Date of Revision: October 25, 2007

Control No. 115736

Table of Contents

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............................................................16 OVERDOSAGE 17 ACTION AND CLINICAL PHARMACOLOGY 18 STORAGE AND STABILITY 22 SPECIAL HANDLING INSTRUCTIONS 22 DOSAGE FORMS, COMPOSITION AND PACKAGING 22

PART II: SCIENTIFIC INFORMATION 24

PHARMACEUTICAL INFORMATION 24 DETAILED PHARMACOLOGY 31 MICROBIOLOGY 32 TOXICOLOGY 33 REFERENCES 35

PART III: CONSUMER INFORMATION. 38

OPTIMARK(r) Gadoversetamide 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. Gadoversetamide is contraindicated in patients with known allergic or hypersensitivity reactions to gadolinium, versetamide or any of the inert ingredients.

WARNINGS AND PRECAUTIONS

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/1.73m2), 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 re-administration.

(Please cross reference to General, Skin, Renal and Post-Market sections.)

Serious Warnings and Precautions

Patients with history of allergy or drug reaction should be observed for several hours after drug administration.

The possibility of a reaction, including serious, life threatening, fatal anaphylactoid or cardiovascular reactions or other idiosyncratic reactions should always be considered (see ADVERSE REACTONS) especially in those patients with a known clinical hypersensitivity.

Repeat procedures: The safety of repeated doses has not been studied. If the physician determines sequential repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body.

OptiMARK may be associated with QT/QTc interval prolongation. (See Clinical Trials.) Many drugs that cause QT/QTc prolongation are suspected to increase the risk of a rare polymorphic ventricular tachyarrhythmia known as torsade de pointes. Torsade de pointes may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope or seizures. If sustained, torsade de points can progress to ventricular fibrillation and sudden cardiac death. The risk of torsade de points during treatment with a QT/QTc prolonging drug is increased in patients who are female or elderly (>=65 years). Particular care should be exercised when administering OptiMARK in patients who are at an increased risk of experiencing torsade de points. Risk factors for torsade de points include, but are not limited to, the following: Female age (>=65 years) presence of genetic variants affecting cardiac ion channels or regulatory proteins, especially congenital long QT syndrome (eg. Romano-Ward syndrome, Jervell and Lange-Nielsen syndrome, Anderson syndrome) family history of sudden cardiac death at <50 years cardiac disease (eg. myocardial ischemia or infarction, congestive heart failure, left ventricular hypertrophy, cardiomyopathy) demonstrated history of arrhythmias (especially ventricular arrhythmias, atrial fibrillation, or recent conversion from atrial fibrillation. bradycardia (<50 beats per minute) acute neurological events (e.g. intracranial or subarachnoid hemorrhage, stroke, intracranial trauma) electrolyte disturbances (e.g. hypokalemia, hypomagnesia, hypocalcemia) nutritional deficits (e.g. eating disorders, extreme diets) diabetes mellitus autonomic neuropathy hepatic or renal function, if relevant to the elimination of the drug (See also Drug-Drug Interactions) Physicians who prescribe drugs that prolong the QT/QTc interval should counsel their patients concerning the nature and implications of the EKG changes, underlying diseases and disorders that are considered to represent risk factors, demonstrated and predicted drug-drug interactions, symptoms of arrhythmias, risk management strategies, and other information relative to the use of the drug.

General

Diagnostic procedures involving the use of MRI contrast agents should be conducted under supervision 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 procedure, as well as for emergency treatment of severe reactions to the contrast itself. Patients should remain under observation for at least one hour after OptiMARK administration.

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/1.73m2), 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 enchance 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 370 patients with severe renal insufficiency who received gadodiamide, the estimated risk for development of NSF was 4% (J Am Soc Nephrol 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 re-administration. (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

See Toxicology section.

Cardiovascular

See Table 1 and Adverse Reactions Section. The most prevalant extreme cardiac event prior to and after the administration of OptiMARK was a prolonged PR interval (>200 msec). After the injection of OptiMARK, the frequency of prolonged PR intervals showed no dose-response relationship to the amount of contrast administered.

Dependence/Tolerance

The safety of repeated doses has not been studied.

Ear/Nose/Throat

See Table 1 and Adverse Reactions Section.

