ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Thefollowing serious adverse reactions are discussed in greater detailin other sections of the prescribing information:Nephrogenic systemic fibrosis [see Boxed Warning and Warnings and Precautions(5.1)] Hypersensitivity reactions [see Contraindications(4) and Warnings and Precautions (5.2)] Nephrogenic systemic fibrosis [see Boxed Warning and Warnings and Precautions(5.1)] Hypersensitivity reactions [see Contraindications(4) and Warnings and Precautions (5.2)] 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 conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The adverse events described in this section were observed in clinical trials involving 3174 subjects (including 2896 adults and 278 pediatric subjects 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 day to 91 years) and the exposure ranged from 0.03 to 0.3 mmol/kg.Overall, approximately 5.8% of subjects reported one or more adverse reactions during follow-up period that ranged from 24 hours to days after ProHance administration.Table lists adverse reactions that occurred in >= 0.4% subjects who 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 in fewer than 0.4% of the subjects:General disorders and administration site conditions:Asthenia; chest discomfort, facial edema, feeling hot, injection site coldness, injection site erythema, injection site pain, injection site 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, gingival pain, oral pruritis, swollen tongue, vomitingInfections and infestations:Gingivitis, rhinitisInvestigations:Alanine aminotransferase increased, aspartate aminotransferase increased, 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 Post-marketing Experience. Thefollowing adverse reactions have been identified during post approvaluse of ProHance that were not observed in the clinical trials. Becausethese reactions are reported voluntarily from population of uncertainsize, it is not always possible to reliably estimate their frequencyor 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 (5.3)]. These include fatigue, asthenia,pain syndromes, and heterogeneous clusters of symptoms in the neurological,cutaneous, and musculoskeletal systems.Cardiac disorders:Cardiac arrest, bradycardia, hypertensionImmune 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 (5.2)].Nervous system disorders:Coma, loss of consciousness, vasovagal reaction, tremorRespiratory, thoracic and mediastinal disorders:Respiratory arrest, pulmonary edemaRenal and urinary system disorders:Acute renal failure.

BOXED WARNING SECTION.

