CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Gadoteridolis paramagnetic agent and, as such, develops magnetic moment whenplaced in magnetic field. The relatively large magnetic moment producedby the paramagnetic agent results in relatively large local magneticfield, which can enhance the relaxation rates of water protons inthe vicinity of the paramagnetic agent.In MRI, visualizationof normal and pathologic brain tissue depends, in part, on variationsin the radiofrequency signal intensity that occur with: 1) differencesin proton density; 2) differences of the spin-lattice or longitudinalrelaxation times (T1); and 3) differences in the spin-spin or transverserelaxation time (T2). When placed in magnetic field, gadoteridoldecreases T1 relaxation times in the target tissues. At recommendeddoses, the effect is observed with greatest sensitivity in the T1-weightedsequences.. 12.2 Pharmacodynamics. Gadoteridolaffects proton relaxation times and consequently the MR signal. Signalintensity is affected by the dose and relaxivity of the gadoteridolmolecule. Consistently, for all gadolinium based contrast agents,the relaxivity of gadoteridol decreases with the increase of the magneticfield strength used in clinical MRI (0.2 3.0T).Disruption of theblood-brain barrier or abnormal vascularity allows accumulation ofgadoteridol in lesions such as neoplasms, abscesses, and subacuteinfarcts. The pharmacokinetics of gadoteridol in various lesions isnot known.. 12.3 Pharmacokinetics. Thepharmacokinetics of intravenously administered gadoteridol in normalsubjects conforms to two-compartment open model.DistributionAfter intravenous administration, gadoteridol is rapidly distributedin the extracellular space. The plasma distribution volume (mean +-SD) for the non-renally impaired adults was 0.205 +- 0.025 L/kg. Itis unknown if protein binding of gadoteridol occurs in vivo.Following GBCA administration,gadolinium is present for months or years in brain, bone, skin, andother organs [see Warnings and Precautions (5.4)].MetabolismIt is unknown if biotransformation or decomposition of gadoteridoloccur in vivo.EliminationGadoteridol is eliminated unchangedvia the kidneys. The elimination half-life (mean +- SD) is about 1.57+- 0.08 hours. Within 24 hours post-injection, 94.4 +- 4.8% of the doseis excreted in the urine. The renal and plasma clearance rates (1.41+- 0.33 mL/ min/kg and 1.50 +- 0.35 mL/ min/kg, respectively) of gadoteridolare essentially identical, indicating no alteration in eliminationkinetics on passage through the kidneys and that the drug is essentiallycleared through the kidney. The volume of distribution (204 +- 58 mL/kg)is equal to that of extracellular water, and clearance is similarto that of substances which are subject to glomerular filtration.Specific PopulationsGenderGender has no clinicallyrelevant effect on the pharmacokinetics of gadoteridol.GeriatricThere were elderly subjects receiving 0.1 (n 3) and 0.3 mmol/kg(n 4) dose of ProHance. The clearance was slightly lower in elderlysubjects as compared to non-elderly subjects [see Use in SpecificPopulations (8.5)].PediatricA population pharmacokinetic analysis incorporated datafrom 79 subjects, 45 males and 34 females. Among 79 subjects, 41 werehealthy subjects including 28 pediatric subjects between years and15 years of age. The pediatric subjects received single intravenousdose of 0.1 mmol/kg of ProHance. From population PK model, the meanCmax was 0.66 +- 0.21 mmol/L in pediatric subjects2 years to years of age, 0.58 +- 0.06 mmol/L in pediatric subjects6 years to 12 years of age, and 0.68 +- 0.12 mmol/L in adolescent subjectsolder than 12 years. The mean AUC0- was 0.74+- 0.20 mmol/Lh in pediatric subjects years to years of age, 0.74+- 0.09 mmol/Lh in pediatric subjects years to 12 years of age,and 0.98 +- 0.09 mmol/Lh in adolescent subjects older than 12 yearsof age. The mean distribution half-life (t1/2,alpha) was 0.14 +- 0.04 hours in pediatric subjects years to yearsof age, 0.18 +- 0.07 hours in pediatric subjects years to 12 yearsof age, and 0.20 +- 0.07 hours in adolescent subjects older than 12years of age. The mean elimination half-life (t1/2,beta) was 1.32 +- 0.006 hours in pediatric subjects years to years,1.32 +- 0.07 hours in pediatric subjects years to 12 years of age,and 1.61 +- 0.19 hours in adolescent subjects older than 12 years ofage. There was no significant gender-related difference in the pharmacokineticparameters in the pediatric patients. Over 80% of the dose was recoveredin urine for pediatric subjects after 10 hours. Pharmacokinetic simulationsindicate similar half-life, AUC, and Cmax valuesfor ProHance in pediatric subjects less than years of age when comparedto those reported for adults; no age-based dose adjustment is necessaryfor this pediatric population.Renal ImpairmentIn patients with impaired renal function, the serum half-life ofgadoteridol is prolonged. After intravenous injection of 0.1 mmol/kg,the elimination half-life of gadoteridol was 10.65 +- 0.06 hours inmild to moderately impaired patients (creatinine clearance 30 to 60mL/min) and 9.10+-0.26 hours in severely impaired patients not on dialysis(creatinine clearance 10 to 30 mL/min). The mean serum clearance ofgadoteridol in patients with normal renal function was 116.14 +- 26.77mL/min, compared to 37.2 +- 16.4 mL/min in patients with mild to moderaterenal impairment and 16.0 +- 3.0 mL/min in patients with severe renalimpairment.In patientswith moderately and severely impaired renal function about 97% and76% of the administered dose was recovered in the urine within daysand 14 days, respectively.For patients receiving hemodialysis, physiciansmay consider the prompt initiation of hemodialysis following the administrationof ProHance in order to enhance the contrast agents elimination.Seventy- two percent (72%) of gadoteridol is removed from the bodyafter the first dialysis, 91% after the second dialysis, and 98% afterthe third dialysis session. [See Warnings and Precautions(5.2) and Use in Specific Populations(8.6).].