Control # 115650

Date of Revision: October 17, 2007

Table of Contents

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PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 10 DRUG INTERACTIONS 15 DOSAGE AND ADMINISTRATION 15 OVERDOSAGE 16 ACTION AND CLINICAL PHARMACOLOGY 16 STORAGE AND STABILITY 18 SPECIAL HANDLING INSTRUCTIONS 19 DOSAGE FORMS, COMPOSITION AND PACKAGING 19

PART II: SCIENTIFIC INFORMATION 20

PHARMACEUTICAL INFORMATION 20 CLINICAL TRIALS 21 DETAILED PHARMACOLOGY 21 TOXICOLOGY 32 REFERENCES 36

PART III: CONSUMER INFORMATION. 37

MultiHance (gadobenate dimeglumine injection)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition, and Packaging section of the product monograph.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Deoxygenated sickle erythrocytes have been shown in in-vitro studies to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by MultiHance may possibly potentiate sickle erythrocyte alignment. MultiHance has not been studied in patients with sickle cell anemia and other hemoglobinopathies. Patients with other hemolytic anemias have not been adequately evaluated following administration of MultiHance to exclude the possibility of increased hemolysis. The possibility of a reaction, including serious, life-threatening, or fatal, anaphylactic or cardiovascular reactions, or other idiosyncratic reactions should always be considered, especially in those patients with a history of a known clinical hypersensitivity or a history of asthma or other allergic respiratory disorders.

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS

Gadolinium-based contrast agents (GBCAs) increase the risk for Nephrogenic Systemic Fibrosis (NSF) in patients with:

• acute or chronic severe renal insufficiency (glomerular filtration rate <30 mL/min/I.73m2), or

• acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period.

In these patients, avoid use of GBCAs unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI). NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a GBCA, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent from the body prior to any readministration. (See General, Skin, Renal, and Post-Market sections)

General

Patients should be observed for one hour post-administration for potential allergic reactions. Patients with a history of allergy, drug reactions, or other hypersensitivity-like disorders should be closely observed during the procedure and for several hours after drug administration (See Serious Warnings and Precautions). Caution is advised in patients with preexisting severe cardiovascular disease (See Cardiovascular section). Diagnostic procedures that involve the use of contrast agents should be carried out under direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed. Appropriate facilities should be available for coping with any complications of the procedures, as well as for emergency treatment of severe reactions to the contrast itself. MultiHance is to be injected strictly intravenously. It will cause tissue irritation and pain if administered extravascularly. Although more lesions are generally visualized on contrast-enhanced images than on unenhanced images, lesions seen on unenhanced images may not all be seen on contrast-enhanced images. Possible causes include changes in imaging parameters, patient motion, misregistration, and effects of the contrast agent. CAUTION SHOULD BE EXERCISED WHEN A CONTRAST- ENHANCED INTERPRETATION IS MADE IN THE ABSENCE OF A COMPANION UNENHANCED MRI. Nephrogenic Systemic Fibrosis (NSF) Gadolinium-based contrast agents (GBCAs) increase the risk for Nephrogenic Systemic Fibrosis (NSF) in patients with acute or chronic severe renal insufficiency (glomerular filtration rate <30 mL/min/l. 73m2), and in patients with acute renal insufficiency of any severity due to the hepato- renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of GBCAs unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI). For patients receiving hemodialysis healthcare professionals may consider prompt hemodialysis following GBCA administration in order to enhance the contrast agent's elimination. However, it is unknown if hemodialysis prevents NSF. 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 function impairment at the time of exposure. NSF development is considered a potential class-related effect of all GBCAs. Post-marketing reports have identified the development of NSF following single and multiple administrations of GBCAs. These reports have not always identified a specific agent. Where a specific agent was identified, the most commonly reported agent was gadodiamide (Omniscan(r)), followed by gadopentetate dimeglumine (Magnevist(r)) and gadoversetamide (OptiMARK(r)). NSF has also developed following the sequential administration of gadodiamide with gadobenate dimeglumine (MultiHance(r)) or gadoteridol (ProHance(r)). The number of post-marketing reports is subject to change over time and may not reflect the true proportion of cases associated with any specific GBCA. The extent of risk for NSF following exposure to any specific GBCA is unknown and may vary among the agents. Published reports are limited and predominantly estimate NSF risks with gadodiamide. In one retrospective study of 370 patients with severe renal insufficiency who received gadodiamide, the estimated risk for development of NSF was 4% (J Am Soc Nephro1 2006; 17:2359). The risk, if any for the development of NSF among patients with mild to moderate renal insufficiency or normal renal function is unknown, and the cautious utilization of the lowest possible dose of GBCA is preferable. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a GBCA, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent from the body prior to any readministration. (See Pharmacology and Dosage and Administration). A skin biopsy is necessary in order to exclude the diagnosis of similarly presenting skin disorders (e.g scleromyxedema). (See Serious Warnings and Precautions, Renal, Skin and Post- Market sections).

Carcinogenesis and Mutagenesis

Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadobenate dimeglumine. MultiHance was not mutagenic in a series of in vitro tests:- Ames test in S. typhimurium and E. coli; gene mutation in mammalian cells (V79 hamster cells); chromosome mutation (human lymphocytes); DNA damage (gene conversion in Saccharomyces cerevisiae, unscheduled DNA Synthesis in human cells- as well as in vivo (micronucleus test in rats at 5 mmol/kg).

Cardiovascular

Caution is advised in patients with preexisting severe cardiovascular disease. (See Cardiac Effects section - page 26).

Dependence/Tolerance

There is no known dependence to MultiHance.

Ear/Nose/Throat

There are no special warnings or precautions with the use of MultiHance in these systems

Endocrine and Metabolism

There are no special warnings or precautions with the use of MultiHance in these systems

Gastrointestinal

There are no special warnings or precautions with the use of MultiHance in this system

Genitourinary

There are no special warnings or precautions with the use of MultiHance in this system

Hematologic

Deoxygenated sickle erythrocytes have been shown in in-vitro studies to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by MultiHance may possibly potentiate sickle erythrocyte alignment. MultiHance has not been studied in patients with sickle cell anemia and other hemoglobinopathies. Patients with other hemolytic anemias have not been adequately evaluated following administration of MultiHance to exclude the possibility of increased hemolysis. (See Serious Warnings and Precautions)

Hepatic/Biliary/Pancreatic

The pharmacokinetic and safety profiles of subjects with hepatic impairment were similar to those of healthy volunteers. Dose adjustments in patients with hepatic impairment are not required. (See CLINICAL PHARMACOLOGY - Pharmacokinetics.)

