WARNING
NEPHROGENIC SYSTEMIC FIBROSIS
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 SYSTEMIC 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 (E.G. 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 MULTIHANCE 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
MULTIHANCE IS INDICATED FOR INTRAVENOUS USE IN MAGNETIC RESONANCE IMAGING (MRI) OF THE CENTRAL NERVOUS SYSTEM (CNS) IN ADULTS AND CHILDREN OVER 2 YEARS OF AGE TO VISUALIZE LESIONS WITH ABNORMAL BLOOD BRAIN BARRIER OR ABNORMAL VASCULARITY OF THE BRAIN, SPINE, AND ASSOCIATED TISSUES.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
MULTIHANCE IS A STERILE, NONPYROGENIC, CLEAR, COLORLESS, AQUEOUS SOLUTION FOR INTRAVENOUS USE ONLY, CONTAINING 529 MG GADOBENATE DIMEGLUMINE PER ML.
MULTIHANCE (GADOBENATE DIMEGLUMINE) IS A CLEAR, COLORLESS SOLUTION CONTAINING 529 MG GADOBENATE DIMEGLUMINE PER ML. MULTIHANCE IS SUPPLIED IN GLASS VIALS; EACH SINGLE DOSE VIAL IS RUBBER STOPPERED WITH AN ALUMINUM SEAL AND THE CONTENTS ARE STERILE. MULTIHANCE IS SUPPLIED IN BOXES OF:
FIVE 5 ML SINGLE DOSE 10 ML VIALS (NDC 0270-5164-12)
FIVE 10 ML SINGLE DOSE 20 ML VIALS (NDC 0270-5164-13)
FIVE 15 ML SINGLE DOSE 20 ML VIALS (NDC 0270-5164-14)
FIVE 20 ML SINGLE DOSE 20 ML VIALS (NDC 0270-5164-15)
STORAGE AND HANDLING
INSPECT THE MULTIHANCE VIAL VISUALLY FOR PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION. DO NOT USE THE SOLUTION IF IT IS DISCOLORED OR PARTICULATE MATTER IS PRESENT. DO NOT MIX INTRAVENOUS MEDICATIONS OR PARENTERAL NUTRITION SOLUTIONS WITH MULTIHANCE. DO NOT ADMINISTER OTHER MEDICATIONS IN THE SAME INTRAVENOUS LINE WITH MULTIHANCE BECAUSE OF THE POTENTIAL FOR CHEMICAL INCOMPATIBILITY. DRAW MULTIHANCE INTO A SYRINGE AND INJECT USING STERILE TECHNIQUE. MULTIHANCE VIALS ARE INTENDED FOR SINGLE USE ONLY. ADMINISTER IMMEDIATELY AFTER OPENING AND DISCARD ANY UNUSED PRODUCT. STORE AT 25°C (77°F), EXCURSIONS PERMITTED TO 15-30°C (59-86°F) [SEE USP CONTROLLED ROOM TEMPERATURE].
DO NOT FREEZE.
MANUFACTURED FOR: BRACCO DIAGNOSTICS INC. - PRINCETON, NJ 08543. BY BIPSO GMBH - 78224 SINGEN (GERMANY). REVISED JULY 2011
DOSAGE AND ADMINISTRATION
THE RECOMMENDED DOSE OF MULTIHANCE IS 0.1 MMOL/KG (0.2 ML/KG) ADMINISTERED AS A RAPID BOLUS INTRAVENOUS INJECTION. TO ENSURE COMPLETE INJECTION OF THE CONTRAST MEDIUM, FOLLOW THE INJECTION WITH A SALINE FLUSH OF AT LEAST 5 ML.
INSPECT THE MULTIHANCE VIAL VISUALLY FOR PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION.
DO NOT USE THE SOLUTION IF IT IS DISCOLORED OR PARTICULATE MATTER IS PRESENT. DRAW MULTIHANCE INTO A SYRINGE AND INJECT USING STERILE TECHNIQUE.
DO NOT MIX INTRAVENOUS MEDICATIONS OR PARENTERAL NUTRITION SOLUTIONS WITH MULTIHANCE. DO NOT ADMINISTER OTHER MEDICATIONS IN THE SAME INTRAVENOUS LINE WITH MULTIHANCE.
MULTIHANCE VIALS ARE INTENDED FOR SINGLE USE ONLY. ADMINISTER IMMEDIATELY AFTER OPENING AND DISCARD ANY UNUSED PRODUCT.
SIDE EFFECTS
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 PRACTICE.