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS. Gadolinium-based contrast agents (GBCAs)increase the risk for NSF among patients with impaired eliminationof the drugs. Avoid use of GBCAs 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 appears highest among patients with:chronic, severe kidney disease (GFR less than 30 mL/min/1.73m2), oracute kidney injuryScreen patients for acute kidney injury and otherconditions that may reduce renal function. For patients at risk forchronically reduced renal function (e.g. age greater than 60 years,hypertension or diabetes), estimate the glomerular filtration rate(GFR) through laboratory testing.For patients at highest risk for NSF, do not exceedthe recommended ProHance dose and allow sufficient period of timefor elimination of the drug from the body prior to re-administration [see Warnings and Precautions (5.1)].. The risk for NSF appears highest among patients with:chronic, severe kidney disease (GFR less than 30 mL/min/1.73m2), oracute kidney injury. chronic, severe kidney disease (GFR less than 30 mL/min/1.73m2), or. acute kidney injury. Screen patients for acute kidney injury and otherconditions that may reduce renal function. For patients at risk forchronically reduced renal function (e.g. age greater than 60 years,hypertension or diabetes), estimate the glomerular filtration rate(GFR) through laboratory testing.. For patients at highest risk for NSF, do not exceedthe recommended ProHance dose and allow sufficient period of timefor elimination of the drug from the body prior to re-administration [see Warnings and Precautions (5.1)].. WARNING: NEPHROGENIC SYSTEMICFIBROSISSee full prescribinginformation for complete boxed warningGadolinium-based contrastagents (GBCAs) increase the risk for NSF among patients with impairedelimination of the drugs. Avoid use of GBCAs in these patients unlessthe diagnostic information is essential and not available with non-contrastedMRI or other modalities. NSF may result in fatal or debilitating systemicfibrosis affecting the skin, muscle and internal organs.The risk for NSF appears highest among patients with:chronic, severe kidney disease (GFR less than 30 mL/min/1.73m2), oracute kidney injuryScreen patients for acute kidney injury and otherconditions that may reduce renal function. For patients at risk forchronically reduced renal function (e.g. age greater than 60 years,hypertension or diabetes), estimate the glomerular filtration rate(GFR) through laboratory testing (5.1).. The risk for NSF appears highest among patients with:chronic, severe kidney disease (GFR less than 30 mL/min/1.73m2), oracute kidney injury. chronic, severe kidney disease (GFR less than 30 mL/min/1.73m2), or. acute kidney injury. Screen patients for acute kidney injury and otherconditions that may reduce renal function. For patients at risk forchronically reduced renal function (e.g. age greater than 60 years,hypertension or diabetes), estimate the glomerular filtration rate(GFR) through laboratory testing (5.1).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanismof Action. Gadoteridol is paramagnetic agent and, as such, develops magnetic moment when placed in magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent.In MRI, visualization of normal and pathologic brain 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 magnetic field, gadoteridol decreases T1 relaxation times in the target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences.. 12.2 Pharmacodynamics. Gadoteridol affects proton relaxation times and consequently the MR signal. Signal intensity is affected by the dose and relaxivity of the gadoteridol molecule. Consistently, for all gadolinium based contrast agents, the relaxivity of gadoteridol decreases with the increase of the magnetic field strength used in clinical MRI (0.2 3.0T).Disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadoteridol in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetics of gadoteridol in various lesions is not known.. 12.3 Pharmacokinetics. The pharmacokinetics of intravenously administered gadoteridol in normal subjects conforms to two-compartment open model.DistributionAfter intravenous administration, gadoteridol is rapidly distributed in the extracellular space. The plasma distribution volume (mean +- SD) for the non-renally impaired adults was 0.205 +- 0.025 L/kg. It is unknown if protein binding of gadoteridol occurs in vivo.Following GBCA administration, gadolinium is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.3)].MetabolismIt is unknown if biotransformation or decomposition of gadoteridol occur in vivo.EliminationGadoteridol is eliminated unchanged via 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 dose is 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 gadoteridol are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume of distribution (204 +- 58 mL/kg) is equal to that of extracellular water, and clearance is similar to that of substances which are subject to glomerular filtration.Specific PopulationsGenderGender has no clinically relevant 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 elderly subjects as compared to non-elderly subjects [see Use in Specific Populations (8.5)].PediatricA population pharmacokinetic analysis incorporated data from 79 subjects, 45 males and 34 females. Among 79 subjects, 41 were healthy subjects including 28 pediatric subjects between years and 15 years of age. The pediatric subjects received single intravenous dose of 0.1 mmol/kg of ProHance. From population PK model, the mean Cmax was 0.66 +- 0.21 mmol/L in pediatric subjects years to years of age, 0.58 +- 0.06 mmol/L in pediatric subjects years to 12 years of age, and 0.68 +- 0.12 mmol/L in adolescent subjects older 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 years of age. The mean distribution half-life (t1/2,alpha) was 0.14 +- 0.04 hours in pediatric subjects years to years of age, 0.18 +- 0.07 hours in pediatric subjects years to 12 years of age, and 0.20 +- 0.07 hours in adolescent subjects older than 12 years 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 of age. There was no significant gender-related difference in the pharmacokinetic parameters in the pediatric patients. Over 80% of the dose was recovered in urine for pediatric subjects after 10 hours. Pharmacokinetic simulations indicate similar half-life, AUC, and Cmax values for ProHance in pediatric subjects less than years of age when compared to those reported for adults; no age-based dose adjustment is necessary for this pediatric population.Renal ImpairmentIn patients with impaired renal function, the serum half-life of gadoteridol is prolonged. After intravenous injection of 0.1 mmol/kg, the elimination half-life of gadoteridol was 10.65 +- 0.06 hours in mild to moderately impaired patients (creatinine clearance 30 to 60 mL/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 of gadoteridol in patients with normal renal function was 116.14 +- 26.77 mL/min, compared to 37.2 +- 16.4 mL/min in patients with mild to moderate renal impairment and 16.0 +- 3.0 mL/min in patients with severe renal impairment.In patients with moderately and severely impaired renal function about 97% and 76% of the administered dose was recovered in the urine within days and 14 days, respectively.For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of ProHance in order to enhance the contrast agents elimination. Seventy- two percent (72%) of gadoteridol is removed from the body after the first dialysis, 91% after the second dialysis, and 98% after the third dialysis session. [See Warnings and Precautions (5.1) and Use in Specific Populations (8.6).].