Immune

MultiHance has no known effects on the immune system

Neurologic

There are no special warnings or precautions with the use of MultiHance in this system

Ophthalmologic

There are no special warnings or precautions with the use of MultiHance in this system

Peri-Operative Considerations

There are no special peri-operative considerations with MultiHance

Psychiatric:

There are no psychiatric warnings or precautions with MultiHance

Renal:

MultiHance is cleared from the body mainly by glomerular filtration (85-95%) and to a minor degree (0.6-4.0%) by hepatobiliary excretion. Since the drug is substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. In subjects with moderate or severe renal impairment, the elimination of MultiHance is severely curtailed. The mean half-life is about 5x longer and mean clearance about 4 - 9x lower than in healthy volunteers. The mean cumulative excretion in urine during 0 - 160 hours period after the dose decreased to 74% in moderate and 69% in severe renal impairment compared to 87% of the total dose during 0-48 hours in subjects with normal renal function. However, no differences were noted in the rate and type of reported adverse events compared with those in healthy volunteers. Administration of MultiHance in patients with moderate or severe renal impairment should be limited to a single 0.1 mmol/kg dose. If MultiHance has to be used in end stage renal disease, the drug should be removed by hemodialysis. (See CLINICAL PHARMACOLOGY - Pharmacokinetics) Exposure to GBCAs increases the risk for NSF in patients with: acute or chronic severe renal insufficiency (glomerular filtration rate <30 mL/min/l.73m2), or acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. The risk, if any for the development of NSF among patients with mild to moderate renal insufficiency or normal renal function is unknown, and the cautious utilization of the lowest possible dose of GBCA is preferable. (See Serious Warnings and Precautions, Warnings, Skin and Post-Marketing sections).

Respiratory

There are no special warnings or precautions with the use of MultiHance in this system

Sensitivity/Resistance

The possibility of a reaction, including serious, life-threatening, or fatal, anaphylactic or cardiovascular reactions, or other idiosyncratic reactions should always be considered, especially in those patients with a history of a known clinical hypersensitivity or a history of asthma or other allergic respiratory disorders. (See Serious Warnings and Precautions)

Sexual Function/Reproduction

Reproduction studies have been performed in rats at daily doses up to 20 times the daily human dose and have revealed no evidence of impaired fertility or harm to the fetus due to MultiHance. Studies in rabbits have shown that administration of gadobenate dimeglumine at doses of 9 to 20 times of human recommended dose for 12 days during the gestation period causes slight increase in developmental effects. No changes in reproductive performance and outcome of pregnancy were caused in rats by daily intravenous administration of gadobenate to parent animals before, during gestation and up to day 17 of gestation up to 2.0 mmol/kg/day.

Skin

NSF was first identified in 1997 and has so far, been observed only in patients with renal disease. This is a systemic disorder with the most prominent and visible effects on the skin. Cutaneous lesions associated with this disorder are caused by excessive fibrosis and are usually symmetrically distributed on the limbs and trunk. Involved skin becomes thickened which may inhibit flexion and extension of joints and result in severe contractures. The fibrosis associated with NSF can extend beyond dermis and involve subcutaneous tissues, striated muscles, diaphragm, pleura, pericardium, and myocardium. NSF may be fatal. (See Serious Warnings and Precautions, General, Renal, and Post-Market sections).

Special Populations

Pregnant Women:

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, MultiHance cannot be recommended for use during pregnancy.

Nursing Women:

It is not known to what extent gadobenate dimeglumine is excreted in human milk. It is known from animal experiments that minimal amounts, less than 0.5% of the administered dose is transferred via milk from mother to neonates. Breast-feeding should be discontinued prior to the administration of MultiHance and should not be recommenced until at least 24 hours after the administration of the contrast agent.

Pediatrics: See Warnings and Precautions (NSF, Renal), Dosage and Administration, CLINICAL PHARMACOLOGY; Pharmacokinetics - pediatric.

The cautious utilization of the lowest possible dose of MultiHance is recommended in the pediatric population. Due to limited clinical trial experience, MultiHance is not recommended for children under 2 years of age. Pharmacokinetic parameters of MultiHance for children 2 to 12 years and adolescents 12 to16 years were similar those of healthy adult subjects. (

)

The safety and efficacy of MultiHance at a single dose of 0.1 mmol/kg have been established in a pediatric population. The safety and efficacy of doses greater than 0.1 mmol/kg and the clinical benefit of repeated procedures have not been studied in pediatric patients. The use of MultiHance in these age groups is supported by evidence from adequate and well-controlled studies of MultiHance in adults (see CLINICAL TRIALS), a pediatric study of MR imaging of the central nervous system (see CLINICAL TRIALS; CNS), and pharmacokinetic studies in adults and children (see CLINICAL PHARMACOLOGY; Pharmacokinetics). Repeat Procedures: Sequential use during the same diagnostic session has only been studied in adult central nervous system and liver use. If the physician determines repeat dosing is required in pediatric administration, in patients with normal renal function the time interval between repeat doses should be at least 7 hours to allow for normal clearance of drug from the body.

Geriatrics:

Of the 546 adult subjects in CNS clinical studies of MultiHance, 17% were 65 and over. Of the 1463 adult subjects in clinical studies of MultiHance for MRA, 52% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly or younger patients, but greater sensitivity of some older individuals cannot be ruled out.

The drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in when administering MultiHance to elderlies, and it may be useful to monitor renal function in these patients. (See Warnings and Precautions, Renal)

Monitoring and Laboratory Tests:

Laboratory abnormalities, such as hypochromic anemia, leukokytosis, leucopenia, basophilia, hypoproteinemia, hypocalcaemia, hyperkalemia, hyperglycaemia or hypoglycaemia, glucosuria, albuminuria, hematuria, hyperlipidaemia, increase in serum iron and increases in serum transaminases, alkaline phosphatase, lactic dehydrogenase, bilirubinemia, and in serum creatinine were reported in less than 0.4% of patients following the administration of MultiHance. However these findings were mostly seen in patients with evidence of pre-existing impairment of hepatic function or pre-existing metabolic disease.

Increased urinary zinc excretion has been observed following intravenous administration of 0.2 mmol/kg of MultiHance in patients with moderate and severe renal insufficiency but was not accompanied by any clinical signs or symptoms of zinc depletion. The amount of zinc excreted during 24 hours post-dose was small (about 3 mg) in comparison with the available pool of the metal in the body (about 2-3 g/70kg). The mechanism by which MultiHance increases urinary zinc excretion in patients with renal insufficiency is not clear. The effect of MultiHance on urinary zinc excretion in subjects with normal renal function has not been investigated. The increased urinary excretion of zinc was not considered clinically relevant since a possible reduction of serum zinc resulting from a single administration of MultiHance would likely be promptly replenished by dietary intake and the body reserves of the metal. Nearly 99% of total body zinc is located inside cells, primarily in bones and erythrocytes, the remainder in plasma (almost completely bound to albumin and a2 -macroglobulin) and extracellular fluids 5.

DRUG INTERACTIONS

Interaction studies with other medicinal products were not carried out during the clinical development of MultiHance. Drug-Food Interaction: Interactions with food have not been established Drug-Herb Interaction: Interactions with herbal products have not been established. Drug-Laboratory Test Interaction: Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Central Nervous System Imaging

Adults

The recommended dose of MultiHance is 0.1 mmol/kg (0.2 mL/kg) administered as an intravenous infusion (approximately 10 mL/minute) or rapid bolus injection. In patients with known or suspected brain metastases, a second injection of 0.1 mmol/kg provides a significant increase in lesion-to-normal parenchyma contrast enhancement that is associated with improved lesion detection. Imaging can be started up to 20 minutes after the injection of MultiHance.

Children (2 years of age and older)

The cautious utilization of the lowest possible dose of MultiHance is recommended in the pediatric population. The recommended dose of MultiHance is 0.1 mmol/kg (0.2 mL/kg) administered as an intravenous infusion (approximately 10 mL/minute) or rapid bolus injection. Imaging can be started up to 20 minutes after the injection of MultiHance. The safety and efficacy of doses > 0.1 mmol/kg, and sequential and/or repeat procedures in children have not been studied.