Endocrine and Metabolism

Genetic polymorphism with this product has not been studied.

Gastrointestinal

See Table 1 and Adverse Reactions Section.

Genitourinary

See Adverse Reactions Section.

Hematologic

Deoxygenated sickle erythrocytes have been shown 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 Gadoversetamide may possible potentiate sickle erythrocyte alignment. Gadoversetamide in patient with sickle cell anemia and other hemoglobinopathies has not been studied. Patients with other hemolytic anemias have not been adequately evaluated following administration of Gadoversetamide to exclude the possibility of increased hemolysis. See Table 2 for abnormal hematologic and clinical chemistry findings.

Hepatic/Biliary/Pancreatic

An alternate route of excretion frequently observed in patients with severe renal impairment receiving iodinated contrast media is the hepatobiliary enteric pathway. This has not been demonstrated with Gadoversetamide in humans but the existence of this pathway has been demonstrated in animals. Gadoversetamide has been shown to be removed from the body by hemodialysis.

Immune

See Warnings and Precautions Section.

Neurologic

See Table 1 and Adverse Reactions Section.

Ophthalmologic

No data available.

Peri-Operative Considerations

No data available.

Psychiatric

No data available.

Renal

Since Gadoversetamide is cleared from the body by glomerular filbration, caution should be exercised in patients with impaired renal function. Dose adjustments in renal impairment have not been studied. Exposure to GBCAs increases the risk for NSF in patients with:

• acute or chronic severe renal insufficiency (glomerular filtration rate <30 mL/min/1.73m2), 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

See Table 1 and Adverse Reactions section.

Sensitivity/Resistance

No data available.

Sexual Function/Reproduction

See Toxicology section.

Skin

See Adverse Reactions section. 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: Gadoversetamide was shown to cause a slight growth retardation in offspring of rats that received doses of 0.5 mmol/kg/day (1980 mg/m2) (0.8 times the clinical dose of 2442 mg/m2, 5 times the recommended human dose of 0.1 mmol/kg) for 5 weeks. Gadoversetamide has been shown to cause a slight increase in visceral abnormalities in the offspring of rabbits at doses of 0.4 and 1.6 mmol/kg/day (2904 and 11616 mg/m2) for 12 days and 4.8 times the clinical dose of 2442 mg/m2; 4 and 16 times the recommended human dose of 0.1 mmol/kg). The incidence of these abnormalities was comparable to that of historical control levels. There are no adequate and well-controlled studies in pregnant women. Gadoversetamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Women: 153

Gd-labelled Gadoversetamide was administered intravenously to lactating rats at a dose of 0.1 mmol/kg. A low but measurable lacteal transfer occurred in rats in a 24-hour period. The concentrations of radioactivity contained in the milk were low and decreased over time. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Gadoversetamide is administered to a nursing woman.

(See Serious Warnings and Precautions, General, Skin and Renal sections.)

Monitoring and Laboratory Tests

Blood pressure, laboratory or other tests are required to monitor response to therapy and possible adverse reactions. Please refer to Warnings and Precautions section above.

DRUG INTERACTIONS

Drug-Drug Interactions

Drug interactions with other contrast agents, other drugs were not studied. Pharmacokinetic studies were performed with non-fasted volunteers or patients. Pharmacokinetic studies between OptiMARK and other drugs that prolong the QT interval have not been performed. An interaction between these drugs and OptiMARK can not be excluded. Drugs that have been associated with QT/QTc prolongation and/or torsade de pointes include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, though not necessarily all, class members have been implicated in QT/QTc prolongation and/or torsade de pointes:

• Class IA antiarrhythmics (e.g. quinidine, procainamide, dispyramide)

• Class III antiarrhythmics (e.g. amiodarone, sotalol, ibutilide)

• Class IC antiarrhythmics (e.g. flecanide, propafenone)

• antipsychotics (e.g.chlorpromazine, pimozide, haloperidol, droperidol)

• tricyclic/tetracyclic antidepressants (e.g. amitripyline, imipramine, maprotiline)

• fluoxetine

• venlafaxine

• methadone

• macrolide antibiotics and analogues (e.g. erythromycin, clarithromycin, telithromycin)

• fluoroquinolone antibiotics (e.g. moxifloxacin, gatifloxacin)