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Use only if imagingis essential during pregnancy and cannot be delayed. (8.1). 8.1 Pregnancy. RiskSummaryGBCAs cross the placenta and resultin fetal exposure and gadolinium retention. The human data on theassociation between GBCAs and adverse fetal outcomes are limited andinconclusive (see Data). Because of the potential risks of gadoliniumto the fetus, use ProHance only if imaging is essential during pregnancyand cannot be delayed.In animal reproductionstudies in rats, gadoteridol doubled the incidence of post-implantationloss at up to 16 times the recommended human dose (RHD). There wereno adverse developmental effects observed in rabbits with intravenousadministration of gadoteridol during organogenesis at doses up to19 times the recommended human dose of 0.1 mmol/kg (see Data).The estimated backgroundrisk of major birth defects and miscarriage for the indicated populationis unknown. All pregnancies have background risk of birth defect,loss, or other adverse outcomes. In the U.S. general population, theestimated background risk of major birth defects and miscarriage inclinically recognized pregnancies is to 4% and is 15 to 20%, respectively.DataHuman DataContrast agent is visualized in the placenta and fetal tissues aftermaternal GBCA administration. Cohort studies and case reports on exposureto GBCAs during pregnancy have not reported clear association betweenGBCAs and adverse effects in the exposed neonates. However, retrospectivecohort study, comparing pregnant women who had GBCA MRI to pregnantwomen who did not have an MRI, reported higher occurrence of stillbirthsand neonatal deaths in the group receiving GBCA MRI. Limitations ofthis study include lack of comparison with non-contrast MRI andlack of information about the maternal indication for MRI.Animal DataGadolinium RetentionGBCAsadministered to pregnant non-human primates (0.1 mmol/kg on gestationaldays 85 and 135) result in measurable gadolinium concentration inthe offspring in bone, brain, skin, liver, kidney, and spleen forat least months. GBCAs administered to pregnant mice (2 mmol/kgdaily on gestational days 16 through 19) result in measurable gadoliniumconcentrations in the pups in bone, brain, kidney, liver, blood, muscle,and spleen at one-month postnatal age.Reproductive ToxicologyGadoteridol was administered in intravenous doses of 0, 0.375, 1.5,6.0, and 10 mmol/kg/day [0.6, 2.4, 9.7, and 16 times the recommendedhuman dose (RHD) based on body surface area (BSA)] to female ratsfrom gestational day (GD)6 until GD17. Gadoteridol at 10 mmol/kg/dayfor 12 days during gestation doubled the incidence of post-implantationloss. When rats were administered 6.0 or 10.0 mmol/kg/day for 12 days,an increase in spontaneous locomotor activity was observed in theoffspring. Pregnant rabbits were administered gadoteridol in intravenousdoses of 0, 0.4, 1.5, and mmol/kg/day (1.3, 4.8, and 19.4 timesthe RHD based on BSA) from GD6 to GD18. Gadoteridol increased theincidence of spontaneous abortion and early delivery in rabbits administered6 mmol/kg/day for 13 days during gestation.. 8.2 Lactation. Risk SummaryThere are no data on the presenceof gadoteridol in human milk, the effects on the breastfed infant,or the effects on milk production. However, published lactation dataon other GBCAs indicate that 0.01 to 0.04% of the maternal gadoliniumdose is present in breast milk and there is limited GBCA gastrointestinalabsorption in the breast-fed infant. Gadoteridol is present in ratmilk (see Data). The developmental and health benefits of breastfeedingshould be considered along with the mothers clinical need for ProHanceand any potential adverse effects on the breastfed infant from ProHanceor from the underlying maternal condition.DataProHance excretion in the milk of lactating rats wasevaluated at 30 minutes, and 24 hours after intravenous administrationof 0.1 mmol/kg of 153Gd-gadoteridol tonursing mothers. Small amounts of compound were found in milk immediatelyafter injection (0.14% of the ID), with the amount declining to alow level 24 hours after injection (<0.01% of the ID).. 8.4 Pediatric Use. The safety and effectivenessof ProHance have been established for use with MRI to visualize lesionswith abnormal blood brain barrier or abnormal vascularity of the brain,spine, and associated tissues in pediatric patients from birth, includingterm neonates, to 17 years of age. Pediatric use is based on evidenceof effectiveness in adults and in 103 pediatric patients years ofage and older, in addition to experience in 125 pediatric patientsbirth to less than years of age that supported extrapolation fromadult data [see Clinical Studies (14)]. Adverse reactions in pediatric patients weresimilar to those reported in adults [see Adverse Reactions(6.1)].The safety and efficacyof 0.1 mmol/kg, and sequential and/or repeat procedures have notbeen studied in pediatric patients [see Indications and Usage(1) and Dosage and Administration (2)].No case of NSF associatedwith ProHance or any other GBCA has been identified in pediatric patientsages years and younger. Pharmacokinetic studies suggest that weightnormalized clearance of ProHance is similar in pediatric patientsand adults, including pediatric patients age younger than years.Normal estimated GFR (eGFR) is around 30 mL/min/1.73m2 at birth and increases to mature levels around 1year of age, reflecting growth in both glomerular function and relativebody surface area. Clinical studies in pediatric patients youngerthan year of age have been conducted in patients with the followingminimum eGRF; 59.37 mL/min/1.73m2 (agejust after birth to 30 days), 118.84 mL/min/1.73m2 (age 30 days to 6 months), 140.44 mL/min/1.73m2 (age to 12 months).. 