MultiHance

1 INDICATIONS AND USAGE magnetic resonance imaging (MRI) of the central nervous system (CNS) in adults and pediatric patients (including term neonates), to visualize lesions with abnormal blood-brain barrier or abnormal vascularity of the brain, spine, and associated tissues. (1.1) magnetic resonance angiography (MRA) to evaluate adults with known or suspected renal or aorto-ilio-femoral occlusive vascular disease. (1.2) 1.1 Magnetic Resonance Imaging (MRI) of the Central Nervous System (CNS) MultiHance is indicated for intravenous use in magnetic resonance imaging (MRI) of the central nervous system (CNS) in adults and pediatric patients (including term neonates), to visualize lesions with abnormal blood-brain barrier or abnormal vascularity of the brain, spine, and associated tissues. 1.2 Magnetic Resonance Angiography (MRA) of Renal and Aorto-ilio-femoral Vessels MultiHance is indicated for use in magnetic resonance angiography (MRA) to evaluate adults with known or suspected renal or aorto-ilio-femoral occlusive vascular disease.

2 DOSAGE AND ADMINISTRATION PHARMACY BULK PACKAGE – NOT FOR DIRECT INFUSION The recommended dose of MultiHance is 0.2 mL/kg (0.1 mmol/kg) administered as a rapid bolus intravenous injection. For MRI of the CNS in pediatric patients below 2 years of age the recommended dosage range is 0.1 to 0.2 mL/kg. To ensure complete injection of the contrast medium, follow the injection with a saline flush of at least 5 mL in MRI of the CNS and at least 20 mL in MRA. (2) 2.1 Dosing and Imaging Instructions 2.1.1 MRI of the CNS In adults and in pediatric patients over 2 years of age, the recommended dose of MultiHance for MRI of the CNS is 0.2 mL/kg (0.1 mmol/kg) administered as a rapid bolus intravenous injection. In pediatric patients below 2 years of age, the recommended dosage range is 0.1 to 0.2 mL/kg administered as a rapid bolus intravenous injection. To ensure complete injection of the contrast medium, follow the injection with a saline flush of at least 5 mL. Imaging of the CNS can be performed starting immediately after the bolus injection of MultiHance. 2.1.2 MRA of Renal and Aorto-ilio-femoral Vessels For MRA examination, the recommended dose is 0.2 mL/kg (0.1 mmol/kg) administered as a rapid bolus intravenous injection followed by at least 20 mL saline flush either manually or using an automatic injector system. Start imaging immediately after the administration of MultiHance, with scan delay calculated by test bolus or automatic bolus detection technique. If an automatic contrast detection pulse sequence is not used for bolus timing, then a test bolus injection of 1-2 mL of MultiHance should be used to calculate the appropriate scan delay. 2.2 Dosing Table *For pediatric patients less than 2 years of age, one-half of the per kg dose may be used. TABLE 1: WEIGHT-BASED DOSING VOLUMES FOR: CNS IMAGING (ADULTS AND PEDIATRICS ≥2 YEARS OF AGE*) AND MRA IMAGING (ADULTS ONLY) 0.1mM/kg dose Kilograms (Kg) Pounds (lb) Volume, Milliliters (mL) 2.5 5.5 0.5 5 11 1.0 10 22 2.0 15 33 3.0 20 44 4.0 25 55 5.0 30 66 6.0 35 77 7.0 40 88 8.0 45 99 9.0 50 110 10.0 55 121 11.0 60 132 12.0 65 143 13.0 70 154 14.0 75 165 15.0 80 176 16.0 85 187 17.0 90 198 18.0 95 209 19.0 100 220 20.0 105 231 21.0 110 242 22.0 115 253 23.0 120 264 24.0 125 275 25.0 130 286 26.0 135 297 27.0 140 308 28.0 145 319 29.0 150 330 30.0 2.3 Administration Inspect the MultiHance vial visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Draw MultiHance into a syringe and inject using sterile technique. Do not mix intravenous medications or parenteral nutrition solutions with MultiHance. Do not administer other medications in the same intravenous line with MultiHance. 2.4 Directions for Proper Use of MultiHance Multipack The pharmacy bulk package is used as a multiple dose container with an appropriate transfer device to fill empty syringes. MultiHance Multipack injection should be drawn into the syringe and administered using sterile technique. Unused portions of the drug must be discarded. When MultiHance Multipack injection is to be injected using plastic disposable syringes, the agent should be drawn into the syringe and used immediately. The transferring of MultiHance (gadobenate dimeglumine) injection from the Pharmacy Bulk Package should be performed in a suitable work area, such as a laminar flow hood, utilizing aseptic technique. The container closure may be penetrated only one time, utilizing a suitable transfer device. Once the pharmacy bulk package is punctured, it should not be removed from the aseptic work area during the entire period of use. The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum time of 8 hours from initial closure entry is permitted to complete fluid transfer operation. Any unused MultiHance Multipack injection must be discarded 8 hours after initial puncture of the bulk package …