• pentamide

• antimalarials (e.g. halofantrine, quinine)

• azole antifungals (e.g. ketoconazole, fluconazole, voriconazole)

• domperidone

• 5-HT3 antagonists (e.g. dolasetron, ondansetron)

• Tacrolimus

OptiMARK should be used with caution with drugs that can disrupt electrolyte levels, including, but not limited to, the following: loop, thiazide, and related diuretics amphotericin B high dose corticosteroids The above lists of potentially interacting drugs are not comprehensive. Current scientific literature should be consulted for newly approved drugs that prolong the QT/QTc interval or cause electrolyte disturbances, as well for older drugs for which these effects have recently been established.

Drug-Food Interactions

Not applicable for this product.

Drug-Herb Interactions

Not applicable for this product.

Drug-Laboratory Interactions

Transient changes in serum iron, calcium, copper and zinc parameters have been observed. The clinical significance is unknown. OptiMARK injection has been shown to cause colorimetric interference with the determination of calcium that results in an apparent decrease in serum concentrations.

Drug-Lifestyle Interactions

Not applicable for this product.

DOSAGE AND ADMINISTRATION

(Please see Storage and Stability and Dosage Forms, Composition and Packaging, Page 19.) Dosing Considerations

Table 3 - Dosage Chart for Gadoversetamide

Concurrent medications should not be physically mixed with contrast agents because of the potential for chemical incompatibility.

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.

Recommended Dose and Dosage Adjustment

Gadoversetamide should be administered as a bolus peripheral intravenous injection at a dose of 0.2 mL (0.1 mmol/kg), and at a rate of 1-2 mL/sec., delivered by manual or by power injector. Gadoversetamide should be drawn into the syringe and administered using sterile technique. If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents. To ensure complete injection of the contrast medium the injection should be followed by a 5 mL normal saline flush. Unused portions of the drug must be discarded. The imaging procedure should be completed within 1 hour of the injection of Gadoversetamide. The safety of repeat doses has not been studied. (See Pharmacodynamics and Clinical Trials.)

Missed Dose

Not applicable for this product.

Administration

According to the patient weight, the solution of OptiMARK may be taken from one vial or from one prefill syringe and the solution delivered intravenously by manual or power injector. Oral solutions: Not applicable Parenteral products: Direct intravenous injection

OVERDOSAGE

Clinical consequences of overdosage with Gadoversetamide have not been reported. Treatment of an overdose is directed toward the support of all vital functions and prompt institution of symptomatic therapy. Gadoversetamide has been shown to be dialyzable in a clinical study. Gadoversetamide does not undergo protein binding in vitro.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

OptiMARK Injection contains Gadoversetamide, a complex formed between a chelating agent (Versetamide) and a paramagnetic ion, gadolinium (III). Gadoversetamide is a paramagnetic agent, which develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment can enhance the relaxation rates of water protons in its vicinity, leading to an increase in signal intensity (brightness) of tissues. Gadoversetamide conforms to a two-compartment model as the mean of all distribution and elimination half lives, reported as the mean +- SD is 13.3 +- 6.8 and 103 +- 19.5 minutes. Gadoversetamide does not undergo metabolic degradation. It is eliminated by the kidneys by glomerular filtration. The kinetics of Gadoversetamide appear to be linear; protein binding appears to be absent. In pregnant rats, only minimal levels of radioactivity were detected in the placenta and the fetus.

Pharmacodynamics

In magnetic resonance imaging (MRI), visualization of normal and pathological brain, spinal and hepatic tissue depends in part on variations in the radiofrequency signal intensity that occurs with: 1) changes in proton density; 2) alterations of the spin-lattice or longitudinal relaxation time (T1); and 3) variation of the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, Gadoversetamide decreases T1 and T2 relaxation times in tissues where it accumulates. At usual doses the effect is primarily on T1 relaxation time, and produces an increase in signal intensity (brightness). Gadoversetamide does not cross the blood brain barrier, and, therefore, does not accumulate in the normal brain or in lesions that do not have abnormal blood-brain barrier or abnormal vascularity (e.g., cysts, mature post-operative scars, etc). However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of Gadoversetamide in the interstitial spaces of lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of Gadoversetamide in various lesions are not known. A dose-related increase in T1-signal intensity was seen in both CNS and liver studies.