8.5 Geriatric Use. Of the total numberof 2673 adult subjects in clinical studies of ProHance, 22% were 65and over. No overall differences in safety were observed between theseelderly subjects and the younger subjects.ProHance is knownto be substantially excreted by the kidneys, and the risk of toxicreactions from ProHance may be greater in patients with impaired renalfunction. Because elderly patients are more likely to have decreasedrenal function, it may be useful to monitor renal function.. 8.6 Renal Impairment. No ProHancedosage adjustment is recommended for patients with renal impairment.Gadoteridol can be removed from the body by hemodialysis [seeWarning and Precautions (5.2) andClinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity: anaphylactic/anaphylactoid reactions withcardiovascular, respiratory and cutaneous manifestations, rangingfrom mild to severe reactions including shock can occur. Monitor patientsclosely for need of emergency cardiorespiratory support (5.3).Gadolinium is retained for months or years in brain, bone,and other organs. (5.4). Hypersensitivity: anaphylactic/anaphylactoid reactions withcardiovascular, respiratory and cutaneous manifestations, rangingfrom mild to severe reactions including shock can occur. Monitor patientsclosely for need of emergency cardiorespiratory support (5.3).. Gadolinium is retained for months or years in brain, bone,and other organs. (5.4). 5.1 Risk Associated with Intrathecal Use. Intrathecal administration of GBCAs cancause serious adverse reactions including death, coma, encephalopathy,and seizures. The safety and effectiveness of ProHance have not beenestablished with intrathecal use. ProHance is not approved for intrathecaluse [see Dosage and Administration (2.1)].. 5.2 Nephrogenic SystemicFibrosis. GCBAs increase therisk for nephrogenic systemic fibrosis (NSF) among patients with impairedelimination of the drugs. Avoid use of ProHance among these patientsunless the diagnostic information is essential and not available withnon-contrast MRI or other modalities. The GBCA-associated NSF riskappears highest for patients with chronic, severe kidney disease (GFRless than 30 mL/min/1.73m2) as well aspatients with acute kidney injury. The risk appears lower for patientswith chronic, moderate kidney disease (GFR 30- 59 mL/min/1.73m2) and little, if any, for patients with chronic, mildkidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting theskin, muscle and internal organs. Report any diagnosis of NSF followingProHance administration to Bracco Diagnostics (1-800-257-5181) orFDA (1-800-FDA-1088 or www.fda.gov/medwatch).Screen patientsfor acute kidney injury and other conditions that may reduce renalfunction. Features of acute kidney injury consist of rapid (over hoursto days) and usually reversible decrease in kidney function, commonlyin the setting of surgery, severe infection, injury or drug-inducedkidney toxicity. Serum creatinine levels and estimated GFR may notreliably assess renal function in the setting of acute kidney injury.For patients at risk for chronically reduced renal function (for example,age greater than 60 years, diabetes mellitus or chronic hypertension),estimate the GFR through laboratory testing.Among the factorsthat may increase the risk for NSF are repeated or higher than recommendeddoses of GBCA and the degree of renal impairment at the time ofexposure. Record the specific GBCA and the dose administered to apatient. For patients at highest risk for NSF, do not exceed the recommendedProHance dose and allow sufficient period of time for eliminationof the drug prior to re-administration. For patients receiving hemodialysis,physicians may consider the prompt initiation of hemodialysis followingthe administration of GBCA in order to enhance the contrast agentselimination. The usefulness of hemodialysis in the prevention of NSFis unknown. [see Clinical Pharmacology (12)].. 5.3 HypersensitivityReactions. Anaphylactic and anaphylactoid reactions have been reported, involvingcardiovascular, respiratory, and/or cutaneous manifestations. Somepatients experienced circulatory collapse and died. In most cases,initial symptoms occurred within minutes of ProHance administrationand resolved with prompt emergency treatment.Prior to ProHance administration, ensurethe availability of trained personnel and medications to treat hypersensitivityreactions. Consider the risk for hypersensitivity reactions, especiallyin patients with history of hypersensitivity reactions or historyof asthma or other allergic disorders. If such reaction occurs,stop ProHance and immediately begin appropriate therapy. Observe patientsfor signs and symptoms of hypersensitivity reaction during and forup to hours after ProHance administration.. 5.4 Gadolinium Retention. Gadolinium is retained formonths or years in several organs. The highest concentrations (nanomolesper gram of tissue) have been identified in the bone, followed byother organs (e.g. brain, skin, kidney, liver, and spleen). The durationof retention also varies by tissue and is longest in bone. LinearGBCAs cause more retention than macrocyclic GBCAs. At equivalent doses,retention varies among the linear agents with Omniscan (gadodiamide)and Optimark (gadoversetamide) causing greater retention than otherlinear agents [Eovist (gadoxetate disodium), Magnevist (gadopentetatedimeglumine), MultiHance (gadobenate dimeglumine)]. Retention is lowestand similar among the macrocyclic GBCAs [Dotarem (gadoterate meglumine),Gadavist (gadobutrol), ProHance (gadoteridol)].Consequences of gadolinium retention inthe brain have not been established. Pathologic and clinical consequencesof GBCA administration and retention in skin and other organs havebeen established in patients with impaired renal function [see Warnings and Precautions (5.2)]. There are rare reports of pathologic skin changes inpatients with normal renal function. Adverse events involving multipleorgan systems have been reported in patients with normal renal functionwithout an established causal link to gadolinium retention [see Adverse Reactions (6.2)].While clinicalconsequences of gadolinium retention have not been established inpatients with normal renal function, certain patients might be athigher risk. These include patients requiring multiple lifetime doses,pregnant and pediatric patients, and patients with inflammatory conditions.Consider the retention characteristics of the agent when choosinga GBCA for these patients. Minimize repetitive GBCA imaging studies,particularly closely spaced studies when possible.. 