MRA Imaging

The recommended dose of MultiHance in adult patients is 0.1 mmol/kg (0.2 mL/kg), administered as a bolus injection (2 mL/sec). Imaging acquisition should be initiated during and immediately after the administration of the agent. If an automatic contrast detection pulse sequence is not used for bolus timing, then a test bolus injection (1-2 mL) of the agent should used to calculate the appropriate scan delay.

General Instructions

MultiHance is to be injected strictly intravenously. To ensure complete injection of the contrast medium, the injection should be followed by a saline flush of at least 5 mL. It is important to ensure that the i.v. needle or cannula is correctly inserted into a vein. Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Concurrent medications or Parenteral Nutrition should not be physically mixed with contrast agents and should not be administered in the same intravenous line because of the potential of chemical incompatibility. When MultiHance injection is to be injected using plastic disposable syringes, the contrast should be drawn into the syringe and used immediately. MultiHance injection should be drawn into the syringe and administered using sterile technique. If non-disposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents. Any residual product must be discarded in accordance with regulations dealing with the disposal of such materials.

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 I clinical study, doses up to 0.4 mmol/kg were administered to patients without any serious adverse events. MultiHance has been shown to be dialyzable. (See CLINICAL PHARMACOLOGY - Pharmacokinetics.)

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Gadobenate dimeglumine is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent.

Pharmacodynamics

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. Unlike other paramagnetic contrast agents, MultiHance demonstrates weak and transient interactions with serum proteins that causes slowing in the molecular tumbling dynamics, resulting in strong increases in relaxivity in solutions containing serum proteins. (See Table 1.)

Gadobenate dimeglumine does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that have a normal blood-brain barrier, e.g., cysts, mature post-operative scars, etc. ; while it enhances normal tissues lacking of blood-brain-barrier. Abnormalities of the blood-brain barrier or abnormal vascularity allow preferential distribution of gadobenate dimeglumine in lesions such as neoplasms, abscesses, and subacute infarcts.

Pharmacokinetics

Three single-dose intravenous studies were conducted in 32 healthy male subjects to assess the pharmacokinetics of gadobenate dimeglumine. The doses administered in these studies ranged from 0.005 to 0.4 mmol/kg. Upon injection, the meglumine salt is completely dissociated from the gadobenate dimeglumine complex. Thus, the pharmacokinetics is based on the assay of gadobenate ion, the MRI contrast effective ion in gadobenate dimeglumine. Data for plasma concentration and area under the curve demonstrated linear dependence on the administered dose. The pharmacokinetics of gadobenate ion following intravenous administration can be best described using a two-compartment model.

Distribution:

Gadobenate ion has a rapid distribution half-life (reported as mean +- SD) of 0.085

+- 0.004 to 0.605 +- 0.072 hours. Volume of distribution of the central compartment ranged from 0.074 +- 0.017 to 0.158 +- 0.038 L/kg, and estimates of volume of distribution by area ranged from 0.170 +- 0.016 to 0.282 +- 0.079 L/kg. These latter estimates are approximately equivalent to the average volume of extracellular body water in man. In vitro studies showed no appreciable binding of gadobenate ion to human serum proteins. Metabolism: There was no detectable biotransformation of gadobenate ion. Dissociation of gadobenate ion in vivo has been shown to be minimal, with less than 1% of the free chelating agent being recovered alone in feces.

Elimination:

Gadobenate ion is eliminated predominately via the kidneys, with 78% to 96% of an administered dose recovered in the urine. Total plasma clearance and renal clearance

estimates of gadobenate ion were similar, ranging from 0.093 +- 0.010 to 0.133 +- 0.270 L/hr/kg and 0.082 +- 0.007 to 0.104 +- 0.039 L/hr/kg, respectively. The clearance is similar to that of substances that are subject to glomerular filtration. The mean elimination half-life ranged from 1.17 +- 0.26 to 2.02 +- 0.60 hours. A small percentage of the administered dose (0.6% to 4%) is eliminated via the biliary route and recovered in feces.

Special Populations and Conditions

Renal Impairment:

A single intravenous dose of 0.2 mmol/kg of MultiHance was administered to 20 subjects with impaired renal function (6 men and 3 women with moderate renal impairment [urine creatinine clearance >30 to <60 mL/min] and 5 men and 6 women with severe renal impairment [urine creatinine clearance >10 to <30 mL/min]). The rate but not the overall extent of elimination of gadobenate was influenced by impaired renal function. Mean estimates of the elimination half-life were 6.1 +-3.0 and 9.5 +- 3.1 hours for the moderate and severe renal impairment groups, respectively as compared with 1.8 to 2 hours in healthy volunteers. No dosage adjustment is warranted since MultiHance is administered as a single or double intravenous bolus dose only. (See Renal section under Warnings and Precautions)

Hemodialysis:

A single intravenous dose of 0.2 mmol/kg of MultiHance was administered to 11 subjects (5 males and 6 females) with end-stage renal disease requiring hemodialysis to determine the pharmacokinetics and dialyzability of gadobenate. Approximately 72% of the dose was recovered by hemodialysis over a 4-hour period. The mean elimination half-life on dialysis was 1.21 +- 0.29 hours as compared with 42.4 +- 24.4 hours when off dialysis. (See Warnings and Precautions, Nephrogenic Systemic Fibrosis)

Hepatic Impairment

: A single intravenous dose of 0.1 mmol/kg of MultiHance was administered to 11 subjects (8 males and 3 females) with impaired liver function (Class B or C modified Child-Pugh Classification). Hepatic impairment had little effect on the pharmacokinetics of MultiHance with the parameters being similar to those calculated for healthy subjects.

Pediatrics:

A single intravenous dose of 0.1 mmol/kg of MultiHance was administered to 25 healthy subjects (14 males and 11 females) between the ages of 2 and 16 years. Population estimates of pharmacokinetic parameters of MultiHance for children 2 to 12 years and adolescents 12 to 16 years were similar those of healthy adult subjects. In addition, there were no significant differences in parameter estimates between children (2 to <12 years) and adolescents (12 to <16 years) or between males and females.

Pharmacokinetics of MultiHance in pediatric patients with renal impairment has not been investigated. (See Warnings and Precautions (NSF, Renal), Dosage and Administration, CLINICAL PHARMACOLOGY; Pharmacokinetics - pediatric.)

Sex:

A multiple regression analysis performed using pooled data from several pharmacokinetic studies found no significant effect of sex upon the pharmacokinetics of gadobenate.

STORAGE AND STABILITY

Protect from light. Store at controlled room temperature between 15degC and 25degC. Do not freeze. Single dose vials. Discard unused portions.

SPECIAL HANDLING INSTRUCTIONS

As with all parenteral drug products, vials and bottles should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used.