Pharmacokinetics

Summary of OptiMARK's (Gadoversetamide) Pharmacokinetic Parameters in Study 1177-01 and 433

Table 3a Recalculated Non-compartmental PK Parameters - Study 1177-01 (Japan)

Table 3b Recalculated Non-compartmental PK Parameters - Study 433 (USA)

Absorption:

In all groups, Gadoversetamide was observed to distribute rapidly into the extracellular fluid volume following an intravenous bolus dose .The pharmacokinetics of intravenously administered Gadoversetamide in normal subjects conforms to a two-compartment open-model.

Distribution: Gadoversetamide does not undergo protein binding in vitro. In pregnant rats who received 153Gd-labelled Gadoversetamide, minimal levels of radioactivity were detected in the placenta and fetus. The volume of distribution at steady state of Gadoversetamide in normal subjects is 162 +- 25 mL/kg, roughly equivalent to that of extracellular water. [See Pregnant Women]

Metabolism:

There is no detectable biotransformation or decomposition of Gadoversetamide.

Excretion:

Gadoversetamide injection (0.1 mmol/kg) is eliminated primarily in the urine with

95.5 +- 17.4% (mean +- SD) of the administered dose eliminated by 24 hours. The renal and plasma clearance rates of Gadoversetamide are essentially identical (69 +- 15.4 and 72 +- 16.3 mL/hr/kg, respectively) in normal subjects indicating that the drug is essentially cleared through the kidneys via glomerular filtration. There was no systematic difference in any of the kinetic parameters as a function of dose level (0.1 to 0.7 mmol/kg). Therefore, within this dose range the kinetics of Gadoversetamide appear to be linear. The mean terminal elimination half-life in normal subjects was 1. 73 hrs. Gadoversetamide is removed from the body by hemodialysis. Approximately 98% of the administered dose (0.1 mmol/kg) was cleared from the circulation over the three dialysis sessions. The mean dialysis clearance of Gadoversetamide was 93.2 +- 17.1 mL/min., or 48% of the creatinine clearance (194 +- 18.6 mL/min. ), using a high flux PMMA membrane.

Table 4 - Elimination Profiles of Normal, Renally Impaired and Hepatically Impaired Men and Women (mean +- SD)

Special Populations and Conditions

Pediatrics:

Safety and pharmacokinetics in pediatric patients (2 - 18 years of age) have not been established.

Geriatrics:

Safety and pharmacokinetics in patients more than 76 years of age have not been established.

Gender:

There were no statistically significant differences in the elimination half-lives between men or women who were either healthy or who had renal or hepatic impairment (see Table 4).

Race:

Pharmacokinetic differences due to race after intravenous Gadoversetamide were not studied.

Hepatic Insufficiency:

A single intravenous dose of 0.1 mmol/kg of Gadoversetamide was administered to 5 subjects with impaired hepatic function (3 men and 2 women). Two patients had concurrent renal impairment. There was no difference in the plasma kinetics (see Table 4), when compared to normal subjects for patients with hepatic impairment. (See Detailed Pharmacology.)

Renal Insufficiency:

A single intravenous dose of 0.1 mmol/kg of Gadoversetamide was administered to 28 subjects with impaired renal function (17 men and 11 women). Sixteen patients had concurrent CNS or liver pathology. Renal impairment was demonstrated to delay the elimination of Gadoversetamide (see Table 4). The mean cumulative urinary excretion of Gadoversetamide at 72 hours was approximately 93.5% for renal impaired patients and 95.8% for subjects with normal renal function. (See Detailed Pharmacology.)

Genetic Polymorphism:

Special studies on genetic polymorphism have not been done.

STORAGE AND STABILITY

Gadoversetamide should be stored at controlled room temperature, 20EC to 25EC and protected from light and freezing. Its shelf life is 2 years.

SPECIAL HANDLING INSTRUCTIONS

Shipped product must be kept in controlled temperature between 20EC to 25EC and protected from freezing.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Gadoversetamide is provided as a sterile, nonpyrogenic, clear, colourless to pale yellow, aqueous solution of Gadoversetamide. No preservative is added. Each mL of Gadoversetamide contains mg of Gadoversetamide, 25.4 mg of Versetamide, 3.7 mg calcium hydroxide, 0.74 mg calcium chloride dihydrate, and water for injection. Sodium hydroxide and hydrochloric acid may be added for pH adjustment.

