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Optimark (Gadoversetamide) - Description and Clinical Pharmacology

 
 



OptiMARK Pharmacy Bulk Package
OptiMARK 0.5 mmol/mL
(Gadoversetamide Injection)

OptiMARK
(gadoversetamide injection)
For Intravenous Injection Only

Mallinckrodt Inc.


PRESCRIBING INFORMATION

Mallinckrodt Inc.
September 2008

Rx only

PHARMACY BULK PACKAGE - NOT FOR DIRECT INFUSION


DESCRIPTION

OptiMARK (gadoversetamide injection) is a formulation of a nonionic gadolinium chelate of diethylenetriamine pentaacetic acid bismethoxyethylamide (gadoversetamide), for use in magnetic resonance imaging (MRI). OptiMARK Injection is to be administered by intravenous injection only.

OptiMARK Injection is provided as a sterile, nonpyrogenic, clear, colorless to pale yellow, aqueous solution of gadoversetamide. No preservative is added. Each mL of OptiMARK Injection contains 330.9 mg of gadoversetamide (0.5 millimole), 28.4 mg of calcium versetamide sodium (0.05 millimole), 0.7 mg calcium chloride dihydrate (0.005 millimole), and water for injection. Sodium hydroxide and/or hydrochloric acid may have been added for pH adjustment.

OptiMARK Injection is designated chemically as [8, 11-bis(carboxymethyl)-14-[2-[(2-methoxyethyl)amino]-2-oxoethyl]-6-oxo-2-oxa-5,8,11,14-tetraazahexadecan-16-oato(3-)] gadolinium with a formula weight of 661.77 g/mol and empirical formula of C20H34N5O10Gd. The structural formula of gadoversetamide in aqueous solution is:

OptiMARK Injection has a pH of 5.5 to 7.5 and pertinent physiochemical data are provided below:

Table 1: Physiochemical Data
Osmolality (mOsmol/kg water) @ 37°C1110
Viscosity (cP)
                      @ 20°C3.1
                      @ 37°C2.0
Density (g/mL) @ 25°C1.160

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

CLINICAL PHARMACOLOGY

General

OptiMARK Injection contains gadoversetamide, a complex formed between a chelating agent (versetamide) and a paramagnetic ion, gadolinium (III). Gadoversetamide is a paramagnetic agent that 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.

Pharmacokinetics

The pharmacokinetics of intravenously administered gadoversetamide in normal subjects conforms to a two-compartment open-model with mean distribution and elimination half-lives (reported as mean ± SD) of about 13.3 ± 6.8 and 103.6 ± 19.5 minutes.

Distribution

Gadoversetamide does not undergo protein binding in vitro. In pregnant and lactating rats which received 153Gd-labeled gadoversetamide, radioactivity was detected in the placenta, fetus, and maternal milk (see PRECAUTIONS, Pregnancy Category C and Nursing Mothers). 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 PRECAUTIONS, Pregnancy Category C).

Metabolism

Biotransformation or decomposition of gadoversetamide was not detected.

Elimination

Gadoversetamide (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. Animal data demonstrated that insignificant levels of radioactive [153Gd] MP-1177/10 are eliminated via the feces. In experimentally induced anephria in the rat, hepatobiliary excretion did not significantly compensate for the absence of urinary elimination. The renal and plasma clearance rates of gadoversetamide in normal subjects are essentially identical (69 ± 15.4 and 72 ± 16.3 mL/hr/kg, respectively) indicating that the drug is essentially cleared through the kidneys via glomerular filtration. Within the studied dose range (0.1 to 0.7 mmol/kg), the kinetics of gadoversetamide appear to be linear (see PRECAUTIONS).

Special Populations

Renal Insufficiency: A single intravenous dose of 0.1 mmol/kg of OptiMARK Injection was administered to 28 (17 men and 11 women) patients with impaired renal function (mean serum creatinine of 2.4 mg/dL). Sixteen patients had concurrent central nervous system or liver pathology. Renal impairment was shown to delay the elimination of gadoversetamide (see Table 2). 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 CLINICAL PHARMACOLOGY, Elimination and Hemodialysis ).

Hemodialysis: 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 that occurred 2 hours, 48 hours, and 120 hours after injection. After each of three dialysis sessions, respectively, 70%, 93%, and 98% of the administered dose was cleared from the plasma. 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 (see CLINICAL PHARMACOLOGY, Special Populations and Elimination, PRECAUTIONS).

