MultiHance: Frequently Asked Questions

QUESTION How does the safety profile of MultiHance compare to the other currently available gadolinium-based contrast agents.

ANSWER The safety profile of MultiHance is similar to that of the other approved gadolinium agents. As stated in the American College of Radiology Manual on Contrast Media, gadolinium-containing contrast media are extremely well tolerated by the vast majority of patients in whom they are injected. Clinical studies have been performed comparing the safety profiles of other gadiolinium-based contrast agents and MultiHance. In these studies the frequency and type of adverse reactions seen after the two agents were similar.

QUESTION Do the container closure or formulation of MultiHance contain latex?

ANSWER No.

QUESTION Since the MultiHance package insert contains a contraindication for use in patients with known allergic or hypersensitivity reactions to gadolinium or any other ingredient, can we use MultiHance in patients who developed a sensitivity reaction such as hives after administration of another gadolinium-based contrast agent?

ANSWER No. It is advisable to seek a different modality anytime a patient exhibits sensitivity to a component of a drug. However, please note that this type of a statement is made in all of the gadolinium agent package inserts. It is contained in the contraindications section of the last two agents approved by the FDA (MultiHance and OptiMARK) and it is contained in the warnings section of the earlier approved agents (ProHance, Magnevist, and Omniscan). There is no evidence that adverse reactions are more frequent or more serious with the more recently approved agents.

QUESTION Should breast feeding be discontinued after administration of MultiHance?

ANSWER The MultiHance package insert suggests that breast feeding be discontinued for approximately 24 hours after administration of MultiHance. There is similar language in the package inserts of the other approved gadolinium contrast agents.

QUESTION Is there any information about the safe use of MultiHance for MR arthrography procedures?

ANSWER Currently there is no literature describing MultiHance use for MR arthrography. This is not an approved indication for any gadolinium contrast agent, however numerous protocols for this procedure have been published.

QUESTION Is there any information available about the use of MultiHance in patients with renal impairment?

ANSWER The MultiHance package insert CLINICAL PHARMACOLOGY section contains a sub-section entitled 'Pharmacokinetics in Special Populations. Renal Impairment' stating that: "the overall extent of elimination of gadobenate was not influenced by impaired renal function. Also, no differences were noted in patients with renal impairment in the rate and type of adverse events reported compared with healthy volunteers, and no deterioration in renal function was observed in this population following the administration of MULTIHANCE. Therefore, dosage adjustment is not recommended". These recommendations are based on studies with MultiHance conducted in patients with varying degrees of renal impairment and in patients on hemodialysis.

QUESTION For what indications has MultiHance been studied that are not contained in the package insert?

ANSWER Liver Imaging, Magnetic Resonance Angiography (MRA), Body/MRA, Breast Imaging, MRI/Acute Myocardial Infarction, CNS Imaging in pediatric patients.

QUESTION Why doesn't MultiHance have a pediatric imaging indication in the US?

ANSWER No safety concerns have been raised about the use of MultiHance in children. In fact, MultiHance is approved for use in pediatric patients in Canada. To date, the safety and efficacy of MultiHance has been evaluated in 174 children between the age of 6 months and 16 years (Ref Colosimo, Ped Radiol 2005). In addition, the pharmacokinetics of MultiHance in children was studied in 25 subjects. This can be compared to the 173 patients that were enrolled in clinical trials with Omniscan. The safety profile of MultiHance in children was found to be equal to that of Magnevist and the pharmacokinetics were found to be similar to those in adult patients. The FDA has requested that a larger population of children be studied before granting the pediatric indication in the US. The manufacturer of MultiHance (Bracco Diagnostics Inc.) decided to launch the product for adults in the US while obtaining the additional requested data in pediatric patients.

QUESTION The package insert states that once MultiHance is filled into a plastic syringe, it should be used immediately. Is there a reason that is specific to MultiHance that would require this precaution?

ANSWER There are no data that suggests that MultiHance acts any differently than the other gadolinium-based contrast agents when exposed to plastic syringes. In fact, the OptiMARK package insert contains the same statement. The FDA now requires that this precaution be placed in the IV administered contrast agent labeling. The reason for the statement is that it is possible for extractable contaminants to leach from the plastic used to make the syringe. Unless there is stability data for all commercially available plastic syringes that proves otherwise, the precaution is required. The Magnevist package insert contains the statement "After Magnevist injection is drawn into the syringe the solution should be used immediately." The ProHance and Omniscan package inserts contain this statement as well. This statement is found in the PRECAUTIONS, General section of these package inserts.

QUESTION Can MultiHance be double dosed as is sometimes done with ProHance or Omniscan?

ANSWER Currently MultiHance is approved in the U.S. at a dose of 0.1 mmo/kg body weight. Due to the higher relaxivity of MultiHance it may not be necessary to give higher doses in certain applications. Several reports in the literature describe the use of dosages greater than that indicated in the DOSAGE AND ADMINISTRATION section of the MultiHance package insert. In a comprehensive safety assessment published in 2000, Kirchin and colleagues found no increase in the rate of adverse events in patients given higher doses of MultiHance.