CLINICAL STUDIES SECTION.

14 CLINICALSTUDIES. 14.1 MRIof the CNS. ProHance was evaluatedin two multicenter trials of 310 evaluable patients suspected of havingneurological pathology. After the administration of ProHance 0.1 mmol/kgIV, the results were similar to those described below [seeClinical 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 MRIof the Head and 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 DOSAGEAND 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. Syringe.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedProHance is supplied as sterile,nonpyrogenic, and colorless to slightly yellow solution containing279.3 mg/mL (0.5 mmol/mL) of gadoteridol in single-dose rubber stopperedvials or prefilled syringes; ProHance is available in boxes of:Five5 mL fills in single dose 15 mL vials (NDC 0270-1111-04)Five 10 mL fills in single dose 30 mL vials (NDC 0270-1111-01)Five 15 mL fills in single dose 30 mL vials (NDC 0270-1111-02)Five 20 mL fills in single dose 30 mL vials (NDC 0270-1111-03)Five 10 mL fills in single dose 20 mL prefilled syringes (NDC 0270-1111-16)Five 17 mL fills in single dose 20 mL prefilled syringes (NDC 0270-1111-45)Storage and HandlingStore at 25C (77 F).Excursions permitted to 15C to 30C (59F to 86F) [See USP ControlledRoom Temperature]. Protect from light. DO NOT FREEZE. Should freezingoccur in the vial, ProHance should be brought to room temperaturebefore use. If allowed to stand at room temperature for minimumof 60 minutes, ProHance should return to clear, colorless to slightlyyellow solution. Before use, examine the product to assure that allsolids are redissolved and that the container and closure have notbeen damaged. Should solids persist, discard vial.

INFORMATION FOR PATIENTS SECTION.

17 PATIENTCOUNSELING INFORMATION. Medication GuideAdvise the patient to read the FDA-approved patient labeling(Medication Guide).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(5.3)].Manufactured for:Bracco Diagnostics Inc.Monroe Twp., NJ 08831By BIPSO GmbH78224 Singen (Germany)December 2020CL6FF05. Advise the patient to read the FDA-approved patient labeling(Medication Guide).. 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(5.3)].