5.5 Acute Kidney Injury. In patients with chronicallyreduced renal function, acute kidney injury requiring dialysis hasoccurred with the use of GBCAs. The risk of acute kidney injury mayincrease with increasing dose of the contrast agent; administer thelowest dose necessary for adequate imaging.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following seriousadverse reactions are discussed in greater detail in other sectionsof the prescribing information:Nephrogenic systemic fibrosis [see Boxed Warning and Warnings and Precautions(5.2)] Hypersensitivity reactions [see Contraindications(4) and Warnings and Precautions (5.3)] Nephrogenic systemic fibrosis [see Boxed Warning and Warnings and Precautions(5.2)] Hypersensitivity reactions [see Contraindications(4) and Warnings and Precautions (5.3)] The most commonly reported adverse reactions arenausea and taste perversion with an incidence >= 0.9% (6.1)To report SUSPECTED ADVERSE REACTIONS,Contact Bracco Diagnostics Inc. at 1-800-257-5181 or FDA at 1-800-FDA-1088or www.fda.gov/medwatch 6.1 Clinical Trials Experience. Because clinical trials are conductedunder widely varying conditions, adverse reaction rates observed inthe clinical trials of drug cannot be directly compared to ratesin the clinical trials of another drug and may not reflect the ratesobserved in practice.The adverse events described in this section were observed in clinicaltrials involving 3174 subjects (including 2896 adults and 278 pediatricsubjects ages to 17 years) exposed to ProHance. Approximately 48%of the subjects were men and ethnic distribution was 78% Caucasian,6% Black, 3% Hispanic, 6% Asian, and 2% other. In 5% of the subjects,race was not reported. Average age was 47 years (range from dayto 91 years) and the exposure ranged from 0.03 to 0.3 mmol/kg.Overall, approximately 5.8% ofsubjects reported one or more adverse reactions during follow-upperiod that ranged from 24 hours to days after ProHance administration.Table lists adverse reactions that occurred in >= 0.4% subjectswho received ProHance.Table 2: More frequent adverse reactions in clinical trialsReactionRate (%)N= 3174Nausea1.4%Dysgeusia0.9%Headache0.7%Dizziness0.4%Urticaria0.4%The following additional adverse events occurred infewer than 0.4% of the subjects:General disorders and administration site conditions:Asthenia; chest discomfort, facial edema, feeling hot, injectionsite coldness, injection site erythema, injection site pain, injectionsite warmth, pain, pyrexiaCardiac:Angina pectoris, palpitations, atrio-ventricular block first degreeEar and labyrinth disorders:Ear discomfort, tinnitusEye disorders:Eye pruritis, lacrimation increasedGastrointestinal disorders:Abdominal discomfort, abdominal pain, diarrhea, dry mouth, gingivalpain, oral pruritis, swollen tongue, vomitingInfections and infestations:Gingivitis, rhinitisInvestigations:Alanine aminotransferase increased, aspartate aminotransferaseincreased, blood chloride increased, blood pressure immeasurable,blood urea decreased, hemoglobin decreased, heart rate increasedMetabolism and nutrition disorders:Decreased appetite, hypoglycemiaMusculoskeletal and connective tissue disorders:Back pain, musculoskeletal stiffnessNervous system disorders:Formication, hypoesthesia, hypokinesia, lethargy, loss of consciousness,migraine, paresthesia, presyncope, seizure, syncope, taste disorderPsychiatric disorders:Anxiety, mental status changesRespiratory, thoracic and mediastinal disorders:Cough, dry throat, dyspnea, nasal discomfort, throat irritationSkin and subcutaneous tissue disorders:Hyperhidrosis, pruritis, rash, rash morbilliformVascular disorders:Flushing, hypotension, peripheral coldness,vascular rupture, vasodilatation, vasospasm. 6.2 Postmarketing Experience. Thefollowing adverse reactions have been identified during post approvaluse of ProHance or other GBCAs that were not observed in the clinicaltrials. Because these reactions are reported voluntarily from populationof uncertain size, it is not always possible to reliably estimatetheir frequency or establish causal relationship to drug exposure. Cases of acute renal failure have beenreported in patients with pre-existing severe renal impairment.The following adverse drug reactionshave also been reported:General Disorders and Administration Site Conditions:Adverse events with variable onset and duration have been reportedafter GBCA administration [see Warnings and Precautions (5.4)]. These include fatigue, asthenia,pain syndromes, and heterogeneous clusters of symptoms in the neurological,cutaneous, and musculoskeletal systems.Cardiac disorders:Cardiac arrest, bradycardia, hypertensionGastrointestinal disorders:Acute pancreatitis with onset within 48 hours after GBCA administrationImmune system disorders:Hypersensitivity/anaphylactoid reactions including cardiac arrest,cyanosis, pharyngeal edema, laryngospasm, bronchospasm, angioedema,cough, sneezing, conjunctivitis, eyelid edema, hyperhidrosis, urticaria [see Warnings and Precautions (5.3)].Nervous system disorders:Coma, loss of consciousness, vasovagal reaction, tremorRespiratory, thoracic and mediastinal disorders:Respiratory arrest, acute respiratory distress syndrome, pulmonaryedemaRenal and urinary system disorders:Acute renal failure.

BOXED WARNING SECTION.