DOSAGE FORMS, COMPOSITION AND PACKAGING

MultiHance (gadobenate dimeglumine) is a clear, colourless solution containing 529 mg gadobenate dimeglumine per mL in water for injection. There are no other nonmedicinal ingredients. 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 vials; in single dose vials of 5mL, 10mL, 15mL, and 20mL. Also available in multiple dose Pharmacy Bulk Packages of 50ml and 100mL bottles. The availability of the Pharmacy Bulk Vials is limited to hospitals with a pharmacy based IV admixture program. The Pharmacy Bulk Vial is intended for single puncture, multiple dispensing for intravenous use only. The withdrawal of the container contents should be accomplished without delay. A maximum time of 4 hours from initial entry is permitted to complete the fluid transfer operation.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance:

Common Name: gadobenate dimeglumine Trade Name: MultiHance Chemical name: (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) Structural Formula: Molecular Formula: C36H62GdN5O21 Molecular Weight: 1058.2 Osmolality: 1.97 mol/kg Solubility: Freely soluble in water, sparingly soluble in methanol, slightly soluble in ethanol, insoluble in chloroform. pH (5% solution) 6.7

Dosage Form:

Composition:

gadobenate dimeglumine, water for injection

CLINICAL TRIALS DETAILED PHARMACOLOGY PRECLINICAL STUDIES

CNS imaging studies comparing 0.25 M gadobenate dimeglumine and 0.5 M gadopentetate dimeglumine were conducted in a rat model of implanted brain tumors. Both drugs were administered at a dose of 0.1 mmol/kg. The results showed that gadobenate dimeglumine increased brain lesion conspicuity more than gadopentetate dimeglumine in conventional SE imaging. Also, Magnetization Transfer in this rat brain tumor model was more effective after gadobenate dimeglumine relative to gadopentetate dimeglumine. The results suggest that gadobenate dimeglumine enhances the conspicuity of rat brain tumors more than gadopentetate dimeglumine because, unlike gadopentetate dimeglumine, it binds to extravasated serum proteins and causes higher interstitial relaxivity The potential for gadobenate dimeglumine to produce unexpected pharmacologic effects was examined in several in vitro and in vivo safety pharmacology studies. The in vivo studies were carried out in healthy animals and in animal models of clinical diseases. Gadobenate dimeglumine was tested for effects on the major physiological systems, such as the cardiovascular and central nervous systems, and for potential effects on specific target organs, such as the heart, liver, and kidneys. Most of the observed pharmacological effects of gadobenate dimeglumine in the studies described below could be explained by the hyperosmolality and volume of the injected solutions. Transient effects showed rapid onset and rapid reversal. The results of the safety pharmacology studies showed that the potential for gadobenate dimeglumine to produce unexpected pharmacological effects at clinical doses is minimal. CNS studies were conducted in mice, rats, and rabbits. In mice, gadobenate dimeglumine (up to 1.0 mmol/kg) had no effect on spontaneous locomotor activity, pentobarbital induced anesthesia, pentylenetetrazole-induced convulsion, acetic acid-induced writhing, or body temperature. In rats, IV gadobenate dimeglumine had no pharmacologically relevant effects on behavior (Irwin test), motor coordination (rotarod test), or brain activity (electroencephalogram, EEG). Slight behavioral effects (reduced activity, mydriasis) were observed after intrathecal administration of 0.06 mmol/kg gadobenate dimeglumine, and the median effective intrathecal dose with respect to effects on motor coordination of 0.018 mmol/kg. Only minor changes in EEG and visual evoked potential were observed in animals that received 0.025 mmol/kg by intracerebroventricular injection. No signs of nausea and malaise were elicited at the same dose in the "taste aversion test". Assuming that the intrathecal gadobenate dimeglumine diffuses homogeneously in the brain and cerebrospinal fluid (cumulative weight of 1.6 grams in a 200 gram rat), the brain concentration of gadobenate dimeglumine at 0.018 mmol/kg would be 2.25 mol per gram of tissue. This concentration is approximately 40 times higher than that (0.06 mol per gram of tissue) found in a rat model that simulates the clinical disruption of the blood brain barrier after IV administration of 0.3 mmol/kg gadobenate dimeglumine. Special activities of gadobenate dimeglumine on main neurotransmitter system and metabolic brain functions in intact animals was investigated by direct administration of gadobenate dimeglumine (0.1 to 2.4 mol per gram of tissue) into the brain tissue at concentrations isoosmolal to CSF. Gadobenate dimeglumine did not affect the synaptic release of dopamine under different basal conditions of release (resting, stimulated, and inhibited), and did not affect the levels of lactic acid in the brain. Gadobenate dimeglumine showed neurotolerability in a rat model of induced brain ischemia. Cardiovascular studies were conducted in healthy rats, rabbits, and pigs at an IV dose of 1 mmol/kg gadobenate dimeglumine. Taking into account the different pharmacokinetics of gadobenate dimeglumine in these species, no relevant pharmacological discrepancies among the various studies were observed. The cardiovascular effects generally produced by gadobenate dimeglumine were central and peripheral hemodynamic changes. Increases in cardiac output, as well as in stroke volume and contemporaneous decreases in total peripheral resistances, coupled to increases in blood flow in renal and pulmonary arteries occurred. These effects were rapid in onset and short in duration, generally peaking in 1 minute after dosing and virtually totally disappearing 20 minutes later. A safety study in Yucatan miniature swine suffering from induced myocardial ischemia was performed to better understand the safety limits for myocardial imaging, because this animal has similar coronary arterial distribution, collateral circulation, and heart to body weight compared to man. The pigs received IV doses of 1.0 to 3.0 mmol/kg gadobenate dimeglumine (the MTD in healthy pigs was 4.0 mmol/kg). In pathological conditions of myocardial ischemia, gadobenate dimeglumine induced central and peripheral hemodynamic effects such as increases in cardiac output and stroke volume, and decreases in systemic vascular resistance, arterial blood pressure, and heart rate. These effects were dose- related, quickly rising, and short-lasting. At 1.0 mmol/kg, they were considered of minimal clinical significance, whereas at 2.0 mmol/kg they appeared noteworthy. These changes were due to the high osmolality of the gadobenate dimeglumine solution. It is well known that intravascular administration of hyperosmolal solutions causes a transient increase in plasma osmolality. This induces a transient expansion of plasma volume, and a decrease in peripheral resistances. The expansion of plasma volume increases venous flow to the right heart, leading to a subsequent increase in cardiac output and stroke volume. The decrease in peripheral resistances is the consequence of loss in vessel muscular tone. This vasodilating effect gave a compensation of blood hypervolemia, so that clinically acceptable changes in arterial blood pressure and heart rate occurred. The peak plasma level in the pig at 1.0 mmol/kg (12.1 mmol/L) is approximately 13 to 36 times higher than peak plasma levels in man at 0.05 (0.331 mmol/L) and 0.1 mmol/kg (0.94 mmol/L). In spontaneously beating atria and stimulated papillary muscle preparations, at exposure concentration that were 23 times human plasma levels at 0.2 mmol/kg, myocardial contractility was reduced only 15%. Continuous ECG studies were conducted in conscious monkeys at doses up to 3 mmol/kg (30 times the recommended human dose). Slight, biologically irrelevant changes in RR, PR interval, and QRS complex duration were observed in the 60 minutes after injection. QTc intervals were not significantly modified by MultiHance up to the maximum tested dose. Also, in vitro electrophysiological studies were conducted to evaluate cardiac action potential and potassium channels. One study compared the effect of MultiHance to a control mannitol solution of equivalent osmolality on HERG tail current recorded from stably transfected HEK293 cells. Both MultiHance and mannitol produced similar variable degrees of HERG tail current inhibition that was not concentration dependent. This inhibition is likely due to increased osmolality, which would not be a factor at recommended human dosing levels. A second study examined the effect of MultiHance on action potential parameters in dog isolated cardiac Purkinje Fibres. MultiHance showed no prolongation of action potential duration when compared to the control treated group or when change from baseline values were determined. Further, no effects were noted on RMP, UA or MRD. When compared to the osmolarity matched mannitol group changes induced by MultiHance were significantly less marked than those of the mannitol group. Potential effects of IV gadobenate dimeglumine (1 mmol/kg) on the respiratory system were studied in large white pigs and guinea pigs. Gadobenate dimeglumine had no effects on respiratory mechanics and did not suggest a potential for bronchospasm or anaphylactoid activity. Potential effects of 0.25 M gadobenate dimeglumine (1.25 and 2.5 mmol/kg) on liver and kidney were studied in the conscious rat. No effects on urinary parameters was noted at 1.25 mmol/kg. A transient polyuria (0-5 hours after dosing), which was attributed to the injection of a large volume (10 mL/kg) of the hyperosmolar solution, was observed at 2.5 mmol/kg. There were no significant changes in urinary parameters, nor in urinary levels of enzymes from tubular cell and brush border (N-acetylbeta-glucosaminidiase and alanyl-aminopeptidase) that are considered as early indicators in renal cell damage. On the basis of Cmax, the exposure at 2.5 mmol/kg is approximately 6 times higher than the human Cmax at clinical doses. In a separate study in rats, 0.5 M gadobenate dimeglumine (0.2 or 1.0 mmol/kg at a dose volume of 2 mL/kg) had no effects on urine volume or urinary electrolyte excretion over a 5 hour post-dose period. Additionally, 0.25 M gadobenate dimeglumine (1.25 or 2.5 mmol/kg, or 5-10 mL/kg) had no effect on hepatic enzymes (aspartate aminotransferase, alanine aminotransferase, or lactate dehydrogenase). A transient increase in plasma bilirubin and a decrease in bromosulfophthalein elimination half life were observed at 2.5 mmol/kg, but this was likely due to common transport mechanism for gadobenate and organic anions, and not due to hepatic impairment A slight but dose-related increase in cytoplasmic vacuolization of hepatocytes and histiocytosis of peri-portal spaces (reversible within 4 hours) was observed microscopically. These changes are cell adaptive reversible phenomena that occur after injection of hyperosmolar solutions, and are not indicative of toxicity. The potential gastrointestinal effect of 0.5 M gadobenate dimeglumine on contractile responses induced by acetylcholine, histamine, and barium chloride was studied in the isolated ileum of rat and guinea pig. The 0.5 M gadobenate dimeglumine had no effect on contractions induced by acetylcholine, histamine, or barium chloride either at 10 or 100 uM, or 1 mM, and no effect on resting tonus of isolated rat and guinea pig ileum at these concentrations. Therefore, gadobenate dimeglumine had no effect on smooth muscle of the ileum in vitro. Additionally, IV gadobenate dimeglumine (0.2 or 1 mmol/kg) had no effect on charcoal intestinal transit in mice. Cardiovascular studies were conducted in anesthetized rabbits to explore the potential for gadobenate dimeglumine to interact with drugs that are likely to be used concomitantly in patients for whom MRI examination is indicated. The drugs studied were epirubicin (antitumoral), isosorbide dinitrate (antianginal), and captopril (antihypertensive). Dobutamine, which is used for the pharmacodynamic test for imaging diagnosis of myocardial ischemia was also included. None of the drugs examined affected cardiovascular peak responses to IV gadobenate dimeglumine.