ADULT
IN CLINICAL TRIALS, A TOTAL OF 2982 ADULT SUBJECTS (119 HEALTHY VOLUNTEERS AND 2863 PATIENTS) RECEIVED MULTIHANCE AT DOSES RANGING FROM 0.005 TO 0.4 MMOL/KG. THERE WERE 1724 (58%) MEN AND 1258 (42%) WOMEN WITH A MEAN AGE OF 55.1 YEARS (RANGE 18 TO 92 YEARS). A TOTAL OF 2644 (89%) SUBJECTS WERE CAUCASIAN, 84 (3%) BLACK, 162 (5%) ASIAN, 29 (1%) HISPANIC, 18 (1%) IN OTHER RACIAL GROUPS, AND FOR 45 (2%) SUBJECTS, RACE WAS NOT REPORTED.
THE MOST COMMONLY REPORTED ADVERSE REACTIONS IN ADULT SUBJECTS WHO RECEIVED MULTIHANCE WERE HEADACHE (1.8%) AND NAUSEA (1.6%). MOST ADVERSE REACTIONS WERE MILD TO MODERATE IN INTENSITY. FOUR SUBJECTS EXPERIENCED SERIOUS ADVERSE REACTIONS. ONE SUBJECT WITH A HISTORY OF SEIZURES EXPERIENCED CONVULSIONS 17 MINUTES AFTER THE ADMINISTRATION OF MULTIHANCE. ANOTHER SUBJECT WITH A HISTORY OF RECENT MYOCARDIAL INFARCTION(MI) AND CONGESTIVE HEART FAILURE (CHF) EXPERIENCED ACUTE PULMONARY EDEMA WITHIN 10 MINUTES AFTER THE ADMINISTRATION OF 30 ML OF MULTIHANCE. THE THIRD SUBJECT DEVELOPED ACUTE NECROTIZING PANCREATITIS. THE FOURTH SUBJECT EXPERIENCED AN ANAPHYLACTOID REACTION WITH LARYNGISMUS ANDDYSPNEA [SEE WARNINGS AND PRECAUTIONS]. ADVERSE REACTIONS THAT OCCURRED IN AT LEAST 0.5% OF 2982 ADULT SUBJECTS WHO RECEIVED MULTIHANCE ARE LISTED BELOW (TABLE 1), IN DECREASING ORDER OF OCCURRENCE WITHIN EACH SYSTEM.
TABLE 1: ADVERSE REACTIONS REPORTED IN ? 0.5% OF ADULT SUBJECTS WHO RECEIVED MULTIHANCE IN CLINICAL TRIALS
NUMBER OF SUBJECTS DOSED 2982
NUMBER OF SUBJECTS WITH ANY ADVERSE REACTION 450 (15.1%)
GASTROINTESTINAL DISORDERS
NAUSEA 48 (1.6%)
VOMITING 14(0.5%)
GENERAL DISORDERS AND ADMINISTRATION SITE DISORDERS
FEELING HOT 31 (1.0%)
INJECTION SITE REACTION 40 (1.3%)
NERVOUS SYSTEM DISORDERS
HEADACHE 54 (1.8%)
TASTE PERVERSION 25 (0.8%)
PARESTHESIA 23 (0.8%)
DIZZINESS 22 (0.7%)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
RASH 19(0.6%)
VASCULAR DISORDERS HYPERTENSION 16(0.5%)
THE FOLLOWING ADVERSE REACTIONS OCCURRED IN LESS THAN 0.5% OF THE 2982 ADULT SUBJECTS WHO RECEIVED MULTIHANCE:
BLOOD AND LYMPHATIC SYSTEM DISORDERS: BASOPHILIA, DECREASEDHEMOGLOBIN, HEMOLYSIS, LEUKOCYTOSIS, LEUKOPENIA;
CARDIAC DISORDERS: ARRHYTHMIA, ATRIAL FIBRILLATION, BRADYCARDIA, CHEST DISCOMFORT, ECG ABNORMALITY (BUNDLE BRANCH BLOCK, COMPLETE AV BLOCK, FIRST-DEGREE AV BLOCK, INVERTED T WAVE, PROLONGED PR INTERVAL, PROLONGED QT INTERVAL, SHORTENED QT INTERVAL), MYOCARDIAL ISCHEMIA, PALPITATIONS, SUPRAVENTRICULAR EXTRASYSTOLES, TACHYCARDIA, VENTRICULAR ARRHYTHMIA, VENTRICULAR EXTRASYSTOLES;
EAR AND LABYRINTH DISORDERS: EAR PAIN, TINNITUS;
EYE DISORDERS: EYELID EDEMA, OCULAR HYPEREMIA, VISUAL DISTURBANCE;