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Thesafety and effectiveness of ProHance have been established for usewith MRI to visualize lesions with abnormal blood brain barrier orabnormal vascularity of the brain, spine, and associated tissues inpediatric patients from birth, including term neonates, to 17 yearsof age. Pediatric use is based on evidence of effectiveness in adultsand in 103 pediatric patients years of age and older, in additionto experience in 125 pediatric patients birth to less than yearsof age that supported extrapolation from adult data [see ClinicalStudies (14)]. Adverse reactionsin pediatric patients were similar 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. Risk SummaryGBCAs cross the placenta andresult in fetal exposure and gadolinium retention. The human dataon the association between GBCAs and adverse fetal outcomes are limitedand inconclusive (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 AdministrationIssued: 12/2020COEB504MEDICATION GUIDEPROHANCE(R) (pro-han(t)s) (Gadoteridol injection)for intravenous useWhat is PROHANCEPROHANCE is prescription medicine called gadolinium-based contrast agent (GBCA). PROHANCE, like other GBCAs, is used with magnetic resonance imaging (MRI) scanner.An MRI exam with GBCA, including PROHANCE, helps your doctor to see problems better than an MRI exam without GBCA.Your doctor has reviewed your medical records and has determined that you would benefit from using GBCA with your MRI exam.What is the most important information should know about PROHANCEPROHANCE contains metal called gadolinium. Small amounts of gadolinium can stay in your body including the brain, bones, skin and 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 not been directly linked to gadolinium.There are different GBCAs that can be used for your MRI exam. The amount of gadolinium that stays in the body is different for different gadolinium medicines. Gadolinium stays in the body more after Omniscan or Optimark than after Eovist, Magnevist, or MultiHance. Gadolinium stays in the body the least after Dotarem, Gadavist, or ProHance.People who get many doses of gadolinium medicines, women who are pregnant and young children may be at increased risk from gadolinium staying in the body.Some people with kidney problems who get gadolinium medicines can develop condition with severe thickening of the skin, muscles and other organs in the body (nephrogenic systemic fibrosis). Your healthcare provider should screen you to see how well your kidneys are working before you receive PROHANCE.Do not receive PROHANCE if you have had severe allergic reaction to PROHANCE.Before receiving PROHANCE, tell your healthcare provider about all your medical conditions, including if you:have had any MRI procedures in the past where you received GBCA. Your healthcare provider may ask you for more information including the dates of these MRI procedures.are pregnant or plan to become pregnant. It is not known if PROHANCE can harm your unborn baby. Talk to your healthcare provider about the possible risks to an unborn baby if GBCA such as PROHANCE is received during pregnancyhave kidney problems, diabetes, or high blood pressurehave had an allergic reaction to dyes (contrast agents) including GBCAsWhat are the possible side effects of PROHANCESee What is the most important information should know about PROHANCEAllergic reactions. PROHANCE can cause allergic reactions that can sometimes be serious. Your healthcare provider will monitor you closely for symptoms of an allergic reaction.The most common side effects of PROHANCE include: nausea, distortion of the sense of taste, and headache.These are not all the possible side effects of PROHANCE.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of PROHANCE.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your healthcare provider for information about PROHANCE that is written for health professionals.What are the ingredients in PROHANCEActive ingredient: gadoteridolInactive ingredients: calteridol calcium, tromethamineManufactured by: BIPSO GmbH-78224 Singen (Germany)Manufactured for: Bracco Diagnostics Inc., Monroe Township, NJ 08831For more information, go to www.imaging.bracco.com or call 1-800-257-5181.. PROHANCE is prescription medicine called gadolinium-based contrast agent (GBCA). PROHANCE, like other GBCAs, is used with magnetic resonance imaging (MRI) scanner.. An MRI exam with GBCA, including PROHANCE, helps your doctor to see problems better than an MRI exam without GBCA.. Your doctor has reviewed your medical records and has determined that you would benefit from using GBCA with your MRI exam.. PROHANCE contains metal called gadolinium. Small amounts of gadolinium can stay in your body including the brain, bones, skin and 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 not been directly linked to gadolinium.. There are different GBCAs that can be used for your MRI exam. The amount of gadolinium that stays in the body is different for different gadolinium medicines. Gadolinium stays in the body more after Omniscan or Optimark than after Eovist, Magnevist, or MultiHance. Gadolinium stays in the body the least after Dotarem, Gadavist, or ProHance.. People who get many doses of gadolinium medicines, women who are pregnant and young children may be at increased risk from gadolinium staying in the body.. Some people with kidney problems who get gadolinium medicines can develop condition with severe thickening of the skin, muscles and other organs in the body (nephrogenic systemic fibrosis). Your healthcare provider should screen you to see how well your kidneys are working before you receive PROHANCE.. have had any MRI procedures in the past where you received GBCA. Your healthcare provider may ask you for more information including the dates of these MRI procedures.. are pregnant or plan to become pregnant. It is not known if PROHANCE can harm your unborn baby. Talk to your healthcare provider about the possible risks to an unborn baby if GBCA such as PROHANCE is 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 should know about PROHANCE. Allergic reactions. PROHANCE can cause allergic reactions that can sometimes be serious. Your healthcare provider will monitor you closely for symptoms of an allergic reaction.

USE IN SPECIFIC POPULATIONS SECTION.