Hepatic Insufficiency: A single intravenous dose of 0.1 mmol/kg of OptiMARK Injection was administered to 4 (2 men and 2 women) patients with impaired hepatic function. Hepatically impaired patients with normal renal function had plasma kinetics similar to normal subjects (see Table 2).

Gender

Gender differences were not statistically significant within the hepatically impaired or renally impaired subgroups (see Table 2).

Table 2: Elimination Profiles of Normal, Renally Impaired and Hepatically Impaired Men and Women (mean ± SD)
PopulationElimination t 1/2 (hours)
Men (N = 52)Women (N = 48)
Healthy Volunteers1.73 ± 0.31 (N = 8)1.73 ± 0.40 (N = 4)
Normal Patients1.90 ± 0.50 (N = 25)1.94 ± 0.57 (N = 31)
Renally Impaired8.74 ± 5.14 (N = 17)6.91 ± 2.46 (N = 11)
Hepatically Impaired2.09 ± 0.03 (N = 2)2.35 ± 1.09 (N = 2)

Age

Pharmacokinetic parameters were retrospectively evaluated in 121 patients with a mean age of 46 years (range 18 to 76 years). In these patients, age related effects on pharmacokinetic parameters were not observed.

Race

Pharmacokinetic differences due to race after intravenous OptiMARK Injection were not studied.

Drug-Drug Interactions

Drug interactions have not been studied.

Dietary Effects

Dietary effects on the pharmacokinetics of OptiMARK Injection have not been studied.

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 the recommended dose, the effect is primarily on T1 relaxation time, and produces an increase in signal intensity (brightness).

OptiMARK Injection does not cross the intact blood brain barrier, and, therefore, does not accumulate in the normal brain or in lesions that may have a normal blood-brain barrier (e.g., cysts, mature post-operative scars, etc.). However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of OptiMARK Injection in the extravascular spaces of lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of OptiMARK Injection in various lesions are not known.

Clinical Trials

A total of 790 patients were evaluated in 4 controlled clinical trials (two liver and two central nervous system studies) of OptiMARK Injection. Of these 790 patients, 461 received OptiMARK Injection. Of the 461 OptiMARK patients, there were 252 men and 209 women with a mean age of 49 years (range 12 to 82 years). The racial and ethnic representations were 83% Caucasian, 9% Black, 3% Asian, and 5% other racial or ethnic groups. These trials were designed to evaluate the results of combined non-contrast MRI and OptiMARK Injection 0.1 mmol/kg contrast MRIs in comparison to non-contrast MRI alone.

In the two controlled central nervous system (CNS) studies, 395 eligible patients were highly suspect for CNS disorders and had an abnormal entry contrast MRI. After enrollment, patients were randomized to receive repeat MRI evaluations with OptiMARK Injection 0.1 mmol/kg or with 0.1 mmol/kg of an approved gadolinium contrast agent. Of these 395 patients, 262 received OptiMARK Injection and 133 received the approved gadolinium contrast agent. The studies were not prospectively designed to demonstrate superiority or equivalence of either imaging drug. Approximately 40% and 25% of the patients that were enrolled in Study A and B, respectively, had a history of either surgery, biopsy, and/or radiation, and/or chemotherapy.

Pre-contrast and pre-plus-post-contrast images were independently evaluated by three blinded readers (each reader examined approximately 1/3 of the images). The images were evaluated by the blinded readers for the following endpoints using a scale from 1 to 10: the level of conspicuity of all lesions, the ability to delineate lesion borders from parenchyma/structures, the number of lesions, and the confidence in the number of lesions. As shown in Table 3, the first row of each endpoint group represents the difference in the mean score of the combined pre- and post-contrast MRI from the mean score of the pre-contrast MRI alone. Also, the table shows the number of patients whose paired MRI images were better, worse or the same as the pre-contrast MRI. Results from the contrast image alone were not evaluated. In Table 3 for these endpoints, when read in combination with the noncontrast images, OptiMARK Injection provided a statistically significant improvement over baseline. In addition to these measures, the images were evaluated for the blinded reader's confidence in the diagnosis. Although improvement over baseline was noted, the diagnosis was not rigorously confirmed.