GASTROINTESTINAL DISORDERS: ACUTE NECROTIZING PANCREATITIS, ABDOMINAL PAIN, CONSTIPATION, DIARRHEA, DRY MOUTH, DYSPEPSIA, FECAL INCONTINENCE, INCREASEDPRURITUS IN PATIENTS WITH CIRRHOSIS, VOMITING;
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: ASTHENIA, BACK PAIN, CHEST PAIN, CHILLS, FEVER, INFECTION, INJECTION SITE EXTRAVASATION, INJECTION SITE INFLAMMATION, INJECTION SITE PAIN, MALAISE, RIGORS;
IMMUNE SYSTEM DISORDERS: ANAPHYLACTIC AND ANAPHYLACTOID REACTIONS,ANAPHYLACTIC SHOCK, HYPERSENSITIVITY REACTIONS;
INVESTIGATIONS: ABNORMAL LABORATORY TEST (INCLUDES CHANGES IN CPK, CREATININE, FERRITIN, TRANSFERRIN, TOTAL IRON BINDING CAPACITY), BILIRUBINEMIA,HYPERGLYCEMIA, HYPERKALEMIA, HYPOCALCEMIA, HYPOGLYCEMIA, HYPONATREMIA, DECREASED BLOOD ALBUMIN, INCREASED ALKALINE PHOSPHATASE, INCREASED GGT, INCREASED LDH, INCREASED SERUM IRON, INCREASED SGOT, INCREASED SGPT;
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: MUSCLE SPASMS,MYALGIA, MYOSITIS;
NERVOUS SYSTEM DISORDERS: APHASIA, CONVULSION, HEMIPLEGIA, HYPERTONIA, HYPOESTHESIA, PARALYSIS, PAROSMIA, STUPOR, SYNCOPE, TREMOR;
RENAL AND URINARY DISORDERS: ALBUMINURIA, GLYCOSURIA, HEMATURIA,PROTEINURIA, URINARY FREQUENCY, URINARY TRACT INFECTION;
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: ACUTE PULMONARY EDEMA, COUGH, DYSPNEA, HYPERVENTILATION, LARYNGOSPASM, NASAL CONGESTION, OBSTRUCTIVE AIRWAY DISORDER, PULMONARY EMBOLUS, WHEEZING;
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: FACIAL EDEMA, HYPERHIDROSIS, PRURITUS, SWEATING, URTICARIA;
VASCULAR DISORDERS: HYPOTENSION.
PEDIATRIC
IN CLINICAL TRIALS, 217 PEDIATRIC SUBJECTS RECEIVED MULTIHANCE AT A DOSE OF 0.1 MMOL/KG. A TOTAL OF 112 (52%) SUBJECTS WERE MALE AND THE OVERALL MEAN AGE WAS 8.3 YEARS (RANGE 4 DAYS TO 17 YEARS). A TOTAL OF 168 (77%) SUBJECTS WERE CAUCASIAN, 12 (6%) BLACK, 12 (6%) ASIAN, 24 (11%), HISPANIC, AND 1 (<1%) IN OTHER RACIAL GROUPS.
ADVERSE REACTIONS WERE REPORTED FOR 14 (6.5%) OF THE SUBJECTS. THE FREQUENCY AND THE NATURE OF THE ADVERSE REACTIONS WERE SIMILAR TO THOSE SEEN IN THE ADULT PATIENTS. THE MOST COMMONLY REPORTED ADVERSE REACTIONS WERE VOMITING (1.4%), PYREXIA (0.9%), AND HYPERHIDROSIS (0.9%). NO SUBJECT DIED DURING STUDY PARTICIPATION. A SERIOUS ADVERSE REACTION OF WORSENING OF VOMITING WAS REPORTED FOR ONE (0.5%) PATIENT WITH A BRAIN TUMOR (GLIOMA) FOR WHICH A CAUSAL RELATIONSHIP TO MULTIHANCE COULD NOT BE EXCLUDED.
POST-MARKETING EXPERIENCE
THE FOLLOWING ADVERSE REACTIONS HAVE BEEN IDENTIFIED DURING POST APPROVAL USE OF MULTIHANCE. 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.