Distribution

- Gadobenate dimeglumine distributed rapidly from the plasma compartment to the extracellular space, and tissue levels increase rapidly in parallel with the decrease in plasma levels.

Metabolism

- Following IV administration, gadobenate dimeglumine is cleared rapidly from the blood, does not accumulate in organs or tissues and is not metabolized.

Excretion

- Gadobenate dimeglumine is rapidly excreted unchanged by both urinary and biliary routes in rats, rabbits, dogs, and monkeys. The elimination half-life was shorter in rats than in rabbits and dogs. The rat and dog eliminate gadobenate dimeglumine unchanged primarily via the biliary route, whereas rabbits and monkeys, like man, excrete gadobenate dimeglumine unchanged primarily via the urinary route. In rabbits, biliary excretion was a saturable process. The hepatic clearance values showed that the gadobenate ion had low hepatic extraction in rabbits, which was consistent with the observation that non-rodent species present a lower biliary transport in comparison to rodents. Additionally, the study in TR- rats showed that the transport of the gadobenate ion from the cytoplasma of hepatocytes to bile occurs via the cMOAT. Studies in rats and rabbits indicated that enterohepatic recirculation of gadobenate dimeglumine is minimal.

Studies in lactating rats showed that low levels of gadobenate dimeglumine are secreted in the milk, and are transferred to the suckling neonate

CLINICAL STUDIES

Central Nervous System (CNS)

MultiHance was studied in three multicenter blinded-read clinical trials in a total of 560 adults who underwent MRI of the CNS for evaluation of known or suspected lesions of the brain or spine. Of these 560 adults, MultiHance was administered to 426 patients (217 men, 209 women) with a mean age of 52 years (range 18 to 88 years). The racial and ethnic representations were 88% Caucasian, 6% Black, 5% Hispanic, 1% Asian, and 0.5% other racial or ethnic groups. Two of these studies were double-blind, multicenter, parallel-group, blinded-read trials comparing MultiHance with an approved gadolinium contrast agent in a total of 410 adults who were highly suspected of having a lesion (s) of the CNS (brain or spine) based on nuclear medicine imaging, contrast-enhanced computed tomography (CECT), computed tomography (CT), contrast-enhanced magnetic resonance imaging (CEMRI), magnetic resonance imaging (MRI), or angiography. Patients were randomized to one of three dosing regimens, which consisted of two bolus injections within 15 minutes of MultiHance (0.05 + 0.1 mmol/kg or 0.1 + 0.1 mmol/kg) or an approved gadolinium contrast agent (0.1 + 0.2 mmol/kg). MultiHance was administered to 276 adults, and an approved gadolinium contrast agent was administered to 134 patients. MRI scans were performed predose and within 5 minutes after each injection. The sets of images were evaluated blindly as predose unenhanced MR images alone and paired predose unenhanced plus postdose contrast-enhanced MRIs for each injection. Image sets were rated on a 3-point scale (limited, adequate, excellent) for the level of diagnostic information provided. The results of contrast-enhanced MRI scans were compared to an approved gadolinium contrast agent and to non-contrast scans. Analyses between image sets were based on increases in the level of diagnostic information and changes in numbers of lesions. When read in combination with the predose unenhanced images, MultiHance-enhanced images provided statistically significant improvement in the level of diagnostic information (LDI) over predose images alone. The proportions of patients with an increase in the level of diagnostic information (LDI) were comparable following administration of a single injection of MultiHance mmol/kg and an approved gadolinium contrast agent 0.1 mmol/kg. The mean number of lesions was greater following contrast-enhanced scans. Table 3 shows the proportion of the 136 patients who were evaluated for efficacy following the first dose of MultiHance 0.1 mmol/kg and had an increase in the level of diagnostic information from predose images to paired first- postdose images. In addition, the number of lesions visualized with predose and paired postdose images is displayed.

