OMNISCAN (Page 3 of 5)

6.2 Clinical Studies Experience (Pediatrics)

In the 97 pediatric patients in CNS studies with OMNISCAN [see Clinical Studies (14.1)] and the 144 pediatric patients in published literature, the adverse reactions were similar to those reported in adults.

6.3 Postmarketing Experience

Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified during the postmarketing use of OMNISCAN:

Nervous System Disorders: Inadvertent intrathecal use causes convulsions, coma, paresthesia, paresis. Convulsions have also been reported with intravenous use in patients with and without a history of convulsions or brain lesions.

General Disorders: Nephrogenic Systemic Fibrosis (NSF) [see Warnings and Precautions (5.2)].

Adverse events with variable onset and duration have been reported after GBCA administration [ see Warnings and Precautions (5.4)]. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems.

Renal and Urinary System Disorders: In patients with pre-existing renal insufficiency: acute renal failure, renal impairment, blood creatinine increased [see Warnings and Precautions (5.5)].

Skin: Gadolinium associated plaques.

7 DRUG INTERACTIONS

Specific drug interaction studies have not been conducted.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive. Because of the potential risks of gadolinium to the fetus, use OMNISCAN only if imaging is essential during pregnancy and cannot be delayed.

Contrast enhancement is visualized in the human placenta and fetal tissues after maternal GBCA administration.

Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported a clear association between GBCAs and adverse effects in the exposed neonates. However, a retrospective cohort study, comparing pregnant women who had a GBCA MRI to pregnant women who did not have an MRI, reported a higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include a lack of comparison with non-contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy.

GBCAs administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, liver, kidney, and spleen for at least 7 months. GBCAs administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one month postnatal age.

OMNISCAN has been shown to have an adverse effect on embryo-fetal development in rabbits at dosages as low as 0.5 mmol/kg/day for 13 days during gestation (approximately 0.6 times the human dose based on a body surface area comparison). These adverse effects are observed as an increased incidence of flexed appendages and skeletal malformations which may be due to maternal toxicity since the body weight of the dams was reduced in response to OMNISCAN administration during pregnancy. In rat studies, fetal abnormalities were not observed at doses up to 2.5 mmol/kg/day for 10 days during gestation (1.3 times the maximum human dose based on a body surface area comparison); however, maternal toxicity was not achieved in these studies and a definitive conclusion about teratogenicity in rats at doses above 2.5 mmol/kg/day cannot be made.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, exercise caution when administering OMNISCAN to a nursing woman.

8.4 Pediatric Use

The safety and efficacy of OMNISCAN at a single dose of 0.05 to 0.1 mmol/kg have been established in pediatric patients over 2 years of age based on adequate and well controlled studies of OMNISCAN in adults, a pediatric CNS imaging study, and safety data in the scientific literature. However, the safety and efficacy of doses greater than 0.1 mmol/kg and of repeated doses have not been studied in pediatric patients.

Pharmacokinetics of OMNISCAN have not been studied in pediatrics. The glomerular filtration rate of neonates and infants is much lower than that of adults. The pharmacokinetics volume of distribution is also different. Therefore, the optimal dosing regimen and imaging times in patients under 2 years of age have not been established.

8.5 Geriatric Use

In clinical studies of OMNISCAN, 243 patients were between 65 and 80 years of age while 15 were over 80. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity in the elderly cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

OMNISCAN is excreted by the kidney, and the risk of toxic reactions to OMNISCAN may be greater in patients with impaired renal function [see Warnings and Precautions (5.4)]. Because elderly patients are more likely to have decreased renal function, select dose carefully and consider assessment of renal function before OMNISCAN use.

8.6 Renal/Hepatic Impairment

Dose adjustments in renal or hepatic impairment have not been studied. Caution should be exercised in patients with impaired renal insufficiency [see Warnings and Precautions (5.2, 5.5)].

10 OVERDOSAGE

Clinical consequences of overdose with OMNISCAN have not been reported. The minimum lethal dose of intravenously administered OMNISCAN in rats and mice is greater than 20 mmol/kg (200 times the recommended human dose of 0.1 mmol/kg; 67 times the cumulative 0.3 mmol/kg dose). OMNISCAN is dialyzable.

11 DESCRIPTION

OMNISCAN (gadodiamide) Injection is the formulation of the gadolinium complex of diethylenetriamine pentaacetic acid bismethylamide, and is an injectable, nonionic extracellular enhancing agent for magnetic resonance imaging. OMNISCAN is administered by intravenous injection.

OMNISCAN is provided as a sterile, clear, colorless to slightly yellow, aqueous solution. Each 1 mL contains 287 mg gadodiamide and 12 mg caldiamide sodium in Water for Injection. The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide. OMNISCAN contains no antimicrobial preservative. OMNISCAN is a 0.5 mol/L solution of aqua[5,8-bis(carboxymethyl)-11-[2-(methylamino)-2-oxoethyl]-3-oxo-2,5,8,11-tetraazatridecan-13-oato (3-)-N5 , N8 , N11 , O3 , O5 , O8 , O11 , O13 ] gadolinium hydrate, with a molecular weight of 573.66 (anhydrous), an empirical formula of C16 H28 GdN5 O9 ∙xH2 O, and the following structural formula:

Chemical Structure
(click image for full-size original)

Pertinent physicochemical data for OMNISCAN are noted below:

PARAMETER
Osmolality (mOsmol/kg water)@ 37°C789
Viscosity (cP)@ 20°C2
@ 37°C1.4
Density (g/mL)@ 25°C1.14
Specific gravity@ 25°C1.15

OMNISCAN has an osmolality approximately 2.8 times that of plasma at 37°C and is hypertonic under conditions of use.

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