ANAPHYLACTIC, ANAPHYLACTOID AND HYPERSENSITIVITY REACTIONS MANIFESTED WITH VARIOUS DEGREES OF SEVERITY UP TO ANAPHYLACTIC SHOCK, LOSS OF CONSCIOUSNESS AND DEATH. THE REACTIONS GENERALLY INVOLVED SIGNS OR SYMPTOMS OF RESPIRATORY, CARDIOVASCULAR, AND/OR MUCOCUTANEOUS ABNORMALITIES. EXTRAVASATION OF MULTIHANCE MAY LEAD TO INJECTION SITE REACTIONS, CHARACTERIZED BY LOCAL PAIN OR BURNING SENSATION, SWELLING, BLISTERING, ANDNECROSIS [SEE WARNINGS AND PRECAUTIONS].
READ THE MULTIHANCE (GADOBENATE DIMEGLUMINE INJECTION) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
CLINICAL CONSEQUENCES OF OVERDOSAGE WITH MULTIHANCE HAVE NOT BEEN REPORTED. TREATMENT OF AN OVERDOSAGE SHOULD BE DIRECTED TOWARD SUPPORT OF VITAL FUNCTIONS AND PROMPT INSTITUTION OF SYMPTOMATIC THERAPY. IN A PHASE 1 CLINICAL STUDY, DOSES UP TO 0.4 MMOL/KG WERE ADMINISTERED TO PATIENTS. MULTIHANCE HAS BEEN SHOWN TO BE DIALYZABLE [SEE CLINICAL PHARMACOLOGY].
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
GADOBENATE DIMEGLUMINE IS A PARAMAGNETIC AGENT AND, AS SUCH, DEVELOPS A MAGNETIC MOMENT WHEN PLACED IN A MAGNETIC FIELD. THE LARGE MAGNETIC MOMENT PRODUCED BY THE PARAMAGNETIC AGENT RESULTS IN A LARGE LOCAL MAGNETIC FIELD, WHICH CAN ENHANCE THE RELAXATION RATES OF WATER PROTONS IN ITS VICINITY LEADING TO AN INCREASE OF SIGNAL INTENSITY (BRIGHTNESS) OF TISSUE.
IN MAGNETIC RESONANCE IMAGING (MRI), VISUALIZATION OF NORMAL AND PATHOLOGICAL TISSUE DEPENDS IN PART ON VARIATIONS IN THE RADIOFREQUENCY SIGNAL INTENSITY THAT OCCUR WITH 1) DIFFERENCES IN PROTON DENSITY; 2) DIFFERENCES OF THE SPIN-LATTICE OR LONGITUDINAL RELAXATION TIMES (T1); AND 3) DIFFERENCES IN THE SPIN-SPIN OR TRANSVERSE RELAXATION TIME (T2). WHEN PLACED IN A MAGNETIC FIELD, GADOBENATE DIMEGLUMINE DECREASES THE T1 AND T2 RELAXATION TIME IN TARGET TISSUES. AT RECOMMENDED DOSES, THE EFFECT IS OBSERVED WITH GREATEST SENSITIVITY IN THE T1-WEIGHTED SEQUENCES.
PHARMACODYNAMICS
UNLIKE OTHER TESTED PARAMAGNETIC CONTRAST AGENTS (SEE TABLE 2), MULTIHANCE DEMONSTRATES WEAK AND TRANSIENT INTERACTIONS WITH SERUM PROTEINS THAT CAUSES SLOWING IN THE MOLECULAR TUMBLING DYNAMICS, RESULTING IN STRONG INCREASES IN RELAXIVITY IN SOLUTIONS CONTAINING SERUM PROTEINS. THE IMPROVED RELAXATION EFFECT CAN CONTRIBUTE TO INCREASED CONTRAST-TO-NOISE RATIO AND LESION-TO-BRAIN RATIO, WHICH MAY IMPROVE VISUALIZATION.
TABLE 2: RELAXIVITY (MM-1S-1) OF GADOLINIUM CHELATES
HUMAN PLASMA
R1 R2
GADOBENATE 9.71 12.51
GADOPENTETATE 4.91 6.31
GADODIAMIDE 5.42 ---
GADOTERIDOL 5.42 ---
R1 AND R2 RELAXIVITIES INDICATE THE EFFICIENCY IN SHORTENING T1 AND T2 RELAXATION TIMES, RESPECTIVELY.