Glass Vials

Gadoversetamide is a clear, colourless to slightly yellow solution containing 330.9 mg/mL of Gadoversetamide. Gadoversetamide is supplied in 10 mL vials containing 5 mL or 10 mL of solution and is also provided in 20 mL vials containing 15 mL or 20 mL of solution. Each single dose vial is rubber stoppered with an aluminum seal and the contents are sterile. Vials are contained in shipping cartons with the following configurations: 5 mL in glass vials 10 mL in glass vials 15 mL in glass vials 20 mL in glass vials

Pharmacy Bulk Package: 50 mL Vial

For Multiple Dispensing

This pharmacy bulk package is not for direct infusion.

This Pharmacy Bulk Package is intended for multiple dispensing for intravenous use only, it must be spiked only once.

Directions for Use

Use proper aseptic techniques when handling injection device for maintenance of sterility during multiple dispensing contrast agent at room temperature.

The availability of the Pharmacy Bulk Package is restricted to hospitals with a recognized intravenous admixture program for multiple dispensing. Once the bottle has been penetrated, withdrawal of contents should be completed without delay. Discard the container no later than four (4) hours after initial entry.

Plastic Syringes

10 mL polypropylene syringe barrel 15 mL polypropylene syringe barrel 20 mL polypropylene syringe barrel 30 mL polypropylene syringe barrel

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Gadoversetamide Chemical name: [8,11-bis(carboxymethyl)-14-[2[(2-methoxyethyl) amino]-2-oxoethyl]-6-oxo-2-oxa-5,8,11,14-tetra azahexadecan-16- oato(3-)]gadolinium Molecular formula and molecular mass: 661.77 g/mol (molecular mass) Structural formula: Physicochemical properties: Empirical Formula: C20H34N5010Gd Physical Form: 5.5 to 7.5 (pH)

Description:

Gadoversetamide is the formulation of a nonionic gadolinium chelate of diethylenetriamine pentaacetic acid bismethoxyethylamide (Gadoversetamide), and is an injectable extracellular enhancing agent for magnetic resonance imaging (MRI). Gadoversetamide is to be administered by intravenous injection.

Table 5 - Physicochemical Data

Gadoversetamide has an osmolality approximately 3.9 times that of plasma (285 mOsm/kg water) and is hypertonic under conditions of use.

CLINICAL TRIALS

The safety and efficacy of Gadoversetamide was examined in 18 clinical studies. A total of 1684 subjects and patients were examined, with 1309 subjects and patients receiving Gadoversetamide (680 men and 629 women, mean age 49 years, age range 12 to 85 years, 84% white, 9% black, 2% Asian, and 4% of other races). However, the Phase 2 program was designed as pseudo cross over studies, patients in these studies received two separate and different doses of Gadoversetamide. Therefore, in the entire clinical program, 1309 subjects or patients received a total of 1663 injections. All safety data are presented by dose, therefore 354 patients are counted twice, raising the number of exposed patients to 2038 overall, and 729 in the Phase 2 studies. A total of 959 subjects and patients received the intended clinical dose of 0.1 mmol/kg Gadoversetamide.

Study demographics and trial design

Of these, 790 patients were enrolled in four comparative Phase 3 pivotal studies that were designed and analyzed to demonstrate the safety and equivalence of 0.1 mmol/kg Gadoversetamide and 0.1 mmol/kg Magnevist(r) for use during CNS and hepatic magnetic resonance imaging (MRI). In these comparative studies, 461 adult patients received OptiMARK Injection and 329 patients received Magnevist(r). For the Gadoversetamide treatment group, 252 (55%) patients were men and 209 (45%) were women; 83% white, 9% black, 3% Asian and 5% other races.

Table 6- Summary of patient demographics for clinical trials in specific indication

Pre-contrast and pre- plus post-contrast images were examined and evaluated for confidence in the diagnosis(es), level of conspicuity of all lesions, and the ability to delineate lesion borders from parenchyma/structures. Blinded review of pre- and pre- plus post-contrast images revealed statistically significant increases for confidence in the diagnosis(es), level of conspicuity of all lesions, and the ability to delineate lesion borders from parenchyma/structures. In addition, the results for Gadoversetamide were shown to be equivalent to Magnevist(r). (See Table 7.)