QUESTION What is the potential for MultiHance interaction with drugs which undergo a similar hepatobiliary elimination?

ANSWER Following IV injection, Gd-BOPTA, the active ingredient of MultiHance, is internalized by hepatocytes through a passive mechanism (simple diffusion though the hepatocyte cell membrane) and a small percentage is actively excreted via the ATP-dependent export pump for anionic conjugates MRP2 (multidrug resistance-associated protein 2, also known as multi-specific organic anion transport system, cMOAT), located in the apical membranes of hepatocytes. MRP2 functions as the major exporter of organic anions from the liver into the bile, such as conjugated bilirubin. Gd-BOPTA, even in patients with reduced liver function, had no impact on the elimination of conjugated bilirubin, although conjugated bilirubin can be only eliminated by the MRP2.

The following drugs with substantial hepatic excretion via the MRP2 and a narrow therapeutic window have been used in combination with MultiHance in clinical trials: daunorubicin, doxorubicin, epirubicin, glyburide (glibenclamide), tamoxifen, taxol, and taxotere. The most frequent concomitant use was of glyburide (43 patients). No adverse events suggestive of hypoglycemia, cholestatic jaundice, agranulocytosis, or aplastic and/or hemolytic anemia (indicative of overdosing of glyburide) were observed. The magnitude of the changes in conjugated bilirubin in these patients was negligible and similar to that observed in patients who did not take drugs competing for the MRP2. No adverse events suggestive of increased blood levels of the anthracyclines or the taxanes (cardiac toxicity, bone marrow depression), nor of increased blood levels of tamoxifen (flushes, nausea, vomiting, or thromboembolic complications) were noted. No other serious clinical adverse events or significant ECG and laboratory abnormalities were reported for these patients. Out of approximately 1.3 million patients exposed to MultiHance to date, no data suggest that Gd-BOPTA interferes with the uptake or metabolism of any drug or biological agent.

This may be explained by the fact that: a) only single administrations of MultiHance are used; b) a small percentage of the injected dose of Gd-BOPTA (0.6-4%) is excreted into the bile; c) most drugs competing for the the MRP2 can also be eliminated by other liver transporters (e.g., MDR1, MRP1, and BCRP); d) MRP2 is not only expressed on the hepatocytes, but also on enterocytes of the proximal small intestine, and proximal renal tubular cells; e) anthracyclines and taxanes lead to overexpression of MDR1, MRP1 and MRP2 in hepatic and non-hepatic tissues, like cancer tissues, small intestine, kidney, and others. In view of the available data, MultiHance is not expected to interfere with the elimination of drugs with a narrow therapeutic window which are excreted via the MRP2 pathway, nor to affect the course of treatment with these drugs.

QUESTION Can anaphylactic reactions occur in patients who are hypersensitive to benzyl alcohol?

ANSWER Hypersensitivity to benzyl alcohol is mainly described in the literature in the form of contact dermatitis following external administration (delayed-type dermatitis). No one has ever shown a correlation between a contact allergy (delayed type, cell-mediated) to benzyl alcohol and systemic reactions (immediate type, not cell-mediated) following parenteral administration. Important: benzyl alcohol is present in many drug formulations, has been administered in millions and millions of people, but the literature reports only 3 reports of possible hypersensitivity following parenteral administration, and none of them was an anaphylactic or anaphylactoid reaction.

Hypersensitivity to gadolinium chelates is more frequent and much more clinically important than possible hypersensitivity to benzyl alcohol. Serious and life threatening hypersensitivity reactions to gadolinium chelates are well documented and may occur with any gadolinium agent. Such documentation for benzyl alcohol is difficult if not impossible to find. Vials of MultiHance may contain only minute traces of benzyl alcohol.

QUESTION Does MultiHance affect colorimetric assays for serum calcium?

ANSWER No. It is well known that some gadolinium chelates, notably gadodiamide (Omniscan) and gadoversetamide (OptiMARK), may interfere with the colorimetric determination of serum calcium or other metal or metabolites. The mechanism of this interference appears to be related to the propensity of the agent to de-chelate once injected. According to Bracco Diagnostics Inc., the manufacturer of MultiHance, this agent has been thoroughly evaluated for potential interference in colorimetric assay tests in two separate batteries of test and no interference was demonstrated. The assays tested included: Albumin (BCG method), Alkaline Phosphatase (AP), Bilirubin (total) (DPD method), Calcium (O-CPC method), Chloride, Cholesterol (CHOD-PAP method), Creatine kinase (CK) (NAC-activated) Creatinine, Glucose, Glutamate oxalacetate transaminase (GOT or ASAT), Glutamate phosphate transinase (GPT or ALAT), Iron (ferrozin-method), Lactate dehydrogenase (LDH) (optimized UV test), Phosphate (direct phosphomolybdate method), Sodium/potassium, Total proteins (Biuret method), Triglycerides (GPO-PAP method), and Urea.