1 IN HEPARINIZED HUMAN PLASMA, AT 39°C.
2 IN CITRATED HUMAN PLASMA, AT 37°C.
--- NOT AVAILABLE
MULTIHANCE INJECTION DOES NOT CROSS THE INTACT BLOOD-BRAIN BARRIER AND, THEREFORE, DOES NOT ENHANCE NORMAL BRAIN OR LESIONS THAT HAVE A NORMALBLOOD-BRAIN BARRIER, E.G., CYSTS, MATURE POSTOPERATIVE SCARS. HOWEVER, DISRUPTION OF THE BLOOD-BRAIN BARRIER OR ABNORMAL VASCULARITY ALLOWS ENHANCEMENT BY MULTIHANCE OF LESIONS SUCH AS NEOPLASMS, ABSCESSES, AND INFARCTS. UPTAKE OF MULTIHANCE INTO HEPATOCYTES HAS BEEN DEMONSTRATED.
PHARMACOKINETICS
THREE SINGLE-DOSE INTRAVENOUS STUDIES WERE CONDUCTED IN 32 HEALTHY MALE SUBJECTS TO ASSESS THE PHARMACOKINETICS OF GADOBENATE DIMEGLUMINE. THE DOSES ADMINISTERED IN THESE STUDIES RANGED FROM 0.005 TO 0.4 MMOL/KG. UPON INJECTION, THE MEGLUMINE SALT IS COMPLETELY DISSOCIATED FROM THE GADOBENATE DIMEGLUMINE COMPLEX. THUS, THE PHARMACOKINETICS IS BASED ON THE ASSAY OF GADOBENATE ION, THE MRI CONTRAST EFFECTIVE ION IN GADOBENATE DIMEGLUMINE. DATA FOR PLASMA CONCENTRATION AND AREA UNDER THE CURVE DEMONSTRATED LINEAR DEPENDENCE ON THE ADMINISTERED DOSE. THE PHARMACOKINETICS OF GADOBENATE ION FOLLOWING INTRAVENOUS ADMINISTRATION CAN BE BEST DESCRIBED USING A TWO-COMPARTMENT MODEL.
DISTRIBUTION
GADOBENATE ION HAS A RAPID DISTRIBUTION HALF-LIFE (REPORTED AS MEAN ± SD) OF 0.084 ± 0.012 TO 0.605 ± 0.072 HOURS. VOLUME OF DISTRIBUTION OF THE CENTRAL COMPARTMENT RANGED FROM 0.074 ± 0.017 TO 0.158 ± 0.038 L/KG, AND ESTIMATES OF VOLUME OF DISTRIBUTION BY AREA RANGED FROM 0.170 ± 0.016 TO 0.282 ± 0.079 L/KG. THESE LATTER ESTIMATES ARE APPROXIMATELY EQUIVALENT TO THE AVERAGE VOLUME OF EXTRACELLULAR BODY WATER IN MAN. IN VITRO STUDIES SHOWED NO APPRECIABLE BINDING OF GADOBENATE ION TO HUMAN SERUM PROTEINS.
ELIMINATION
GADOBENATE ION IS ELIMINATED PREDOMINATELY VIA THE KIDNEYS, WITH 78% TO 96% OF AN ADMINISTERED DOSE RECOVERED IN THE URINE. TOTAL PLASMA CLEARANCE AND RENAL CLEARANCE ESTIMATES OF GADOBENATE ION WERE SIMILAR, RANGING FROM 0.093 ± 0.010 TO 0.133 ± 0.270 L/HR/KG AND 0.082 ± 0.007 TO 0.104 ± 0.039 L/HR/KG, RESPECTIVELY. THE CLEARANCE IS SIMILAR TO THAT OF SUBSTANCES THAT ARE SUBJECT TO GLOMERULAR FILTRATION. THE MEAN ELIMINATION HALF-LIFE RANGED FROM 1.17 ± 0.26 TO 2.02 ± 0.60 HOURS. A SMALL PERCENTAGE OF THE ADMINISTERED DOSE (0.6% TO 4%) IS ELIMINATED VIA THE BILIARY ROUTE AND RECOVERED IN FECES.
METABOLISM
THERE WAS NO DETECTABLE BIOTRANSFORMATION OF GADOBENATE ION. DISSOCIATIONOF GADOBENATE ION IN VIVO HAS BEEN SHOWN TO BE MINIMAL, WITH LESS THAN 1% OF THE FREE CHELATING AGENT BEING RECOVERED ALONE IN FECES.