WARNING: RISK ASSOCIATED WITH INTRATHECAL USE and NEPHROGENIC SYSTEMICFIBROSIS. Risk Associated with Intrathecal UseIntrathecal administration of gadolinium-basedcontrast agents (GBCAs) can cause serious adverse reactions includingdeath, coma, encephalopathy, and seizures. ProHance is not approvedfor intrathecal use [see Warnings and Precautions (5.1)].Nephrogenic Systemic FibrosisGBCAs increase the risk for nephrogenicsystemic fibrosis (NSF) among patients with impaired elimination ofthe drugs. Avoid use of ProHance in these patients unless the diagnosticinformation is essential and not available with non- contrasted MRIor other modalities. NSF may result in fatal or debilitating systemicfibrosis affecting the skin, muscle and internal organs.The risk for NSF appearshighest among patients with:chronic, severe kidney disease (GFR less than 30 mL/min/1.73m2), oracute kidney injuryScreen patientsfor acute kidney injury and other conditions that may reduce renalfunction. For patients at risk for chronically reduced renal function(e.g. age greater than 60 years, hypertension or diabetes), estimatethe glomerular filtration rate (GFR) through laboratory testing.For patientsat highest risk for NSF, do not exceed the recommended ProHance doseand allow sufficient period of time for elimination of the drugfrom the body prior to re-administration [see Warnings andPrecautions (5.2)].. chronic, severe kidney disease (GFR less than 30 mL/min/1.73m2), or. acute kidney injury. WARNING: RISK ASSOCIATEDWITH INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSISSee full prescribinginformation for complete boxed warningIntrathecal administration of gadolinium based contrastagents (GBCAs) can cause serious adverse reactions including death,coma, encephalopathy, and seizures. ProHance is not approved for intrathecaluse. (5.1)GBCAs increase the risk for nephrogenic systemic fibrosis(NSF) among patients with impaired elimination of the drugs. Avoiduse of ProHance in these patients unless the diagnostic informationis essential and not available with non-contrasted MRI or other modalities.NSF may result in fatal or debilitating systemic fibrosis affectingthe skin, muscle and internal organs. The risk for NSF appears highestamong patients with:chronic, severe kidney disease (GFR less than 30mL/min/1.73m2), oracute kidney injuryScreen patients for acute kidney injury and other conditionsthat may reduce renal function. For patients at risk for chronicallyreduced renal function (e.g. age greater than 60 years, hypertensionor diabetes), estimate the glomerular filtration rate (GFR) throughlaboratory testing (5.2).. Intrathecal administration of gadolinium based contrastagents (GBCAs) can cause serious adverse reactions including death,coma, encephalopathy, and seizures. ProHance is not approved for intrathecaluse. (5.1). GBCAs increase the risk for nephrogenic systemic fibrosis(NSF) among patients with impaired elimination of the drugs. Avoiduse of ProHance in these patients unless the diagnostic informationis essential and not available with non-contrasted MRI or other modalities.NSF may result in fatal or debilitating systemic fibrosis affectingthe skin, muscle and internal organs. The risk for NSF appears highestamong patients with:chronic, severe kidney disease (GFR less than 30mL/min/1.73m2), oracute kidney injuryScreen patients for acute kidney injury and other conditionsthat may reduce renal function. For patients at risk for chronicallyreduced renal function (e.g. age greater than 60 years, hypertensionor diabetes), estimate the glomerular filtration rate (GFR) throughlaboratory testing (5.2).. chronic, severe kidney disease (GFR less than 30mL/min/1.73m2), or. acute kidney injury.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 MRI of the CNS. ProHancewas evaluated in two multicenter trials of 310 evaluable patientssuspected of having neurological pathology. After the administrationof ProHance 0.1 mmol/kg IV, the results were similar to those describedbelow [see Clinical Studies (14.2)].In another multicenterstudy of 49 evaluable adult patients with known intracranial tumorwith high suspicion of having cerebral metastases, two doses of ProHancewere administered. First ProHance 0.1 mmol/kg was injected followed30 minutes later with 0.2 mmol/kg. In comparison to the 0.1 mmol/kgdose alone, the addition of the 0.2 mmol/kg dose improved visualizationin 67% and improved border definition in 56% of patients. In comparisonto non-contrast MRI, the number of lesions after 0.1 mmol/kg increasedin 34% of patients. After ProHance 0.2 mmol/kg, this increased to44%.PediatricPatientsProHance was evaluated in multicenterstudy of 103 patients undergoing brain or spine MRI. Among these patients,the age range was to 20 years; 54 were between and 12 years ofage; 74% were Caucasian, 11% Black, 12% Hispanic, 2% Asian, and 2%other. ProHance was given in one single 0.1 mmol/kg dose. Repeat dosingwas not studied. The results of the non-contrast and ProHance MRIscans were compared. In this database, MRI enhancement was noted inapproximately 60% of the scans and additional diagnostic informationin 30 to 95% of the scans.A prospectivelyplanned study of 125 pediatric patients younger than years of ageretrospectively selected was performed. These patients (70 boys and55 girls) had an age range of day to 24 months old; 17 were lessthan month of age, 40 were between month and months of age,29 were between months and 12 months of age, and 39 were between12 months and 24 months of age; 56% were Caucasian, 25% Black, 5%Asian, and 14% other. ProHance was given in one single 0.1 mmol/kgdose. Repeat dosing was not studied. Three independent, blinded readersevaluated pre-contrast MRI image sets and paired pre-plus-post-contrastMRI image sets using ProHance and rated the images according to threeco-primary visualization endpoints: lesion border delineation, visualizationof lesion internal morphology, and lesion contrast enhancement. Allthree blinded readers reported improvement in the paired image setsfor each of the three co-primary endpoints.. 14.2 MRI of the Headand Neck. ProHance was evaluatedin two blinded read studies in total of 133 adults who had an indicationfor head and neck extracranial or extraspinal MRI. These 133 adults(74 men, 59 women) had mean age of 53 with range of 19 to 76 years.Of these patients, 85% were Caucasian, 13% Black, 2% Asian, and lessthan 1% other. The results of the non-contrast and contrast MRI scanswere compared. Approximately 75-82% of the scans were enhanced, 45-48%of the scans provided additional diagnostic information, and 8-25%of the diagnoses were changed. The relevance of the findings to diseasesensitivity and specificity has not been fully evaluated.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dose in adult and pediatric patients is 0.2mL/kg (0.1 mmol/kg) body weight administered as rapid intravenousinfusion or bolus (2.1)Follow injection with saline flush of at least mL normalsaline (2.1). Recommended dose in adult and pediatric patients is 0.2mL/kg (0.1 mmol/kg) body weight administered as rapid intravenousinfusion or bolus (2.1). Follow injection with saline flush of at least mL normalsaline (2.1). 