8 USEIN SPECIFIC POPULATIONS. Pregnancy: Use only if imagingis essential during pregnancy and cannot be delayed. (8.1). 8.1 Pregnancy. Risk SummaryGBCAs cross the placenta andresult in fetal exposure and gadolinium retention. The human dataon the association between GBCAs and adverse fetal outcomes are limitedand inconclusive (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. RiskSummaryThere are no data on the presence ofgadoteridol in human milk, the effects on the breastfed infant, orthe 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. Thesafety and effectiveness of ProHance have been established for usewith MRI to visualize lesions with abnormal blood brain barrier orabnormal vascularity of the brain, spine, and associated tissues inpediatric patients from birth, including term neonates, to 17 yearsof age. Pediatric use is based on evidence of effectiveness in adultsand in 103 pediatric patients years of age and older, in additionto experience in 125 pediatric patients birth to less than yearsof age that supported extrapolation from adult data [see ClinicalStudies (14)]. Adverse reactionsin pediatric patients were similar 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 thetotal number of 2673 adult subjects in clinical studies of ProHance,22% were 65 and over. No overall differences in safety were observedbetween these elderly subjects and the younger subjects.ProHanceis known to be substantially excreted by the kidneys, and the riskof toxic reactions from ProHance may be greater in patients with impairedrenal function. Because elderly patients are more likely to have decreasedrenal function, it may be useful to monitor renal function.. 8.6 Renal Impairment. No ProHance dosageadjustment is recommended for patients with renal impairment. Gadoteridolcan be removed from the body by hemodialysis [see Warningand Precautions (5.1) and ClinicalPharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGSAND PRECAUTIONS. Nephrogenic Systemic Fibrosis has occurred in patients withimpaired elimination of GBCAs. Higher than recommended dosing or repeateddosing appears to increase risk (5.1).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 (5.2).Gadolinium is retained for months or years in brain, bone,and other organs. (5.3). Nephrogenic Systemic Fibrosis has occurred in patients withimpaired elimination of GBCAs. Higher than recommended dosing or repeateddosing appears to increase risk (5.1).. 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 (5.2).. Gadolinium is retained for months or years in brain, bone,and other organs. (5.3). 5.1 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 among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR less than 30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following ProHance administration to Bracco Diagnostics (1-800-257-5181) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch).Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably 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 factors that may increase the risk for NSF are repeated or higher than recommended doses of GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to patient. For patients at highest risk for NSF, do not exceed the recommended ProHance dose and allow sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of GBCA in order to enhance the contrast agents elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. [see Clinical Pharmacology (12)].. 5.2 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.. 5.3 GadoliniumRetention. Gadolinium is retained for months or years in several organs. The highest concentrations (nanomoles per gram of tissue) have been identified in the bone, followed by other organs (e.g. brain, skin, kidney, liver, and spleen). The duration of retention also varies by tissue and is longest in bone. Linear GBCAs 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 other linear agents [Eovist (gadoxetate disodium), Magnevist (gadopentetate dimeglumine), MultiHance (gadobenate dimeglumine)]. Retention is lowest and similar among the macrocyclic GBCAs [Dotarem (gadoterate meglumine), Gadavist (gadobutrol), ProHance (gadoteridol)].Consequences of gadolinium retention in the brain have not been established. Pathologic and clinical consequences of GBCA administration and retention in skin and other organs have been established in patients with impaired renal function [see Warnings and Precautions (5.1)]. There are rare reports of pathologic skin changes in patients with normal renal function. Adverse events involving multiple organ systems have been reported in patients with normal renal function without an established causal link to gadolinium retention [see Adverse Reactions (6.2)].While clinical consequences of gadolinium retention have not been established in patients with normal renal function, certain patients might be at higher 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 choosing GBCA for these patients. Minimize repetitive GBCA imaging studies, particularly closely spaced studies when possible.. 5.4 AcuteKidney Injury (AKI). In patients with chronically reduced renalfunction, acute kidney injury requiring dialysis has occurred withthe use of GBCAs. The risk of acute kidney injury may increase withincreasing dose of the contrast agent; administer the lowest dosenecessary for adequate imaging.