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Optimark (Gadoversetamide) - Warnings and Precautions

 
 



WARNING: NEPHROGENIC SYSTEMIC FIBROSIS

Gadolinium-based contrast agents 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 gadolinium-based contrast agents 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 gadolinium-based contrast agent, 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 WARNINGS).

 

WARNINGS

Deoxygenated sickle erythrocytes have been shown in vitro studies to align perpendicular to a magnetic field; this may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by gadoversetamide may potentiate sickle erythrocyte alignment. OptiMARK Injection in patients with sickle cell anemia and other hemoglobinopathies has not been studied.

The potential risk of hemolysis after injection of OptiMARK Injection in patients with other hemolytic anemias has not been studied.

Patients with history of allergy, renal insufficiency or drug reaction should be observed for several hours after drug administration (see PRECAUTIONS).

Nephrogenic Systemic Fibrosis (NSF)

Gadolinium-based contrast agents 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 gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced MRI. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a gadolinium-based contrast agent in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention of NSF is unknown.

Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a gadolinium-based contrast agent and the degree of renal function impairment at the time of exposure.

Post-marketing reports have identified the development of NSF following single and multiple administrations of gadolinium-based contrast agents. These reports have not always identified a specific agent. Where a specific agent was identified, the most commonly reported agent was gadodiamide (Omniscan), followed by gadopentetate dimeglumine (Magnevist®) and gadoversetamide (OptiMARK). NSF has also developed following sequential administrations of gadodiamide with gadobenate dimeglumine (MultiHance®) or gadoteridol (ProHance®). 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 gadolinium-based contrast agent.

The extent of risk for NSF following exposure to any specific gadolinium-based contrast agent 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 the 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.

Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent prior to any readministration (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

PRECAUTIONS

General

Some paramagnetic contrast agents may impair the visualization of existing lesions, which are seen on the unenhanced, noncontrast MRI. This may be due to effects of the paramagnetic contrast agent, imaging parameters, misregistration, etc. CAUTION SHOULD BE EXERCISED WHEN A CONTRAST ENHANCED INTERPRETATION IS MADE IN THE ABSENCE OF A COMPANION UNENHANCED MRI.

Since gadoversetamide is cleared from the body by glomerular filtration, caution should be exercised in patients with impaired renal function. Dose adjustments in renal impairment have not been studied. Dialysis may be needed to clear OptiMARK Injection if it is administered to patients with significant renal impairment. OptiMARK Injection has been shown to be removed from the body by hemodialysis (see CLINICAL PHARMACOLOGY, Elimination and Special Populations, Renal Insufficiency).

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

Repeat procedures: The safety of repeated doses has not been studied.

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 complication of the procedure, as well as for emergency treatment of severe reactions to the contrast itself.

Information For Patients

Patients receiving OptiMARK Injection should be instructed before injection to:

  1. Inform their physician or health care provider if they are pregnant or breast feeding (see PRECAUTIONS, Pregnancy Category C and Nursing Mothers).
  2. Inform their physician or health care provider if they have a history of renal disease, anemia, hemoglobinopathies, or diseases that affect red blood cells.
  3. Inform their physician or health care provider if they have a history of asthma or allergic respiratory disorders, seizures, or heart disease.
  4. Inform their physician or health care provider of all medications they may be taking.

Drug Interactions

Drug interactions with other contrast agents and other drugs have not been studied.

Laboratory Test Interactions

Interference by OptiMARK Injection in the measurement of serum iron, copper and zinc has been observed. OptiMARK Injection causes interference in the measurement of serum calcium using the ortho-cresophthalin complexone (OCP) colorimetric method. In the presence of OptiMARK Injection, OCP produces an erroneous, low value for serum calcium. The magnitude of this artifact is proportional to the concentration of OptiMARK Injection in the blood, and accurate values can be obtained approximately 90 minutes following injection. In patients with renal insufficiency, clearance of OptiMARK Injection is slowed and the interference with calcium determination by OCP is prolonged. Neither the arsenazo III dye system nor the inductively coupled plasma mass spectroscopy methods for calcium assay are affected by OptiMARK Injection.

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, and the in vivo mammalian micronucleus assay. The in vitro CHO chromosome aberration assay without metabolic activation was positive.

OptiMARK Injection administered to rats in a fertility study was shown to have irreversible reduction and degeneration of spermatocytes in testes and epididymides, and impaired male fertility, following intravenous doses of 2.0 mmol/kg/day (4 times the human dose based on body surface area) for 7 weeks. These effects were not observed at 0.5 mmol/kg/day (1 times the human dose based on a body surface area).

In a separate 28-day repeat dose study in rats, OptiMARK Injection was shown to have irreversible reduction of male reproductive organ weights, degeneration of the germinal epithelium of the testes, presence of germ cells in the epididymides, and reduced sperm count following daily intravenous doses of 3.0 mmol/kg/day (6 times the human dose based on body surface area). These effects were not observed at 0.6 mmol/kg/day (1 times the human dose based on surface area). These effects were not observed in similar studies conducted in dogs.

In a single dose study in rats, OptiMARK Injection did not produce adverse effects on the male reproductive system 24 hours and 14 days after intravenous administration of 0.5 to 15 mmol/kg (1 to 25 times the human dose based on body surface area).

Pregnancy Category C

OptiMARK Injection reduced neonatal weights from birth through weaning at maternal doses of 0.5 mmol/kg/day (1 times the human dose based on body surface area) for 5 weeks (including gestation) and paternal doses of 0.5 mmol/kg/day for 12 weeks. This effect was not observed at 0.1 mmol/kg (0.2 times the human dose based on a body surface area). Maternal toxicity was not observed at any dose.

OptiMARK Injection caused a reduced mean fetal weight, abnormal liver lobation, delayed ossification of sternebrae, and delayed behavioral development (startle reflex and air rights reflex) in fetuses from female rats dosed with 4.9 mmol/kg/day (10 times the human dose based on body surface area) on days 7 through 17 of gestation. These effects were not observed at 0.7 mmol/kg/day (1 times the human dose based on body surface area). Maternal toxicity was observed at 4.9 mmol/kg/day.

OptiMARK Injection caused forelimb flexures and cardiovascular changes in fetuses from female rabbits dosed with 0.4 and 1.6 mmol/kg/day (respectively, 1 and 4 times the human dose based on body surface area) on gestation days 6 through 18. The cardiovascular changes were malformed thoracic arteries, a septal defect, and abnormal ventricle. These effects were not observed at 0.1 mmol/kg/day (0.3 times the human dose based on body surface area). Maternal toxicity was not observed at any dose.

Adequate and well-controlled studies were not conducted in pregnant women. OptiMARK Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

153Gd-labeled OptiMARK Injection was excreted in the milk of lactating rats receiving a single intravenous dose of 0.1 mmol/kg. Women should discontinue nursing and discard breast milk up to 72 hours after OptiMARK Injection administration (see CLINICAL PHARMACOLOGY, Distribution).

Pediatric Use

Safety and effectiveness of OptiMARK Injection in pediatric patients have not been established.

Page last updated: 2008-11-12

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