Table 7 Results of study #488 in specific indication

The safety and pharmacokinetics of a single does of 0.1 mmol/kg Gadoversetamide was studied in 54 patients (27 males and 27 females); 13 patients with renal impairment, 12 patients each with CNS or liver pathology, 8 patients without CNS or liver pathology, 7 patients with CNS pathology and renal impairment; and 2 patients with liver pathology and renal impairment. There were no clinically significant differences in safety observations (adverse events, tolerance, ECGs, laboratory parameters, physical examinations, or vital signs) between the risk subgroups, and only renal impairment was observed to have an effect on drug elimination. In another study, a single intravenous dose of 0.1 mmol/kg of Gadoversetamide was administered to 8 adult subjects (7 males, 1 female) maintained on chronic hemodialysis and was found to be well-tolerated and dialyzable. Approximately 98% of the administered dose of 0.1 mmol/kg of Gadoversetamide was removed from the body over three consecutive hemodialysis sessions. In clinical trials, doses up to 0.7 mmol/kg were safely administered. The highest dose any individual patient received was 118 mL at a dose of 0.5 mmol/kg.

Effect on QTc Interval

Study 774

A Double-Masked, Randomized, Multicenter, Phase 2 Dose Ranging Study to Evaluate the Safety and Efficacy of OptiMARK

The most common AE was QT/QTc prolongation (14/28 events). There was a statistically significant change (Fridericia's correction) at 1hour post dose (p<0.05) in the 0.05 mmol/kg and the 0.2 mmol/kg dose group; at 2 hours in the 0.1 mmol/kg , 0.2 mmol/kg and 0.3 mmol/kg dose groups. No statistically significant changes were seen at 24 hours post dose.

Table 8 a

Study 774:

Mean (90% CI) Change from Baseline for QTc Intervals (msec) (Fridericia's Correction)

Denotes a statistically significant (P<0.05) change from baseline

Four patients in total had QTc increases of 60 msec. There were 4, 7, 11, 8 in the respective dose groups who had increases of 31-60msec. (See Table 8b)

Eighteen patients had a QTc of >450 msec prior to the study drug and at the 2 hour point, 27 patients had a QTc>450msec. The number returned to the baseline number at 24 hours. This number did not appear to be dose dependent.

Study 775

A Double-Masked, Randomized, Multicenter, Phase 2 Dose Ranging Study to Evaluate the Safety and Efficacy of OptiMARK

The most common AE was QT prolongation (11 patients). There was a statistically significant change (Fridericia's correction) at 1hour post dose (p<0.05) in the 0.05 mmol/kg,the 0.2 mmol/kg and 0.3 mmol/kg dose group; at 2 hours in the 0.2 mmol/kg dose groups. No statistically significant changes were seen at 24 hours post dose.

Table 8 c

Study 775:

Mean (90% CI) Change from Baseline for QTc Intervals (msec) (Fridericia's Correction)

• Denotes a statistically significant (P<0.05) change from baseline

4 patients had an increase of QTc>60msec and 42 patients had an increase from 31-60 seconds. Patients with the duration of QTc interval >450msec were 8 patients prior to injection and 12, 14 and 12 patients at the 1, 2, and 24 hour mark post injection, respectively.

DETAILED PHARMACOLOGY

Pharmacodydnamics

Non-clinical: In vitro and In vivo

The nonclinical data demonstrate that OptiMARK has identical relaxation properties, biodistribution, and signal enchancement in animal models which is similar to other gadolinium- based MRI agents.

Pharmacokinetics

Non-clinical: In vitro and In vivo

Human blood compatibility and plasma protein binding were assessed in 4 non-clinical studies. These studies demonstrate that OptiMARK is compatible with human blood and does not bind to human plasma proteins to any detectable extent.