3 DOSAGE FORMS AND STRENGTHS MultiHance is a sterile, nonpyrogenic, clear, colorless to slightly yellow aqueous solution for intravenous use only, containing 529 mg gadobenate dimeglumine per mL. Each mL of MultiHance Injection contains 529 mg gadobenate dimeglumine and is available in single use vials. (3)

4 CONTRAINDICATIONS MultiHance is contraindicated in patients with known allergic or hypersensitivity reactions to gadolinium-based contrast agents [ see Warnings and Precautions (5.3) ]. MultiHance is contraindicated in patients with known allergic or hypersensitivity reactions to gadolinium-based contrast agents. (4)

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Nephrogenic systemic fibrosis [see Warnings and Precautions (5.2) ] Hypersensitivity reactions [see Warnings and Precautions (5.3) ] The most commonly reported adverse reactions are nausea (1.3%) and headache (1.2%). (6) To report SUSPECTED ADVERSE REACTIONS, contact Bracco Diagnostics Inc. at 1-800-257-5181 or FDA at 1-800-FDA-1088 or 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults In clinical trials with MultiHance, a total of 4967 adult subjects (137 healthy volunteers and 4830 patients) received MultiHance at doses ranging from 0.005 to 0.4 mmol/kg. There were 2838 (57%) men and 2129 (43%) women with a mean age of 56.5 years (range 18 to 93 years). A total of 4403 (89%) subjects were Caucasian, 134 (3%) Black, 275 (6%) Asian, 40 (1%) Hispanic, 70 (1%) in other racial groups, and for 45 (1%) subjects, race was not reported. The most commonly reported adverse reactions in adult subjects who received MultiHance were nausea (1.3%) and headache (1.2%). Most adverse reactions were mild to moderate in intensity. One subject experienced a serious anaphylactoid reaction with laryngeal spasm and dyspnea [ see Warnings and Precautions (5.3) ]. Serious adverse reactions consisting of convulsions, pulmonary edema, acute necrotizing pancreatitis, and anaphylactoid reactions were reported in 0.1% of subjects in clinical trials. Adverse reactions that occurred in at least 0.5% of 4967 adult subjects who received MultiHance are listed below (Table 2), in decreasing order of occurrence within each system. TABLE 2: ADVERSE REACTIONS REPORTED IN ≥ 0.5% OF ADULT SUBJECTS WHO RECEIVED MULTIHANCE IN CLINICAL TRIALS Number of subjects dosed 4967 Number of subjects with any adverse reaction 517 (10.4%) Gastrointestinal Disorders Nausea 67 (1.3%) General Disorders and Administration Site Disorders Injection Site Reaction Feeling Hot 54 (1.1%) 49 (1.0%) Nervous System Disorders Headache Dysgeusia Paresthesia Dizziness 60 (1.2%) 33 (0.7%) 24 (0.5%) 24 (0.5%) The following adverse reactions occurred in less than 0.5% of the 4967 adult subjects who received MultiHance. Serious adverse reactions described above are not repeated below. Blood and Lymphatic System Disorders: Basophilia; Cardiac Disorders: Atrioventricular block first degree; Eye Disorders: Eye pruritus, eye swelling, ocular hyperemia, visual disturbance; Gastrointestinal Disorders: Abdominal pain or discomfort, diarrhea, dry mouth, lip swelling, paresthesia oral, tongue edema, vomiting; General Disorders and Administration Site Conditions: Chest pain or discomfort, chills, malaise; Immune System Disorders: Hypersensitivity; Investigations: Nonspecific changes in laboratory tests (including hematology, blood chemistry, liver enzymes and urinalysis), blood pressure and electrocardiogram parameters (including PR, QRS and QT intervals and ST-T segment changes). Musculoskeletal and Connective Tissue Disorders: Myalgia; Nervous System Disorders: Parosmia, tremor; Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, laryngospasm, nasal congestion, sneezing, wheezing; Skin and Subcutaneous Tissue Disorders: Hyperhidrosis, pruritus, rash, swelling face, urticaria. Pediatric Patients In clinical trials of MultiHance in MRI of the CNS, 307 pediatric subjects received MultiHance at a dose of 0.1 mmol/kg. A total of 160 (52%) subjects were male and the overall mean age was 6.0 years (range, 2 days to 17 years). A total of 211 (69%) subjects were Caucasian, 24 (8%) Black, 15 (5%) Asian, 39 (13%), Hispanic, 2 (<1%) in other racial groups, and for 16 (5%), race was not reported. Adverse reactions were reported for 14 …

7 DRUG INTERACTIONS 7.1 Transporter-Based Drug-Drug Interactions MultiHance and other drugs may compete for the canalicular multispecific organic anion transporter (MOAT also referred to as MRP2 or ABCC2). Therefore MultiHance may prolong the systemic exposure of drugs such as cisplatin, anthracyclines (e.g. doxorubicin, daunorubicin), vinca alkaloids (e.g. vincristine), methotrexate, etoposide, tamoxifen, and paclitaxel. In particular, consider the potential for prolonged drug exposure in patients with decreased MOAT activity (e.g. Dubin Johnson syndrome).