The third study was a double-blind, multicenter, parallel-group trial in a total of 150 adults who had proven malignancy outside the CNS and intraaxial metastatic disease to the CNS already diagnosed by CEMRI or CECT. Patients were randomized to one of two dosing regimens, which consisted of three bolus injections (0.05 + 0.05 + 0.1 mmol/kg or 0.1 + 0.1 + 0.1 mmol/kg) of MultiHance. The injections were administered in 10-minute intervals. MRI scans were performed predose and after each injection. The sets of images were evaluated blindly as predose unenhanced MR images alone, postdose contrast-enhanced images alone, and paired predose unenhanced plus postdose contrast-enhanced MRIs for each injection. The results of contrast-enhanced MRI scans following single and cumulative injections were compared between dosing regimens. Analyses between dosing regimens were based on quantitative measures of lesion-to-background ratio and lesion signal enhancement, and qualitative measures (i.e., changes in numbers of lesions). The mean change from predose MRI in lesion-to-background ratio as well of the percent of enhancement of lesion signal intensity increased significantly (p < 0.001) with dosing up to the second dose of both regimens (cumulative doses of 0.1 and 0.2 mmol/kg, respectively). Increases in lesion counts, as well as improvement in lesion conspicuity, delineation of lesion borders, and reviewer confidence in detection or exclusion of lesions were also reported. However, a cumulative dose of 0.2 mmol/kg provided an increase in lesion counts comparable to a cumulative dose of 0.3 mmol/kg. MultiHance was also evaluated in a parallel-group comparison study with an approved gadolinium contrast agent in a total of 174 children who were referred for MRI of the CNS. The children received either MultiHance or an approved gadolinium contrast agent as a single 0.1- mmol/kg dose. MultiHance was administered to 85 children (46 males and 39 females) of a mean age of 6.8 years (range 4 days to 17 years). Of these patients, 96% were Caucasian and 4% Black. The demographics were similar for the 89 children who received an approved gadolinium contrast agent. The sets of images were evaluated blindly as predose unenhanced MR images alone, postdose contrast-enhanced images alone, and paired predose unenhanced plus postdose contrast-enhanced MRIs. The results of contrast-enhanced MRI scans were compared to an approved gadolinium contrast agent and to non-contrast scans. Analyses between image sets were based on increases in the level of diagnostic information (rated on a 4- point scale of limited, adequate, good, or excellent) and changes in number of lesions. The proportions of children with an increase in the level of diagnostic information was greater when combined pre- plus post-contrast scans were compared to separate pre-contrast images and was comparable between MultiHance 0.1 mmol/kg and the same dose of an approved gadolinium contrast agent.

MRA

MultiHance was studied in four (3 confirmatory, 1 supportive) multicenter blinded-read clinical trials in a total of 992 adults who underwent MRA. Patients in each study received a single intravenous injection of 0.1 mmol/kg MULTIHANCE at 2 mL/s. The three confirmatory studies aimed at the intra-subject comparison of CE-MRA (Contrast Enhanced Magnetic Resonance Angiography) and UE-MRA (Unenhanced Magnetic Resonance Angiography) in the carotid arteries, the renal arterial territory, and the iliofemoral arteries. Digital subtraction angiography (DSA) was used as the gold standard. The primary focus of the comparisons was detection of clinically relevant steno-occlusive disease in the subject arteries. (See Table 4)

Table 4: Diagnostic Performance for Clinically Significant Stenosis in Phase III Confirmatory Studies, Intent-to-Treat Population

The results of the confirmatory trials showed that the bolus (2 mL/s) intravenous injection of 0.1 mmol/kg MULTIHANCE:

• significantly improves the technical performance of MRA of supra-aortic extra-cranial, renal, and peripheral arteries (down to the calf arteries), by significantly increasing the number of vascular segments properly displayed and significantly improving the display of blood flow, especially in smaller vessels with slower arterial inflow, thus improving the possibility of detecting significant steno-occlusive disease;

• significantly improves the diagnostic performance of MRA of supra-aortic extra-cranial, renal, and peripheral arteries; more specifically, the administration of MULTIHANCE produced:

• A statistically significant (p<0.001) increase in sensitivity, specificity and accuracy over UE-MRA in detecting significant (>= 51%) arterial steno-occlusive disease of the renal and peripheral arteries;

• A statistically significant (p<0.001) increase in specificity and accuracy over UE-MRA in detecting significant (>= 60%) arterial steno-occlusive disease of the supra-aortic extra-cranial arteries;

• improves the reliability of MRA of supra-aortic extra-cranial, renal, and peripheral arteries, as demonstrated by a higher inter-reader agreement and higher Kappa values.

• improves the MRA assessment of associated vascular disorders such as aneurysms;

• improves the diagnostic performance of MRA in the detection of collateral circulation in the assessment of peripheral arterial occlusive disease;

• decreases the technical failure rate (TFR) in the assessment of segmental and accessory renal arteries as compared to UE-MRA.

The supportive study showed that the bolus (2 mL/s) intravenous injection of 0.1 mmol/kg MULTIHANCE makes MRA of the foot arteries significantly more accurate at displaying vessels and steno-occlusive lesions.

Cardiac Effects

A prospective single-blind, placebo controlled, randomized crossover study using double the recommended dose of MultiHance (i.e. 0.2mmol/kg) was conducted. Subjects included healthy volunteers and patients with cardiovascular disease. ECG components were measured using 12- lead continuous monitoring. For QTc intervals using the individualized correction, increases of potential clinical concern (>30 msec) were less frequent than decreases of the same magnitude. This trend was evident following administration of both MultiHance and placebo. The proportion of subjects with changes of potential clinical concern was comparable following administration of MultiHance and placebo. For MultiHance, no increases >60 msec were observed in the first 15 minutes postdose (compared to 1/44, 2.3% following placebo). For MultiHance, the only increase >60 msec (1/47, 2.1%) occurred between 15 minutes and 2 hours postdose. No increases >60 msec occurred between 2 hours and 24 hours postdose following MultiHance, whereas, 1 subject (1/44, 2.3%) had an increase >60 msec in the same time period following administration of placebo. For QTc intervals using the Bazett's correction, increases of potential clinical concern (>30 msec) were more frequent than decreases of the same magnitude. This trend was evident following administration of both MultiHance and placebo. The proportion of subjects with changes of potential clinical concern was slightly higher following administration of MultiHance than following placebo. For both MultiHance and placebo, the increases >60 msec tended to occur more frequently within the first 2 hours after study agent administration (MultiHance: 4/47, 8.5%; placebo: 2/44, 4.5%); after the first 2 hours postdose, only 2 additional subjects had increases >60 msec following MultiHance and 1 additional subject following placebo. Changes from baseline of potential clinical importance for QTc (>30 msec) over the first 15 minutes, first 2 hours, or 24 hours postdose based on the automated reading are summarized in Table J.