2.1 Recommended Dose. The recommended dose for adultand pediatric patients, including term neonates, is 0.2 mL/kg (0.1mmol/kg) administered as rapid intravenous infusion (10 mL/min to60 mL/min) or bolus (greater than 60 mL/min). Table provides weight-adjustedrecommended dose volumes.Table 1: RecommendedVolume of ProHance Injection by Body WeightBody Weight (kg)Volume to be Administered(mL)2.50.55110220430640850106012701480169018100201102212024130261402815030MRIof the CNS in Adults:A supplementary dose of 0.4 mL/kg (0.2 mmol/kg) may be givenup to 30 minutes after the first dose in adult patients with normalrenal function suspected of having poorly visualized CNS lesions,in the presence of negative or equivocal scansThe safety and efficacy of supplementary dosing have notbeen established in pediatric patients. supplementary dose of 0.4 mL/kg (0.2 mmol/kg) may be givenup to 30 minutes after the first dose in adult patients with normalrenal function suspected of having poorly visualized CNS lesions,in the presence of negative or equivocal scans. The safety and efficacy of supplementary dosing have notbeen established in pediatric patients. 2.2 Administration. Visually inspect ProHance for particulate matter and discolorationprior to useDo not administer the solution if it is discolored or particulatematter is presentConcurrent medications or parenteral nutrition should notbe physically mixed with contrast agents and should not be administeredin the same intravenous line because of the potential for chemicalincompatibilityInject at least 5 mL normal saline flush immediately afterProHance injection to ensure complete administrationImaging procedures should be completed within hourProHance vials are intended only for single-dose administration.Administer immediately after opening and discard any unused product. Visually inspect ProHance for particulate matter and discolorationprior to use. Do not administer the solution if it is discolored or particulatematter is present. Concurrent medications or parenteral nutrition should notbe physically mixed with contrast agents and should not be administeredin the same intravenous line because of the potential for chemicalincompatibility. Inject at least 5 mL normal saline flush immediately afterProHance injection to ensure complete administration. Imaging procedures should be completed within hour. ProHance vials are intended only for single-dose administration.Administer immediately after opening and discard any unused product. 2.3 Directions for Use VialsDraw ProHance into the syringe immediately before use. Donot pierce the rubber stopper more than once. Discard any unused vialcontents.ProHance single dose syringeScrew the threaded tip of the plunger rod clockwise intothe cartridge plunger and push forward few millimeters to breakany friction between the cartridge plunger and syringe barrelHolding syringe erect, unscrew the plastic tip cap fromthe tip of the syringe and attach either sterile, disposable needleor tubing with compatible Luer lock using push-twist action (sliptip)Hold the syringe erect and push plunger forward until allof the air is evacuated and fluid either appears at the tip of theneedle or the tubing is filledFollowing the usual aspiration procedure, complete the injectionInject at least 5 mL normal saline flush immediately afterProHance injection to ensure complete administrationProperly dispose of the syringe and any other materialsusedThe syringe assembly is HYPAK SCF(R) single dose syringe suppliedby Becton Dickinson. Draw ProHance into the syringe immediately before use. Donot pierce the rubber stopper more than once. Discard any unused vialcontents.. Screw the threaded tip of the plunger rod clockwise intothe cartridge plunger and push forward few millimeters to breakany friction between the cartridge plunger and syringe barrel. Holding syringe erect, unscrew the plastic tip cap fromthe tip of the syringe and attach either sterile, disposable needleor tubing with compatible Luer lock using push-twist action (sliptip). Hold the syringe erect and push plunger forward until allof the air is evacuated and fluid either appears at the tip of theneedle or the tubing is filled. Following the usual aspiration procedure, complete the injection. Inject at least 5 mL normal saline flush immediately afterProHance injection to ensure complete administration. Properly dispose of the syringe and any other materialsused.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Medication GuideAdvise the patient to read the FDA-approved patient labeling(Medication Guide) foundat www.prohancemedicationguide.com.Nephrogenic Systemic FibrosisInstructpatients to inform their physician if they: have history of kidney disease have recently received GBCAGBCAs increase the risk for NSF in patients with impaired eliminationof the drugs. To counsel patients at risk for NSF: describe the clinical manifestations of NSF describe procedures to screen for the detection of renalimpairmentInstruct patients to contact their physician if they develop signsor symptoms of NSF following ProHance administration, such as burning,itching, swelling, scaling, hardening and tightening of the skin;red or dark patches on the skin; stiffness in joints with troublemoving, bending or straightening the arms, hands, legs or feet; painin the hip bones or ribs; or muscle weakness.General PrecautionsPregnancy: Advise pregnant woman of the potential riskof fetal exposure to ProHance [see Use in Specific Populations(8.1)] Gadolinium retention: Advise patients that gadolinium isretained for months or years in brain, bone, skin, and other organsin patients with normal renal function. The clinical consequencesof retention are unknown. Retention depends on multiple factors andis greater following administration of linear GBCAs than followingadministration of macrocyclic GBCAs [see Warnings and Precautions(5.4)].Manufactured for:Bracco Diagnostics Inc.Princeton, NJ 08540By BIPSO GmbH78224 Singen (Germany)March 2025CL101A-06. Advise the patient to read the FDA-approved patient labeling(Medication Guide) foundat www.prohancemedicationguide.com.. have history of kidney disease. have recently received GBCA. describe the clinical manifestations of NSF. describe procedures to screen for the detection of renalimpairment. Pregnancy: Advise pregnant woman of the potential riskof fetal exposure to ProHance [see Use in Specific Populations(8.1)] Gadolinium retention: Advise patients that gadolinium isretained for months or years in brain, bone, skin, and other organsin patients with normal renal function. The clinical consequencesof retention are unknown. Retention depends on multiple factors andis greater following administration of linear GBCAs than followingadministration of macrocyclic GBCAs [see Warnings and Precautions(5.4)].

