAS USED FOR ALL OTHER REGIONS.
THE ASSESSMENT OF MALIGNANT DISEASE WAS PERFORMED USING A REGION BASED WITHIN-SUBJECT SENSITIVITY. SENSITIVITY FOR EACH READING MODALITY WAS DEFINED AS THE MEAN OF THE PERCENTAGE OF MALIGNANT BREAST REGIONS CORRECTLY INTERPRETED FOR EACH SUBJECT. THE WITHIN-SUBJECT SENSITIVITY OF GADAVIST BMR WAS SUPERIOR TO THAT OF BMR. THE LOWER BOUND OF THE 95% CONFIDENCE INTERVAL (CI) FOR THE DIFFERENCE IN WITHIN-SUBJECT SENSITIVITY RANGED FROM 19% TO 42% FOR STUDY 1 AND FROM 12% TO 27% FOR STUDY 2. THE WITHIN-SUBJECT SENSITIVITY FOR GADAVIST BMR AND BMR AS WELL AS FOR GADAVIST BMR PLUS XRM AND BMR PLUS XRM IS PRESENTED IN TABLE 8.
TABLE 8: SENSITIVITY OF GADAVIST BMR FOR DETECTION OF MALIGNANT BREAST DISEASE
STUDY 1 STUDY 2
SENSITIVITY(%)
N=388 PATIENTS SENSITIVITY(%)
N=390 PATIENTS
READER BMR BMR + XRM GADAVIST BMR GADAVIST BMR +XRM READER BMR BMR + XRM GADAVIST BMR GADAVIST BMR +XRM
1 37 71 83 84 4 73 83 87 90
2 49 76 80 83 5 57 81 89 90
3 63 75 87 87 6 55 80 86 88
SPECIFICITY WAS DEFINED AS THE PERCENTAGE OF NON-MALIGNANT BREASTS CORRECTLY IDENTIFIED AS NON-MALIGNANT. THE LOWER LIMIT OF THE 95% CONFIDENCE INTERVAL FOR SPECIFICITY OF GADAVIST BMR WAS GREATER THAN 80% FOR 5 OF 6 READERS. (TABLE 9)
TABLE 9: SPECIFICITY OF GADAVIST BMR IN NON-MALIGNANT BREASTS
STUDY 1 STUDY 2
SPECIFICITY (%)
N=372 PATIENTS SPECIFICITY (%)
N=367 PATIENTS
READER GADAVIST BMR LOWER LIMIT 95% CI READER GADAVIST BMR LOWER LIMIT 95% CI
1 86 82 4 92 89
2 95 93 5 84 80
3 89 85 6 83 79
THREE ADDITIONAL READERS IN EACH STUDY READ XRM ALONE. FOR THESE READERS OVER BOTH STUDIES, SENSITIVITY RANGED FROM 68% TO 73% AND SPECIFICITY IN NON-MALIGNANT BREASTS RANGED FROM 86% TO 94%.
IN BREASTS WITH MALIGNANCY, A FALSE POSITIVE DETECTION RATE WAS CALCULATED AS THE PERCENTAGE OF SUBJECTS FOR WHICH THE READERS ASSESSED A REGION AS MALIGNANT WHICH COULD NOT BE VERIFIED BY SOT. THE FALSE POSITIVE DETECTION RATES FOR GADAVIST BMR RANGED FROM 39% TO 53% (95% CI UPPER BOUNDS RANGED FROM 44% TO 58%).