A retrospective analysis was conducted of over 1000 patients monitored using intermittent 12- lead ECGs. Most changes were in the <20 msec range, evenly distributed between increases and decreases of the same magnitude, and similar to those seen for placebo. The percentages of patients who had changes in QTc between 31 to 60 msec were small (generally <5%), and no particular pattern was noted across timepoints. Changes >60 msec occurred at sporadic timepoints in <1% of the patients. Again, the percentages of patients with increases were similar to the percentages of patients with decreases. For QT intervals, >75 % of the patients across all timepoints had no changes or had changes <30 msec. The percentage of patients with increases 31 to 60 msec ranged from 5.9% to 12.2%. Decreases between 31 to 60 msec ranged from 0% to 11.2%. The number of changes >60 msec were small (<3%) and occurred at sporadic timepoints with no clinical significance. The percentages of patients with increases were similar to the percentages of patients with decreases.

TOXICOLOGY

Toxicity - Acute

The acute toxicity of gadobenate dimeglumine was evaluated in adult mice, rats, and in newborn rats using single intravenous, intracerebral and oral routes of administration. In dogs and monkeys repeated intravenous administrations were used. The results of the acute toxicity studies in mice and rats are summarized in the following table: (Table 4)

* Osmotic load was calculated as osmolality of drug x injected volume per L of blood

* * Recommended clinical dose of 0.1 mmol/kg has an osmotic load of 3.82 mOsmol per L of blood

The toxic doses varied depending on the injection rate of the solutions administered to the animals; slower rates resulted in less toxicity. The toxic effects observed in adult and newborn animals including death, dyspnea, prostration and convulsion were attributed mainly to the effect of high osmotic load rather than to the drug directly. Since the osmotic load of administered solution in the animals relative to the human clinical doses was approximately 50 - 100 times higher; the margin of safety is considered to be adequate. Studies were also conducted to evaluate the maximum tolerated dose (MTD) of gadobenate dimeglumine in dogs using single and repeated doses and in monkeys using single escalating doses. Six (6) mmol/kg dose was toxic to dogs but 2 mmol/kg produced only slight reduction in body weight and slight increases in serum enzymes but not histopathological changes. In Cynomolgus monkeys, 7 and 8 mmol/kg doses were found to be toxic but 6 mmol/kg was well tolerated without any clinical signs or macroscopic findings at necropsy. The MTD was considered to be 2 mmol/kg and 6 mmol/kg in dogs and monkeys, respectively.

Toxicity - Chronic

The toxicity of 0.5 M and 0.25 M gadobenate dimeglumine after repeated dosing was studied in rats and dogs for up to 4 weeks of daily dosing. The toxicity of 0.5 M gadobenate dimeglumine was studied in monkeys for 14 days of daily dosing. The monkey was considered the best animal model for potential human toxicity and extrapolation of interspecies scaling based upon Cmax and AUC because the pharmacokinetics of gadobenate dimeglumine in the monkey are similar to the pharmacokinetics in humans, particularly with respect to the predominantly renal excretion of gadobenate dimeglumine. A 4 week repeated dose study was conducted in rats at IV doses of 0.3, 1.0 and 3.0 mmol/kg/day 0.5 M gadobenate dimeglumine. The study design included a one month drug-free recovery period to assess reversibility of drug-related effects. This dose range represents approximately 1 to 15 times human exposures based upon Cmax values for gadobenate dimeglumine, and approximately 0.3, 1, and 3 times human exposure based upon AUC values for gadobenate dimeglumine. However, at these doses, the rats received approximately 3 to 60 times the human osmotic load at clinical doses. Reversible findings in these rats included increased water consumption (which was considered a response to the IV injection of highly osmolar solutions) at 1.0 to 3.0 mmol/kg/day, slight increases in plasma sodium and chloride at 1.0 to 3.0 mmol/kg/day, slight decreases in plasma potassium at 3.0 mmol/kg/day, and decreased urinary sodium and chloride excretions at 3.0 mmol/kg/day. Macroscopic findings at necropsy included an increased incidence of pale/thickened corpus mucosa in the stomach associated with calcium mineralization of the superficial and mid layers of the corpus region of the glandular stomach at 1.0 and 3.0 mmol/kg/day. The pathogenesis of the mineralization was not clear. The macroscopic findings partially reversed after a 1 month recovery period. These serum chemistry and macroscopic findings were not observed in rats that received daily IV injections of 0.25 M gadobenate dimeglumine (0.5 to 2.0 mmol/kg/day) for 4 weeks. Increased kidney weights were observed at the end of the treatment period and at the end of the drug-free recovery period 1.0 and 3.0 mmol/kg/day. A partially reversible dose-related vacuolation of the renal cortical tubules, which is a common and expected finding following IV administration of large doses of compound that have high osmolarity, was observed at 1.0 and 3.0 mmol/kg/day. Epithelial vacuolation of the urinary bladder was also observed at these doses. The minimal vacuolation of renal tubular cells at 0.3mmol/kg dose disappeared after a recovery period of 4 weeks. A 4 week repeated dose study was conducted in dogs at IV doses of 0.25, 0.5, 1.0 or 2.0 mmol/kg/day 0.5M gadobenate dimeglumine. The study design included a one month drug-free recovery period to assess reversibility of drug-related effects. This dose range represents approximately 0.6, 1, 3 and 8 times human exposure based upon AUC values for gadobenate dimeglumine. These dogs received dose volumes that delivered 2.5 to 40 times the osmotic load to humans at clinical doses. Drug-related clinical signs during the dosing period, principally noted in the 1 and 2 mmol/kg/day groups, included trembling at or during dosing, vomiting after dosing, licking of the lips during dosing, drinking water immediately after dosing, and occasional instances of subdued/quiet behavior, particularly in the first week of treatment. No drug-related clinical signs were noted during the recovery period. Significant dose-related decreases in body weight gain and food consumption occurred at 1 and 2 mmol/kg/day; these changes reversed during the recovery period. There were no overall treatment related effects on water consumption. There were no drug-related effects on opthalmoscopic or ECG examinations, or hematology parameters. Alkaline phosphatase activity was increased approximately 2-fold in 2 mmol/kg/day males and females relative to control values at Week 4, and mean glutamic-pyruvic transaminase activity was slightly higher in 2 mmol/kg/day females at Week 4. A general dose-related decrease in phosphorus, cholesterol, and phospholipids was noted in 1 and 2 mmol/kg/day males and females, which probably reflected dose-related changes in food consumption at these levels, rather than a direct effect of treatment. All clinical chemistry values were normal at the end of the recovery period. Urinary electrolytes (sodium, potassium, and chloride) and creatinine were decreased in 1 and 2 mmol/kg/day males and in 2 mmol/kg/day females relative to controls in Week 4; osmolarity was decreased in 2 mmol/kg/day males and females. Urinalysis parameters returned to normal during the recovery period. There were no treatment related macroscopic findings at necropsy, and no effects on bone marrow smears. The 2 mmol/kg/day males showed increased mean kidney weights. Minor liver changes males at 1 mmol/kg/day and females at 2 mmol/kg/day consisted of centrilobular inflammatory cells accompanied by centrilobular hepatocyte vacuolation. Male and female dogs showed a dose-related incidence and degree of renal cortical tubule vacuolation at 0.5, 1, and 2 mmol/kg/day. Vacuolation of renal cortical tubules is a common and expected finding after IV injection of highly osmolar solutions. All microscopic changes reversed at the end of the recovery period. The NOEL in dogs after daily IV administration of 0.5 M gadobenate dimeglumine for 4 weeks was 0.25 mmol/kg/day. A 14 day repeated dose study was conducted in monkeys at IV doses of 0.25, 1.0 or 3.0 mmol/kg/day 0.5M gadobenate dimeglumine. Based upon AUC values, these doses represented approximately 1, 4, and 15 times human exposure. Respectively, these doses delivered 2.5, 10, and 30 times the osmotic load that is delivered to humans at clinical doses. Administration of 0.5 M gadobenate dimeglumine caused decreased food consumption in female monkeys at 3.0 mmol/kg/day, and body weight loss in females at 1 or 3 mmol/kg/day. There were no drug- related clinical signs, ocular changes, electrocardiographic changes, or hematological, clinical chemistry, or urinalysis changes. At necropsy, a dose-related increase in mean absolute or relative kidney weight among male and female animals after two weeks of treatment at 1.0 or 3.0 mmol/kg/day in comparison to controls. No differences in weight were measured at 0.25 mmol/kg/day. The increased kidney weights were associated with a dose-related incidence and degree of vacuolation in cortical tubules in kidneys was observed in monkeys receiving 1.0 or 3.0 mmol/kg/day. Minimal vacuolation of islet cells in the pancreas of monkeys receiving 3.0 mmol/kg/day was also considered to be treatment-related. No changes were seen in monkeys receiving 0.25 mmol/kg/day. Vacuolation of the renal cortical tubules is a common and expected treatment effect following administration of high volumes of highly osmolar solutions. The extent of systemic exposure to gadobenate dimeglumine in the monkeys was characterized generally by dose-independent (linear) kinetics over the dose range 0.25 to 3.0 mmol/kg/day. No accumulation was observed in either sex at any of the doses tested. On the basis of the results obtained, 0.25 mmol/kg/day was established as a NOEL for this study.