Clinical: In vivo

A placebo controlled, double-blind, ascending dose (0.1, 0.3, 0.5 and 0.7 mmol/kg) Phase 1 study (433) was conducted in 20 healthy male volunteers. Serum and urine concentrations were used to estimate pharmacokinetic parameters and total recovery (%) of the gadolinium dose. The pharmacokinetic parameters of OptiMARK demonstrated linearity across the dose range tested and were consistent with values reported for other gadolinium contrast agents. Total clearance of OptiMARK did not vary with dose and was not significantly different from renal drug clearance or creatinine clearance. The apparent volume of distribution for OptiMARK was consistent with the volume of extracellular water. The total 72-hour recovery of the administered dose was greater than 90% and consistent with values reported for similar gadolinium agents. Serum and urine samples analyzed by HPLC showed no evidence of metabolic transformation. A second Phase I, open-label, single dose, multicenter study (538) evaluated pharmacokinetics and elimination of OptiMARK in six groups of patients with different combinations of CNS, liver or renal disease all receiving 0.1 mmol/kg of OptiMARK.. Pharmacokinetic parameters were calculated from plasma and urine concentrations of gadoversetamide. The apparent elimination half-life of OptiMARK was significantly longer (8hours) in renally impaired patients compared to patients with normal renal function (including CNS and liver patients) and normal subjects (2 hours). The relationship between total clearance of OptiMARK and baseline creatinine clearance indicated that the degree of renal impairment alone determined the magnitude of increased exposure to OptiMARK. Decreases in renal function did not affect the volume of distribution of OptiMARK. Analytical analysis of the urine showed that gadoversetamide was excreted as the intact complex indicating the absence of OptiMARK metabolism. The only other pathology which might be reasonable hypothesized to have any effect on the disposition was liver insufficiency because of a small secondary route of elimination (hepatobiliary) has been observed in animal studies. For the patients with decreased liver function, no effect on pharmacokinetic parameters was seen. A multi-center, double-blind, randomized, parallel-group (0.1, 0.3, 0.5 mmol/kg) study (489) evaluated the dose related effects of OptiMARK in patients with existing CNS or liver pathology, with or without renal insufficiency. Serum and urine samples were collected and measured for gadolinium content. Non-compartmental pharmacokinetic parameters were calculated from these data. The pharmacokinetic analysis showed that the exposure to OptiMARK (AUC) was proportional to the dose; the elimination half-life, clearance and volume of distribution were dose independent. In patients with normal renal function with CNS or liver disease neither sex and age nor pathology had an effect on the pharmacokinetics of OptiMARK. In subjects with renal impairment the degree of exposure, elimination half-life and clearance were dependent on the degree of renal impairment. Patients with moderate to severe renal impairment showed an approximately 2 - 4 fold (based on AUC) increase in exposure as compared to patients without renal disease. A single center study (543) was carried out to evaluate the pharmacokinetic behavior of OptiMARK in renally compromised patients requiring hemodialysis. Blood and dialysate were collected during regular dialysis sessions after OptiMARK (0.1 mmol/kg) administration and analyzed for gadolinium content. These data were used to evaluate the elimination of OptiMARK. The dialysis half-life of OptiMARK was 1.7 hours with an estimated recovery in the dialysate of approximately 48% the creatinine clearance. At the end of the 5-day period about 98% of the OptiMARK was cleared from the plasma with about 70% recovered in the dialysis fluid demonstrating that OptiMARK can be efficiently removed by extracorporeal hemodialysis. OptiMARK is eliminated primarily in the urine at a rate consistent with glomerular filtration. Renal function significantly affects the rate of OptiMARK elimination such that the more severe the renal impairment, the longer the elimination half-life and the greater the amount of systemic exposure. Data from these studies show that although poor renal function may delay the elimination of OptiMARK from the body, no clinical consequences result from the prolonged exposure. The pharmacokinetic studies demonstrate that OptiMARK distributes quickly into the extracellular space and has biodistribution and elimination characteristics similar to other extracellular MRI contrast agents. After intravenous administration, these contrast agents equilibrate rapidly within the extracellular fluid/space and are eliminated primarily by glomerular filtration.

MICROBIOLOGY

There was no special microbiology studies done except on the finished product at the time of the release.