PHARMACOKINETICS IN SPECIAL POPULATIONS
RENAL IMPAIRMENT: A SINGLE INTRAVENOUS DOSE OF 0.2 MMOL/KG OF MULTIHANCE WAS ADMINISTERED TO 20 SUBJECTS WITH IMPAIRED RENAL FUNCTION (6 MEN AND 3 WOMEN WITH MODERATE RENAL IMPAIRMENT [URINE CREATININE CLEARANCE >30 TO <60 ML/MIN] AND 5 MEN AND 6 WOMEN WITH SEVERE RENAL IMPAIRMENT [URINE CREATININE CLEARANCE >10 TO <30 ML/MIN]). MEAN ESTIMATES OF THE ELIMINATION HALF-LIFE WERE 6.1 ± 3.0 AND 9.5 ± 3.1 HOURS FOR THE MODERATE AND SEVERE RENAL IMPAIRMENT GROUPS, RESPECTIVELY ASCOMPARED WITH 1.0 TO 2.0 HOURS IN HEALTHY VOLUNTEERS.
HEMODIALYSIS: A SINGLE INTRAVENOUS DOSE OF 0.2 MMOL/KG OF MULTIHANCE WAS ADMINISTERED TO 11 SUBJECTS (5 MALES AND 6 FEMALES) WITH END-STAGE RENAL DISEASE REQUIRING HEMODIALYSIS TO DETERMINE THE PHARMACOKINETICS AND DIALYZABILITY OF GADOBENATE. APPROXIMATELY 72% OF THE DOSE WAS RECOVERED BY HEMODIALYSIS OVER A 4-HOUR PERIOD. THE MEAN ELIMINATION HALF-LIFE ONDIALYSIS WAS 1.21 ± 0.29 HOURS ASCOMPARED WITH 42.4 ± 24.4 HOURS WHEN OFF DIALYSIS.
HEPATIC IMPAIRMENT: A SINGLE INTRAVENOUS DOSE OF 0.1 MMOL/KG OF MULTIHANCE WAS ADMINISTERED TO 11 SUBJECTS (8 MALES AND 3 FEMALES) WITH IMPAIRED LIVER FUNCTION (CLASS B OR C MODIFIED CHILD-PUGH CLASSIFICATION). HEPATIC IMPAIRMENT HAD LITTLE EFFECT ON THE PHARMACOKINETICS OF MULTIHANCE WITH THE PARAMETERS BEING SIMILAR TO THOSE CALCULATED FOR HEALTHY SUBJECTS.
GENDER, AGE, RACE: A MULTIPLE REGRESSION ANALYSIS PERFORMED USING POOLED DATA FROM SEVERAL PHARMACOKINETIC STUDIES FOUND NO SIGNIFICANT EFFECT OF SEX UPON THE PHARMACOKINETICS OF GADOBENATE. CLEARANCE APPEARED TO DECREASE SLIGHTLY WITH INCREASING AGE. SINCE VARIATIONS DUE TO AGE APPEARED MARGINAL, DOSAGE ADJUSTMENT FOR GERIATRIC POPULATION IS NOT RECOMMENDED. PHARMACOKINETIC DIFFERENCES DUE TO RACE HAVE NOT BEEN SYSTEMATICALLY STUDIED.
PEDIATRIC: A POPULATION PHARMACOKINETIC ANALYSIS INCORPORATED DATA FROM 25 HEALTHY SUBJECTS (14 MALES AND 11 FEMALES) AND 15 SUBJECTS UNDERGOING MR IMAGING OF THE CENTRAL NERVOUS SYSTEM (7 MALES AND 8 FEMALES) BETWEEN AGES OF 2 AND 16 YEARS. THE SUBJECTS RECEIVED A SINGLE INTRAVENOUS DOSE OF 0.1 MMOL/KG OF MULTIHANCE. THE GEOMETRIC MEAN CMAX WAS 62.3 ?G/ML (N=16) IN CHILDREN 2 TO 5 YEARS OF AGE, AND 64.2 ?G/ML (N=24) IN CHILDREN OLDER THAN 5 YEARS. THE GEOMETRIC MEAN AUC0-? WAS 77.9 ?G-H/ML IN CHILDREN 2-5 YEARS OF AGE (N=16) AND 82.6 ?G-H/ML IN CHILDREN OLDER THAN 5 YEARS (N=24). THE GEOMETRIC MEAN HALF-LIFE WAS 1.2 HOURS IN CHILDREN 2 TO 5 YEARS OF AGE AND 0.93 HOURS IN CHILDREN OLDER THAN 5 YEARS. THERE WAS NO SIGNIFICANT GENDER-RELATED DIFFERENCE IN THE PHARMACOKINETIC PARAMETERS IN THE PEDIATRIC PATIENTS. OVER 80% OF THE DOSE WAS RECOVERED IN URINE AFTER 24 HOURS.
