MultiHance

MultiHance

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Nephrogenic Systemic Fibrosis (NSF)

Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR <30 mL/min/1.73m²) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR <30-59 mL/min/1.73m²) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m²). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following MultiHance administration to Bracco Diagnostics (1-800-257-5181) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch).

Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or druginduced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.

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 impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended MultiHance dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention of NSF is unknown [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Hypersensitivity Reactions

Anaphylactic and anaphylactoid reactions have been reported, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of MultiHance administration and resolved with prompt emergency treatment.

Prior to MultiHance administration, ensure the availability of personnel trained and medications to treat hypersensitivity reactions. Additionally, consider the risk for hypersensitivity reactions, especially in patients with a history of hypersensitivity reactions or a history of asthma or other allergic disorders. Observe patients for signs and symptoms of a hypersensitivity reaction during and for up to 2 hours after MultiHance administration.

Acute Renal Failure

In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred with the use of gadolinium-based contrast agents. The risk of renal failure may increase with increasing dose of the contrast agent. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction.

Extravasation and Injection Site Reactions

Extravasation of MultiHance may lead to injection site reactions, characterized by local pain or burning sensation, swelling, blistering, and necrosis. In animal experiments, local reactions including eschar and necrosis were noted even on Day 8 post perivenous injection of MultiHance. Exercise caution to avoid local extravasation during intravenous administration of MultiHance. If extravasation occurs, evaluate and treat as necessary if local reactions develop.

Cardiac Arrhythmias

Cardiac arrhythmias have been observed in patients receiving MultiHance in clinical trials [see ADVERSE REACTIONS]. Assess patients for underlying conditions or medications that predispose to arrhythmias.

A double-blind, placebo-controlled, 24-hour post dose continuous monitoring, crossover study in 47 subjects evaluated the effect of 0.2 mmol/kg MultiHance on ECG intervals, including QTc. The average changes in QTc values compared with placebo were minimal (< 5 msec). QTc prolongation between 30 and 60 msec were noted in 20 subjects who received MultiHance vs. 11 subjects who received placebo. Prolongations ≥ 61 msec were noted in 6 subjects who received MultiHance and in 3 subjects who received placebo. None of these subjects had associated malignant arrhythmias. The effects on QTc by MultiHance dose, other drugs, and medical conditions were not systematically studied.

Interference with Visualization of Certain Lesions

Certain lesions seen on non-contrast images may not be seen on contrast-images. Exercise caution when interpreting contrast MR images in the absence of companion non-contrast MR images.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of MultiHance.

The results for MultiHance were negative in the following genetic toxicity studies: 1) in vitro bacteria reverse mutation assays, 2) an in vitro gene mutation assay in mammalian cells, 3) an in vitro chromosomal aberration assay, 4) an in vitro unscheduled DNA synthesis assay, and 5) an in vivo micronucleus assay in rats.

MultiHance had no effect on fertility and reproductive performance at IV doses of up to 2 mmol/kg/day (3 times the human dose on body surface basis) for 13 weeks in male rats and for 32 days in female rats. However, vacuolation in testes and abnormal spermatogenic cells were observed when MultiHance was intravenously administered to male rats at 3 mmol/kg/day (5 times the human dose on body surface basis) for 28 days. The effects were not reversible following 28-day recovery period. The effects were not reported in dog and monkey studies (at doses up to about 11 and 10 times the human dose on body surface basis for dogs (28 days dosing) and monkeys (14 days dosing), respectively).

Use In Specific Populations

Pregnancy

Pregnancy Category C

MultiHance has been shown to be teratogenic in rabbits when given intravenously administered at 2 mmol/kg/day (6 times the human dose based on body surface area) during organogenesis (day 6 to 18) inducing microphthalmia/small eye and/or focal retinal fold in 3 fetuses from 3 separate litters. In addition, MultiHance intravenously administered at 3 mmol/kg/day (10 times the human dose based on body surface area) has been shown to increase intrauterine deaths in rabbits. There was no evidence that MultiHance induced teratogenic effects in rats at doses up to 2 mmol/kg/day (3 times the human dose based on body surface area), however, rat dams exhibited no systemic toxicity at this dose. There were no adverse effects on the birth, survival, growth, development and fertility of the F1 generation at doses up to 2 mmol/kg in a rat periand post-natal (Segment III) study. There are no adequate and well-controlled studies in pregnant women. MultiHance should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known to what extent gadobenate dimeglumine is excreted in human milk. It is known from rat experiments that 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 restarted until at least 24 hours after the administration of MultiHance.

Pediatric Use

A total of 217 pediatric subjects (93% of subjects aged 2 years and above) were studied in clinical trials. No overall differences in safety or effectiveness were observed between these pediatric subjects and the adult subjects. The safety and efficacy of MultiHance in neonates and infants (ages 0-2 years) have not been established. The risk of NSF related to gadolinium may be increased in these patients due to their immature kidney function.

Geriatric Use

Of the total number of 2982 adult subjects in clinical studies of MultiHance, 27% were 65 and over. No overall differences in safety or effectiveness were observed between these elderly subjects and the younger subjects.

The drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to MultiHance may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function it may be useful to monitor renal function.

Last reviewed on RxList: 7/12/2012
This monograph has been modified to include the generic and brand name in many instances.

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