TOXICOLOGY

The non-clinical studies in acute, subacute or in special related studies, indicate that Gadoversetamide has a very good safety profile at doses which significantly exceed the intended clinical dose. The acute toxicity of Gadoversetamide was evaluated in mice, rats and dogs. The LD50 value in mice was 28 mmol/kg; the maximum non-lethal dose of Gadoversetamide in mice was 14 mmol/kg, and the no-observable-effect-level (NOEL) in dogs was 3 mmol/kg. The CNS toxicity of Gadoversetamide, used to enhance CNS lesions which disrupt the blood- brain barrier (BBB), was evaluated in rats by direct injection into the cerebrospinal fluid at the cisterna magna. The estimated combined median lethal intracisternal dose (LD50) was 166 mol/kg (0.166 mmol/kg) which is comparable to that of Omniscan(r) (147 mol/kg) and substantially greater than that of ProHance(r) (27 mol/kg), commercially available nonionic extracellular MR contrast agents. The subacute toxicity of Gadoversetamide was evaluated in rats and in dogs in a 28 day study with a 4-week and an 8-week recovery period for rats and an 8-week recovery period for dogs. These studies used an early formulation of Gadoversetamide designated MP-1177/10T. Micro-vacuolation of the proximal convoluted tubules of the kidneys of rats and dogs was observed in high dose animals at the completion of dosing. This change was not associated with any signs of renal dysfunction and was not seen following recovery. This is considered a benign histological finding consistent with the findings of studies with other MR contrast media. Microscopic examination of the testes and epididymides of male rats in the high dose group at the end of the dosing period showed degeneration of the testicular germinal epithelium with the presence of spermatid giant cells and markedly reduced sperm content in the epididymides. Similar testicular alterations were also observed in a multiple-dose (3 weeks, 3 times per week) intravenous toxicity study of Omniscan7, an approved agent, in rats. In a reproductive toxicity study in rats, a loss of germinal epithelium was observed in male rats receiving a dose of 2.0 mmol/kg/day (7920 mg/m2) of Gadoversetamide (3.2 times the clinical dose of 2442 mg/m2 based on body surface area, 20 times the recommended human dose of 0.1 mmol/kg) for approximately 50 days. There was irreversible loss of germinal epithelium in the majority of seminiferous tubules after 8 or 19 weeks of recovery. There was, however, some evidence of recovery of spermatogenesis in the remaining tubules. Gadoversetamide was shown to cause a slight growth retardation in offspring of rats that received doses of 0.5 mmol/kg/day (1980 mg/m2) (0.8 times the clinical dose of 2442 mg/m2, 5 times the recommended human dose of 0.1 mmol/kg) for 5 weeks. Gadoversetamide has been shown to cause a slight increase in visceral abnormalities in the offspring of rabbits at doses of and 1.6 mmol/kg/day (2904 and 11616 mg/m2) for 12 days (1.2 and 4.8 times the clinical dose of 2442 mg/m2; 4 and 16 times the recommended human dose of 0.1 mmol/kg). The incidence of these abnormalities was comparable to that of historical control levels.

Gd-labeled Gadoversetamide was administered intravenously to lactating rats at a dose of 0.1 mmol/kg. A low but measurable lacteal transfer occurred in rats in a 24-hour period. The concentrations of radioactivity contained in the milk were low and decreased over time.

The results of both in vivo and in vitro studies have clearly demonstrated that Gadoversetamide does not bind to proteins in human, dog, or rat plasma and is compatible with the erythrocyte and plasma components of human blood. In anephric rats, greater than 12% of the dose was associated with liver and gastrointestinal tract compared to less that 2.5% of the dose in normal rats indicating that the hepatobiliary system is available as a secondary route of elimination.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Long-term animal studies have not been performed to evaluate the carcinogenic potential of Gadoversetamide. The results of the following genotoxicity assays were negative: Salmonella/E. Coli reverse mutation (Ames) assay, mouse lymphoma mutagenesis assay, CHO chromosome aberration assay, and the in vivo mammalian micronucleus assay. In a reproductive toxicity study in rats, a loss of germinal epithelium was observed in male rats receiving a dose of 2.0 mmol/kg/day (7920 mg/m2) of Gadoversetamide (3.2 times the clinical dose of 2442 mg/m2 based on body surface area, 20 times the recommended human dose of 0.1 mmol/kg) for approximately 50 days. There was irreversible loss of germinal epithelium in the majority of seminiferous tubules after 8 or 19 weeks of recovery. There was, however, some evidence of recovery of spermatogenesis in the remaining tubules.

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