CLINICAL STUDIES
MULTIHANCE WAS EVALUATED IN 426 ADULT PATIENTS IN 2 CONTROLLED CLINICAL TRIALS OF THE CENTRAL NERVOUS SYSTEM (STUDY A AND STUDY B), ENROLLING 217 MEN AND 209 WOMEN WITH A MEAN AGE OF 52 YEARS (RANGE 18 TO 88 YEARS). THE RACIAL AND ETHNIC REPRESENTATIONS WERE 88% CAUCASIAN, 6% BLACK, 4% HISPANIC, 1% ASIAN, AND 1% OTHER RACIAL OR ETHNIC GROUPS. THESE TRIALS WERE DESIGNED TOCOMPAREMULTIHANCE CONTRAST MRI TO NON-CONTRAST MRI ALONE. IN STUDY A, PATIENTS HIGHLY SUSPECTED OF HAVING A LESION(S) OF THE CNS BASED ON NUCLEAR MEDICINE IMAGING, COMPUTED TOMOGRAPHY (CT), CONTRAST CT, MRI, CONTRAST- MRI, OR ANGIOGRAPHY WERE RANDOMIZED TO RECEIVE TWO MRI EVALUATIONS WITH 0.05 MMOL/KG (N=140) OR 0.1 MMOL/KG (N=136) OF MULTIHANCE. IN STUDY B, PATIENTS WITH KNOWN METASTATIC DISEASE TO THE CNS WERE RANDOMIZED TO RECEIVE TWO MRI EVALUATIONS WITH 0.05 MMOL/KG (N=74) OR 0.1 MMOL/KG (N=76) OF MULTIHANCE. MRI SCANS WERE PERFORMED PRE-CONTRAST AND WITHIN 5 MINUTES AFTER EACH INJECTION. THE STUDIES WERE DESIGNED TO EVALUATE THE EFFECT OF MULTIHANCE MRICOMPARED TO THE NON-CONTRAST MRI ON A LESION LEVEL. PRE-CONTRAST, POST-CONTRAST, AND PRE-PLUS-POST CONTRAST IMAGES (PAIRED IMAGES) WERE INDEPENDENTLY EVALUATED BY THREE BLINDED READERS. THE IMAGES WERE EVALUATED FOR THE FOLLOWING ENDPOINTS USING A SCALE FROM 0 TO 4: THE DEGREE OF LESION BORDER DELINEATION, THE DEGREE OF VISUALIZATION OF LESION INTERNAL MORPHOLOGY, AND THE DEGREE OF LESION CONTRAST ENHANCEMENT. LESION COUNTING WAS ALSO PERFORMED FOR THE PRE-CONTRAST AND PAIRED IMAGE SETS.
THE 0.1 MMOL/KG DOSE OF MULTIHANCE DEMONSTRATED CONSISTENTLY BETTER VISUALIZATION FOR ALL READERS FOR ALL VISUALIZATION ENDPOINTS. HOWEVER, THE 0.05 MMOL/KG DOSE OF MULTIHANCE PROVIDED INCONSISTENT VISUALIZATION RESULTS BETWEEN READERS.
COMPARISON OF PRE-CONTRAST VERSUS POST-CONTRAST (0.1 MMOL/KG) IMAGES SHOWED THAT THE MEAN SCORE DIFFERENCES WERE SIGNIFICANT AND FAVORED CONTRAST FOR SUBJECTS IN STUDY B (ALL SUBJECTS WITH KNOWN METASTATIC LESIONS) AND FOR SUBJECTS WITH KNOWN TUMORS IN STUDY A. HOWEVER, THE MEAN SCORE DIFFERENCES BETWEEN THE PRE-CONTRAST AND POST-CONTRAST IMAGES WERE NOT SIGNIFICANT FOR NON-TUMOR PATIENTS IN STUDY A. THESE NEGATIVE RESULTS MAY BE ATTRIBUTED TO A LACK OF LESION ENHANCEMENT IN NON-TUMOR CNS DISEASE.
TABLE 3 SHOWS A COMPARISON OF PAIRED IMAGES (PRE-AND POST-CONTRAST) VERSUS PRE-CONTRAST IMAGES WITH RESPECT TO THE DIFFERENCE IN THE MEAN SCORE AND WITH RESPECT TO THE PROPORTION OF LESIONS READ AS BETTER, WORSE, OR THE SAME AS THE PRE-CONTRAST MRI IMAGES. TABLE 3 SHOWS THAT BASED ON A LESION-LEVEL ANALYSIS 0.1 MMOL/KG MULTIHANCE PROVIDED A STATISTICALLY SIGNIFICANT IMPROVEMENT FOR THE THREE STRUCTURAL PARAMETERS EVALUATED. ALSO, MORE LESIONS WERE SEEN IN THE PAIRED IMAGES THAN IN THE PRE-CONTRAST IMAGES ALONE.