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectivenessof ProHance have been established for use with MRI to visualize lesionswith abnormal blood brain barrier or abnormal vascularity of the brain,spine, and associated tissues in pediatric patients from birth, includingterm neonates, to 17 years of age. Pediatric use is based on evidenceof effectiveness in adults and in 103 pediatric patients years ofage and older, in addition to experience in 125 pediatric patientsbirth to less than years of age that supported extrapolation fromadult data [see Clinical Studies (14)]. Adverse reactions in pediatric patients weresimilar to those reported in adults [see Adverse Reactions(6.1)].The safety and efficacyof 0.1 mmol/kg, and sequential and/or repeat procedures have notbeen studied in pediatric patients [see Indications and Usage(1) and Dosage and Administration (2)].No case of NSF associatedwith ProHance or any other GBCA has been identified in pediatric patientsages years and younger. Pharmacokinetic studies suggest that weightnormalized clearance of ProHance is similar in pediatric patientsand adults, including pediatric patients age younger than years.Normal estimated GFR (eGFR) is around 30 mL/min/1.73m2 at birth and increases to mature levels around 1year of age, reflecting growth in both glomerular function and relativebody surface area. Clinical studies in pediatric patients youngerthan year of age have been conducted in patients with the followingminimum eGRF; 59.37 mL/min/1.73m2 (agejust after birth to 30 days), 118.84 mL/min/1.73m2 (age 30 days to 6 months), 140.44 mL/min/1.73m2 (age to 12 months).

PREGNANCY SECTION.

8.1 Pregnancy. RiskSummaryGBCAs cross the placenta and resultin fetal exposure and gadolinium retention. The human data on theassociation between GBCAs and adverse fetal outcomes are limited andinconclusive (see Data). Because of the potential risks of gadoliniumto the fetus, use ProHance only if imaging is essential during pregnancyand cannot be delayed.In animal reproductionstudies in rats, gadoteridol doubled the incidence of post-implantationloss at up to 16 times the recommended human dose (RHD). There wereno adverse developmental effects observed in rabbits with intravenousadministration of gadoteridol during organogenesis at doses up to19 times the recommended human dose of 0.1 mmol/kg (see Data).The estimated backgroundrisk of major birth defects and miscarriage for the indicated populationis unknown. All pregnancies have background risk of birth defect,loss, or other adverse outcomes. In the U.S. general population, theestimated background risk of major birth defects and miscarriage inclinically recognized pregnancies is to 4% and is 15 to 20%, respectively.DataHuman DataContrast agent is visualized in the placenta and fetal tissues aftermaternal GBCA administration. Cohort studies and case reports on exposureto GBCAs during pregnancy have not reported clear association betweenGBCAs and adverse effects in the exposed neonates. However, retrospectivecohort study, comparing pregnant women who had GBCA MRI to pregnantwomen who did not have an MRI, reported higher occurrence of stillbirthsand neonatal deaths in the group receiving GBCA MRI. Limitations ofthis study include lack of comparison with non-contrast MRI andlack of information about the maternal indication for MRI.Animal DataGadolinium RetentionGBCAsadministered to pregnant non-human primates (0.1 mmol/kg on gestationaldays 85 and 135) result in measurable gadolinium concentration inthe offspring in bone, brain, skin, liver, kidney, and spleen forat least months. GBCAs administered to pregnant mice (2 mmol/kgdaily on gestational days 16 through 19) result in measurable gadoliniumconcentrations in the pups in bone, brain, kidney, liver, blood, muscle,and spleen at one-month postnatal age.Reproductive ToxicologyGadoteridol was administered in intravenous doses of 0, 0.375, 1.5,6.0, and 10 mmol/kg/day [0.6, 2.4, 9.7, and 16 times the recommendedhuman dose (RHD) based on body surface area (BSA)] to female ratsfrom gestational day (GD)6 until GD17. Gadoteridol at 10 mmol/kg/dayfor 12 days during gestation doubled the incidence of post-implantationloss. When rats were administered 6.0 or 10.0 mmol/kg/day for 12 days,an increase in spontaneous locomotor activity was observed in theoffspring. Pregnant rabbits were administered gadoteridol in intravenousdoses of 0, 0.4, 1.5, and mmol/kg/day (1.3, 4.8, and 19.4 timesthe RHD based on BSA) from GD6 to GD18. Gadoteridol increased theincidence of spontaneous abortion and early delivery in rabbits administered6 mmol/kg/day for 13 days during gestation.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S.Food and Drug AdministrationRevised: 03/2025MEDICATION GUIDEPROHANCE(R) (pro-han(t)s) (Gadoteridol injection)for intravenous useWhat is themost important information should know about PROHANCEGBCAs like PROHANCE may cause serious side effects includingdeath, coma, encephalopathy, and seizures when it is given intrathecally(injection given into the spinal canal). It is not known if PROHANCEis safe and effective with intrathecal use. PROHANCE is not approvedfor this use.PROHANCE contains metal called gadolinium. Small amountsof gadolinium can stay in your body including the brain, bones, skinand other parts of your body for long time (several months to years).It is not known how gadolinium may affect you, but so far,studies have not found harmful effects in patients with normal kidneys.Rarely, patients have reported pains, tiredness, and skin,muscle or bone ailments for long time, but these symptoms have notbeen directly linked to gadolinium.There are different GBCAs that can be