8 USE IN SPECIFIC POPULATIONS Pregnancy: Use only if imaging is essential during pregnancy and cannot be delayed. ( 8.1 ) 8.1 Pregnancy Risk Summary GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive (see Data ) . In animal reproduction studies, gadobenate dimeglumine has been shown to be teratogenic in rabbits following repeated intravenous administration during organogenesis at doses up to 6 times the recommended human dose. There were no adverse developmental effects observed in rats with intravenous administration of gadobenate dimeglumine during organogenesis at doses up to three times the recommended human dose (see Data ) . Because of the potential risks of gadolinium to the fetus, use MultiHance only if imaging is essential and cannot be delayed. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and is 15 to 20%, respectively. Data Human Data Contrast enhancement is visualized in the placenta and fetal tissues after maternal GBCA administration. Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported a clear association between GBCAs and adverse effects in the exposed neonates. However, a retrospective cohort study, comparing pregnant women who had a GBCA MRI to pregnant women who did not have an MRI, reported a higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include a lack of comparison with non-contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy. Animal Data Gadolinium Retention GBCAs administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, liver, kidney, and spleen for at least 7 months. GBCAs administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one month postnatal age. Reproductive Toxicology Gadobenate dimeglumine has been shown to be teratogenic in rabbits when administered intravenously at 2 mmol/kg/day (6 times the recommended human dose based on body surface area) during organogenesis (day 6 to 18) inducing microphthalmia/small eye and/or focal retinal fold in 3 fetuses from 3 separate litters. In addition, MultiHance administered intravenously at 3 mmol/kg/day (10 times the recommended human dose based on body surface area) has been shown to increase intrauterine deaths in rabbits. There was no evidence that MultiHance induced teratogenic effects in rats at doses up to 2 mmol/kg/day (3 times the recommended human dose based on body surface area), however, rat dams exhibited no systemic toxicity at this dose. There were no adverse effects on the birth, survival, growth, development and fertility of the F1 generation at doses up to 2 mmol/kg in a rat peri- and post-natal (Segment III) study. 8.2 Lactation Risk Summary Limited literature reports that breastfeeding after gadobenate dimeglumine administration to the mother would result in the infant receiving an oral dose of 0.001%-0.04% of the maternal dose. There is no information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Additionally, there is limited GBCA gastrointestinal absorption. The developmental and health benefits of breastfeeding should be considered together with t …

12.1 Mechanism of Action Gadobenate dimeglumine is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The large magnetic moment produced by the paramagnetic agent results in a large local magnetic field, which can enhance the relaxation rates of water protons in its vicinity leading to an increase of signal intensity (brightness) of tissue. In magnetic resonance imaging (MRI), visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadobenate dimeglumine decreases the T1 and T2 relaxation time in target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences.

11 DESCRIPTION MultiHance injection is supplied as a sterile, nonpyrogenic, clear, colorless to slightly yellow aqueous solution intended for intravenous use only. Each mL of MultiHance contains 529 mg gadobenate dimeglumine and water for injection. MultiHance contains no preservatives. Gadobenate dimeglumine is chemically designated as (4RS)-[4-carboxy-5,8,11-tris(carboxymethyl)- 1-phenyl-2-oxa-5,8,11-triazatridecan-13-oato(5-)] gadolinate(2-) dihydrogen compound with 1-deoxy-1-(methylamino)-D-glucitol (1:2) with a molecular weight of 1058.2 and an empirical formula of C 22 H 28 GdN 3 O 11 • 2C 7 H 17 NO 5 . The structural formula is as follows: MultiHance has a pH of 6.5-7.5. Pertinent physicochemical parameters are provided below: Osmolality 1.970 osmol/kg @ 37°C Viscosity 5.3 mPas @ 37°C Density 1.220 g/mL @ 20°C MultiHance has an osmolality 6.9 times that of plasma (285 mOsmol/kg water) and is hypertonic under conditions of use. MultiHance Structure

10 OVERDOSAGE Clinical consequences of overdosage with MultiHance have not been reported. Treatment of an overdosage should be directed toward support of vital functions and prompt institution of symptomatic therapy. In a Phase 1 clinical study, doses up to 0.4 mmol/kg were administered to patients. MultiHance has been shown to be dialyzable [see Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied MultiHance (gadobenate dimeglumine) is a clear, colorless to slightly yellow solution containing 529 mg gadobenate dimeglumine per mL. MultiHance is supplied in glass vials; each single dose vial is rubber stoppered with an aluminum seal and the contents are sterile. MultiHance is supplied in boxes of: Five 5 mL single dose 10 mL vials (NDC 0270-5164-12) Five 10 mL single dose 20 mL vials (NDC 0270-5164-13) Five 15 mL single dose 20 mL vials (NDC 0270-5164-14) Five 20 mL single dose 20 mL vials (NDC 0270-5164-15) 16.2 Storage and Handling Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Do not freeze.