TABLE 3: LESION LEVEL RESULTS OF MRI CENTRAL NERVOUS SYSTEM ADULT STUDIES WITH 0.1 MMOL/KG MULTIHANCE
ENDPOINTS STUDY A STUDY B
READER 1 READER 2 READER 3 READER 1 READER 2 READER 3
N = 395 N = 384 N = 299 N = 245 N = 275 N = 254
BORDER DELINEATION: DIFFERENCE OF MEANS A 0.8* 0.6* 0.8* 1.8* 1.5* 1.9*
WORSEB 44 (11 %) 61 (16%) 57 (19%) 13(5%) 24 (9%) 15 (6%)
SAME 146(37%) 168(44%) 89 (30%) 11 (5%) 19(7%) 18 (7%)
BETTER 205 (52%) 155(40%) 153(51%) 221 (90%) 232 (84%) 221 (87%)
INTERNAL MORPHOLOGY: DIFFERENCE OF MEANS 0.8* 0.6* 0.7* 1.7* 1.4* 2.1*
WORSE 37 (10%) 63 (17%) 62(21%) 13(5%) 26 (10%) 14 (5%)
SAME 147(37%) 151 (39%) 84 (28%) 16(7%) 22 (8%) 22 (9%)
BETTER 211 (53%) 170(44%) 153(51%) 216(88%) 227 (82%) 218(86%)
CONTRAST ENHANCEMENT: DIFFERENCE OF MEANS 0.7* 0.5* 0.8* 1.9* 1.3* 1.9*
WORSE 75 (19%) 74 (19%) 50 (17%) 13(5%) 32 (12%) 17 (7%)
SAME 148(37%) 152(40%) 109(36%) 11 (5%) 21 (7%) 14 (5%)
BETTER 172(44%) 158(41%) 140(47%) 221 (90%) 222(81%) 223 (88%)
A DIFFERENCE OF MEANS = (PAIRED MEAN) - (PRE MEAN)
B WORSE = PAIRED SCORE IS LESS THAN THE PRE SCORE
SAME = PAIRED SCORE IS THE SAME AS THE PRE SCORE
BETTER = PAIRED SCORE IS GREATER THAN THE PRE SCORE
* STATISTICALLY SIGNIFICANT FOR THE MEAN (PAIRED T TEST)
THE EFFICACY AND SAFETY OF MULTIHANCE WERE EVALUATED IN 92 PEDIATRIC PATIENTS WITH KNOWN OR HIGHLY SUSPECTED DISEASE OF THE CENTRAL NERVOUS SYSTEM. MRI SCANS WERE PERFORMED PRE-CONTRAST AND WITHIN 3 TO 10 MINUTES FOLLOWING THE ADMINISTRATION OF MULTIHANCE 0.1 MMOL/KG. PRE-CONTRAST, POST-CONTRAST, AND PRE-PLUS-POST CONTRAST IMAGES (PAIRED IMAGES) WERE INDEPENDENTLY EVALUATED BY THREE BLINDED READERS ON A LESION LEVEL. THE IMAGES WERE EVALUATED FOR THE SAME ENDPOINTS AS IN THE ADULT CENTRAL NERVOUS SYSTEM TRIALS USING A SCALE FROM 0 TO 4: THE DEGREE OF LESION BORDER DELINEATION, THE DEGREE OF VISUALIZATION OF LESION INTERNAL MORPHOLOGY, AND THE DEGREE OF LESION CONTRAST ENHANCEMENT. LESION COUNTING WAS ALSO PERFORMED FOR THE PRE-CONTRAST AND PAIRED IMAGE SETS. THE PRE-CONTRAST VERSUS THE PAIRED IMAGE SET WAS THE PRIMARY COMPARISON. FORTYNINE PERCENT OF STUDY SUBJECTS WERE MALE AND THE OVERALL MEAN AGE WAS 10.6 YEARS (RANGE 2 TO 17 YEARS). THE RACIAL AND ETHNIC REPRESENTATIONS WERE 77% CAUCASIAN, 13% ASIAN, 5% BLACK, AND 4% OTHER RACIAL OR ETHNIC GROUPS. MULTIHANCE INCREASED LESION BORDER DELINEATION, LESION INTERNAL MORPHOLOGY, AND LESION CONTRAST ENHANCEMENT RELATIVE TO NON-CONTRAST AND THESE RESULTS WERECOMPARABLETO THOSE SEEN IN ADULTS.