Gadobenate Dimeglumine

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.

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. (3)

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)

Hypersensitivity: anaphylactic/anaphylactoid reactions with cardiovascular, respiratory and cutaneous manifestations, ranging from mild to severe reactions including shock can occur. Monitor patients closely 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 can cause serious adverse reactions including death, coma, encephalopathy, and seizures. The safety and effectiveness of MultiHance have not been established with intrathecal use. MultiHance is not approved for intrathecal use [see Dosage and Administration (2.1) ] .

5.2 Nephrogenic Systemic Fibrosis GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of MultiHance among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR <30 mL/min/1.73m 2 ) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m 2 ). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following MultiHance 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 (e.g., age >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 a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended MultiHance dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown [see Dosage and Administration (2) and Clinical Pharmacology (12) ] .

5.3 Hypersensitivity Reactions Anaphylactic and anaphylactoid reactions have been reported, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of MultiHance administration and resolved with prompt emergency treatment. Prior to MultiHance administration, ensure the availability of personnel trained and medications to treat hypersensitivity reactions. If such a reaction occurs stop MultiHance and immediately begin appropriate therapy. Additionally, consider the risk for hypersensitivity reactions, especially in patients with a history of hypersensitivity reactions or a history of asthma or other allergic disorders. Observe patients for signs and symptoms of a hypersensitivity reaction during and for up to 2 hours after MultiHance administration.

5.4 Gadolinium Retention 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, gadolinium 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 (5.2) ] . 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 a GBCA for these patients. Minimize repetitive GBCA imaging studies, particularly closely spaced studies when possible.

5.5 Acute Renal Failure In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred with the use of gadolinium-based contrast agents. The risk of renal failure may increase with increasing dose of the contrast agent. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction.

5.6 Extravasation and Injection Site Reactions Extravasation of MultiHance may lead to injection site reactions, characterized by local pain or burning sensation, swelling, blistering, and necrosis. In animal experiments, local reactions including eschar and necrosis were noted even on Day 8 post perivenous injection of MultiHance. Exercise caution to avoid local extravasation during intravenous administration of MultiHance. If extravasation occurs, evaluate and treat as necessary if local reactions develop.

5.7 Cardiac Arrhythmias Cardiac arrhythmias have been observed in patients receiving MultiHance in clinical trials [ see Adverse Reactions (6.1) ]. Assess patients for underlying conditions or medications that predispose to arrhythmias. A double-blind, placebo-controlled, 24-hour post dose continuous monitoring, crossover study in 47 subjects evaluated the effect of 0.2 mmol/kg MultiHance on ECG intervals, including QTc. The average changes in QTc values compared with placebo were minimal (<5 msec). QTc prolongation between 30 and 60 msec were noted in 20 subjects who received MultiHance vs. 11 subjects who received placebo. Prolongations ≥61 msec were noted in 6 subjects who received MultiHance and in 3 subjects who received placebo. None of these subjects had associated malignant arrhythmias. The effects on QTc by MultiHance dose, other drugs, and medical conditions were not systematically studied.

5.8 Interference with Visualization of Certain Lesions Certain lesions seen on non-contrast images may not be seen on contrast- images. Exercise caution when interpreting contrast MR images in the absence of companion non-contrast MR images.

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 54 (1.1%) Feeling Hot 49 (1.0%) Nervous System Disorders Headache 60 (1.2%) Dysgeusia 33 (0.7%) Paresthesia 24 (0.5%) Dizziness 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 (4.6%) of the subjects. The frequency and the nature of the adverse reactions were similar to those seen in the adult patients. The most commonly reported adverse reactions were vomiting (1.0%), pyrexia (0.7%), and hyperhidrosis (0.7%). No subject died during study participation.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of MultiHance or other GBCAs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Acute pancreatitis with onset within 48 hours after GBCA administration. Immune System Disorders: Anaphylactic, anaphylactoid and hypersensitivity reactions manifested with various degrees of severity up to anaphylactic shock, loss of consciousness and death. The reactions generally involved signs or symptoms of respiratory, cardiovascular, and/or mucocutaneous abnormalities. General Disorders and Administration Site Conditions: Extravasation of MultiHance may lead to injection site reactions, characterized by local pain or burning sensation, swelling, blistering, and necrosis [see Warnings and Precautions ( 5.5 )] . Adverse events with variable onset and duration have been reported after 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. Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, pulmonary edema Skin: Gadolinium associated plaques.

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).

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 the mother’s clinical need for MultiHance and any potential adverse effects on the breastfed infant from MultiHance or from the underlying maternal condition.

8.4 Pediatric Use MultiHance is approved for intravenous use for MRI of the CNS to visualize lesions with abnormal blood brain barrier or abnormal vascularity of the brain, spine, and associated tissues in pediatric patients from birth, including term neonates, to less than 17 years of age. Pediatric use is based on evidence of effectiveness in adults and in 202 pediatric patients 2 years of age and older, in addition to experience in 105 pediatric patients birth to less than 2 years of age that supported extrapolation from adult data [see Clinical Studies ( 14 )] . Adverse reactions in pediatric patients were similar to those reported in adults [see Adverse Reactions ( 6.1 )] . No dose adjustment according to age is necessary in pediatric patients two years of age and older. For pediatric patients, less than 2 years of age, the recommended dosage range is 0.1 to 0.2 mL/kg [see Dosage and Administration ( 2.1 ), Pharmacokinetics ( 12.3 )] . The safety of MultiHance has not been established in preterm neonates.

8.5 Geriatric Use Of the total number of 4967 adult subjects in clinical studies of MultiHance, 33% were 65 or older. No overall differences in safety or effectiveness were observed between these elderly subjects and the younger subjects. The drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to MultiHance may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function it may be useful to monitor renal function.

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.