REFERENCES

Kirchin MA, Pirovano GP, Spinazzi A. Gadobenate dimeglumine (Gd-BOPTA): An overview. Invest Radiol 1998; 33:798-809.

Arbughi T, Bertani F, Celeste R, Grotti A, Sillari S, Tirone P. High-performance chromatographic determination of the magnetic resonance imaging contrast agent gadobenate ion in plasma, urine, faeces, bile and tissue. J of Chromatography B 1998; 713: 415-426.

1. Rosati G, Priovano G, Spinazzi A. Interim results of phase II clinical testing of gadobenate dimeglumine. Invest Radiol 1994; 29:S183-S185.

2. Vogl T, Pegios W, McMahon C, Blazer J, Waitzinger J, Pirovano G, Lissner J. Gadobenate dimeglumine--a new contrast agent for MR imaging: preliminary evaluation in healthy volunteers. AJR 1992; 158:887-892.

Falchuck KH. Disturbances in trace elements. In: Harrison's Principles of Internal Medicine, edited by Fauci A et al.,14th edition, McGraw-Hill Inc, 1998: pp. 488- 492..

IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

MultiHance gadobenate dimeglumine injection

This leaflet is part III of a three-part "Product Monograph" published when MultiHance was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about MultiHance. Contact your doctor if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

MultiHance is used:

• to assist in magnetic resonance imaging (MRI) to better show tissue abnormalities of the central nervous system including the brain, spine and surrounding tissue.

• to assist in magnetic resonance angiography (MRA) to detect changes in your blood vessels known or suspected to be abnormal.

What it does:

MultiHance helps tissues appear brighter in MRI and MRA than without MultiHance, to highlight abnormalities and help

the doctor in diagnosis.

When it should not be used:

Do not use MultiHance if you are allergic to the medicinal ingredient gadobenate dimeglumine.

What the medicinal ingredient is:

Gadobenate dimeglumine

What the non-medicinal ingredients are: MultiHance contains only the medicinal ingredient gadobenate dimeglumine and water for injection.

What dosage forms it comes in:

- gadobenate dimeglumine injection 529 mg/mL (0.5M)

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• For those with sickle cell anemia, there is a possibility of complications in blood flow with MultiHance MRI/MRA treatment and your doctor will decide if this treatment is appropriate. This medication has not been studied in individuals with sickle cell anemia and other hemoglobinopathies.

• For those with hemolytic anemia, there is a possibility of increased hemolysis (destruction of blood cells) and your doctor will decide if this treatment is appropriate. This medication has not been studied in individuals with this condition.

• For those with a history of allergic reactions, asthma or allergic respiratory disorders, there is a possibility of a serious life threatening or fatal allergic reaction including heart reactions, with MultiHance treatment. You will be observed for at least one hour after administration of MultiHance.

There have been post-market reports of a rare disease called Nephrogenic Systemic Fibrosis (NSF) following gadolinium- based contrast agent (GBCA) use.

NSF is a rare condition which has only been observed so far in patients with severe kidney disease. At present, there is no evidence that other patient groups are at risk of developing the condition. Due to NSF the skin becomes thickened, coarse and hard, which sometimes makes bending of the joints difficult. NSF may spread to other organs and even cause death.

Patients with severe kidney disease should avoid the use of MultiHance unless the health care professional believes the possible benefits outweigh the potential risks. Those who

have already had an MR imaging procedure and who have

any of the following symptoms should seek medical attention as soon as possible:

• Swelling, hardening and tightening of the skin

• Reddened or darkened patches on the skin

• Burning or itching of the skin

• Yellow spots on the whites of the eyes

• Stiffness in the joints, problems moving or straightening arms, hands, legs or feet

• Pain deep in the hip bone or ribs

• Weakness of the muscles

Your doctor will monitor your health after administering MultiHance, if you are considered to be at risk for developing NSF.

BEFORE you use MultiHance talk to your doctor if:

1. You are pregnant or breast feeding,

2. You have anemia or diseases that affect the red blood cells,

MultiHance Page 37 of 38

You have a history of renal disease, heart disease (including the condition Qt prolongation), seizure, hemoglobinopathies, or asthma or allergic respiratory diseases,

You are taking any medications.

You have a known allergic or hypersensitivity reaction to gadolinium.

INTERACTIONS WITH THIS MEDICATION

No drugs are known to interact with MultiHance. Interaction studies have not been done with MultiHance during product development.

PROPER USE OF THIS MEDICATION

Usual dose:

Adults and children over 2 years of age:

0.2 mL/kg (0.1 mmol/kg) as an intravenous infusion or rapid bolus injection.

Overdose:

If you feel you have been given too much MultiHance, talk to the doctor or health professional attending your MRI/MRA procedure.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

You will be administered MultiHance only while under the direct care of a physician. Common side effects with MultiHance include headache, nausea, injection site reactions, alteration of taste, fever, and vomiting.

Protect from light. Store at controlled room temperature between 15degC and 25degC. Do not freeze. Discard unused portions.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs . If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate

Tunney's Pasture, AL 0701C Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

This document plus the full product monograph, prepared for health professionals can be obtained by contacting the sponsor, Bracco Diagnostics Canada Inc., at:

3700 Steeles Avenue West, Suite 301, Vaughan, Ontario, Canada L4L8K8

1-888-988-2333

This leaflet was prepared by Bracco Diagnostics Canada Inc. Last revised: October 17, 2007.

This is not a complete list of side effects. For any unexpected effects while taking MultiHance, contact your doctor.

HOW TO STORE IT

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