Table 3: Results of MRI Central Nervous System Studies with 0.1 mmol/kg OptiMARK Injection

(a) Difference of means = (Side-by-side pre and post OptiMARK mean) - (pre mean)

(b) Pair = Side-by-side pre and post OptiMARK

* Statistically significant for both the median (Wilcoxon test) and mean (paired t test)

◊ Statistically significant for median (Wilcoxon test)

† 1 patient was excluded from this analysis because a non-contrast image was not obtained for that patient

Study AStudy B
EndpointsOptiMARK
N = 132 †
OptiMARK
N = 129
Conspicuity:
Difference of Means (a)0.39*0.66*
   Worse24 (18%)24 (19%)
   Same69 (52%)52 (40%)
   Better39 (30%)53 (41%)
Border Delineation:
Difference of Means0.70*0.86*
   Worse23 (17%)25 (19%)
   Same55 (42%)51 (40%)
   Better54 (41%)53 (41%)
Number of Lesions:
Difference of Means
   Pre1.83.0
   Pair (b)2.0◊3.3*
   Worse9 (7%)16 (12%)
   Same101 (77%)86 (67%)
   Better22 (16%)27 (21%)
Confidence in Number of Lesions:
Difference of Means0.11*0.56*
   Worse19 (14%)18 (14%)
   Same86 (65%)60 (47%)
   Better27 (20%)51 (40%)

In the two controlled liver studies of 395 patients, all eligible patients had a contrast CT that was considered highly suspect for a liver abnormality(ies). Of these 395 patients, 199 received OptiMARK Injection 0.1 mmol/kg. Patients had both pre-contrast and post-contrast MRI scans covering the entire liver. In each study, the images were read by 3 blinded readers (each reader examined approximately 1/3 of the images). Using a scale of 1 to 10, the images were evaluated by the blinded readers for the level of conspicuity of all lesions, the ability to delineate lesion borders from parenchyma/structures, the number of lesions and confidence in the number of lesions. The results are shown in Table 4.

The first row of each endpoint group represents the difference in the mean score of the combined pre- and post-contrast MRI from the mean score of the pre-contrast MRI alone. Also, the table shows the number of patients whose paired MRI images were better, worse or the same as the pre-contrast MRI. Results from the contrast image alone were not evaluated. As shown in Table 4 for these endpoints, when read in combination with the noncontrast image, OptiMARK Injection provided a statistically significant improvement over noncontrast images. In addition to these measures, the images were evaluated for the blinded reader's confidence in the diagnosis. Although improvement over baseline was noted, the trial was not designed to rigorously confirm the diagnosis.

Table 4: Results of MRI Liver Studies with 0.1 mmol/kg OptiMARK Injection

(a) Difference of means = (Side-by-side pre and post OptiMARK mean) - (pre mean)

(b) Pair = Side-by-side pre and post OptiMARK

* Statistically significant for both the median (Wilcoxon test) and mean (paired t test)

† Borderline statistical significance in paired t test

Study CStudy D
EndpointsOptiMARK
N = 99
OptiMARK
N = 100
Conspicuity:
Difference of Means (a)0.77*0.75*
   Worse21 (21%)14 (14%)
   Same37 (37%)50 (50%)
   Better41 (41%)36 (36%)
Border Delineation:
Difference of Means0.77*0.69*
   Worse21 (21%)15 (15%)
   Same38 (38%)45 (45%)
   Better40 (40%)40 (40%)
Number of Lesions:
Difference of Means
   Pre2.43.5
   Pair (b)3.0*3.8†
   Worse13 (13%)16 (16%)
   Same50 (51%)58 (58%)
   Better36 (36%)26 (26%)
Confidence in Number of Lesions:
Difference of Means1.6*1.0*
   Worse39 (39%)38 (38%)
   Same2 (2%)8 (8%)
   Better58 (59%)54 (54%)

A subsequent study of 140 normal volunteers evaluated the safety of OptiMARK Injection 0.1 mmol/kg delivered by power injector. Imaging results were not studied. The normal volunteers were randomized to receive OptiMARK injected manually, or OptiMARK or saline injected at 3 different power injector rates. At 2 mL/sec, the adverse event rates were comparable in the OptiMARK and saline controls when delivered manually and by power injector. In these small sample sizes, there was a trend towards increasing adverse events with increasing rates of power injection. Patients with abnormal vascularity were not evaluated. The safety and efficacy of power injector rates higher than 2 mL/sec has not been established.

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