used for your MRIexam. The amount of gadolinium that stays in the body is differentfor different gadolinium medicines. Gadolinium stays in the body moreafter Omniscan or Optimark than after Eovist, Magnevist, or MultiHance.Gadolinium stays in the body the least after Dotarem, Gadavist, orProHance.People who get many doses of gadolinium medicines, womenwho are pregnant and young children may be at increased risk fromgadolinium staying in the body.Some people with kidney problems who get gadolinium medicinescan develop condition with severe thickening of the skin, musclesand other organs in the body (nephrogenic systemic fibrosis). Yourhealthcare provider should screen you to see how well your kidneysare working before you receive PROHANCE.What is PROHANCEPROHANCE is prescription medicine called gadolinium-basedcontrast agent (GBCA). PROHANCE, like other GBCAs, is used with amagnetic resonance imaging (MRI) scanner.An MRI exam with GBCA, including PROHANCE, helps yourdoctor to see problems better than an MRI exam without GBCA.Your doctor has reviewed your medical records and has determinedthat you would benefit from using GBCA with your MRI exam.Do not receivePROHANCE if you have had severe allergic reaction to PROHANCE.Before receivingPROHANCE, tell your healthcare provider about all your medical conditions,including if you:have had any MRI procedures in the past where you receiveda GBCA. Your healthcare provider may ask you for more informationincluding the dates of these MRI procedures.are pregnant or plan to become pregnant. It is not knownif PROHANCE can harm your unborn baby. Talk to your healthcare providerabout the possible risks to an unborn baby if GBCA such as PROHANCEis received during pregnancyhave kidney problems, diabetes, or high blood pressurehave had an allergic reaction to dyes (contrast agents)including GBCAsWhat arethe possible side effects of PROHANCESee What is the most important information shouldknow about PROHANCEAllergic reactions. PROHANCE can cause allergic reactionsthat can sometimes be serious. Your healthcare provider will monitoryou closely for symptoms of an allergic reaction.The most common side effects of PROHANCE include: nausea,distortion of the sense of taste, and headache.Theseare not all the possible side effects of PROHANCE.Callyour doctor for medical advice about side effects. You may reportside effects to FDA at 1-800-FDA-1088.General informationabout the safe and effective use of PROHANCE.Medicinesare sometimes prescribed for purposes other than those listed in aMedication Guide. You can ask your healthcare provider for informationabout PROHANCE that is written for health professionals.What arethe ingredients in PROHANCEActive ingredient:gadoteridolInactive ingredients: calteridolcalcium, tromethamineManufactured by: BIPSO GmbH-78224Singen (Germany)Manufactured for: Bracco Diagnostics Inc.,Princeton, NJ 08540 For more information, go to www.imaging.bracco.comor call 1-800-257-5181.. GBCAs like PROHANCE may cause serious side effects includingdeath, coma, encephalopathy, and seizures when it is given intrathecally(injection given into the spinal canal). It is not known if PROHANCEis safe and effective with intrathecal use. PROHANCE is not approvedfor this use.. PROHANCE contains metal called gadolinium. Small amountsof gadolinium can stay in your body including the brain, bones, skinand other parts of your body for long time (several months to years).. It is not known how gadolinium may affect you, but so far,studies have not found harmful effects in patients with normal kidneys.. Rarely, patients have reported pains, tiredness, and skin,muscle or bone ailments for long time, but these symptoms have notbeen directly linked to gadolinium.. There are different GBCAs that can be used for your MRIexam. The amount of gadolinium that stays in the body is differentfor different gadolinium medicines. Gadolinium stays in the body moreafter Omniscan or Optimark than after Eovist, Magnevist, or MultiHance.Gadolinium stays in the body the least after Dotarem, Gadavist, orProHance.. People who get many doses of gadolinium medicines, womenwho are pregnant and young children may be at increased risk fromgadolinium staying in the body.. Some people with kidney problems who get gadolinium medicinescan develop condition with severe thickening of the skin, musclesand other organs in the body (nephrogenic systemic fibrosis). Yourhealthcare provider should screen you to see how well your kidneysare working before you receive PROHANCE.. PROHANCE is prescription medicine called gadolinium-basedcontrast agent (GBCA). PROHANCE, like other GBCAs, is used with amagnetic resonance imaging (MRI) scanner.. An MRI exam with GBCA, including PROHANCE, helps yourdoctor to see problems better than an MRI exam without GBCA.. Your doctor has reviewed your medical records and has determinedthat you would benefit from using GBCA with your MRI exam.. have had any MRI procedures in the past where you receiveda GBCA. Your healthcare provider may ask you for more informationincluding the dates of these MRI procedures.. are pregnant or plan to become pregnant. It is not knownif PROHANCE can harm your unborn baby. Talk to your healthcare providerabout the possible risks to an unborn baby if GBCA such as PROHANCEis received during pregnancy. have kidney problems, diabetes, or high blood pressure. have had an allergic reaction to dyes (contrast agents)including GBCAs. See What is the most important information shouldknow about PROHANCE. Allergic reactions. PROHANCE can cause allergic reactionsthat can sometimes be serious. Your healthcare provider will monitoryou closely for symptoms of an allergic reaction.