2.1 Dosing Guidelines

Administer VASOVIST as an intravenous bolus injection, manually or by power injection, at a dose of 0.12 mL/kg body weight (0.03 mmol/kg) over a period of time up to 30 seconds followed by a 25-30 mL normal saline flush. (See Table 1 for weight-adjusted dose volumes).

Inspect the VASOVIST vial visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present.

VASOVIST is intended for single use only and should be used immediately upon opening. Discard any unused portion of the VASOVIST vial.

Do not mix intravenous medications or parenteral nutrition solutions with VASOVIST. Do not administer any other medications in the same intravenous line simultaneously with VASOVIST.

2.2 Imaging Guidelines

VASOVIST imaging is completed in two stages: the dynamic imaging stage and the steady-state imaging stage. Both stages are essential for adequate evaluation of the arterial system, and dynamic imaging always precedes steady-state imaging. During interpretation of the steady-state images, VASOVIST within the venous system may limit or confound the detection of arterial lesions.

To assess the initial distribution of VASOVIST within the arterial system, begin dynamic imaging immediately upon injection. Begin steady state imaging after dynamic imaging has been completed, generally 5 to 7 minutes following VASOVIST administration. At this time point, VASOVIST is generally distributed throughout the blood. In clinical trials, steady-state imaging was completed within approximately one hour following VASOVIST injection.

5.1 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) 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 MRA. 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. VASOVIST binds to blood albumin and use of a high-flux dialysis procedure is essential to optimized VASOVIST elimination in patients receiving chronic hemodialysis. The usefulness of hemodialysis in the prevention of NSF is unknown [see Boxed Warning and Clinical Pharmacology (12.3)].

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. Prior to marketing of Vasovist®, where a specific agent was identified, the most commonly reported agent was gadodiamide (OmniscanTM), 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 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 re-administration. NSF was not reported in clinical trials of VASOVIST [see Clinical Pharmacology (12) and Dosage and Administration (2)].

5.2 Hypersensitivity Reactions

VASOVIST may cause anaphylactoid and/or anaphylactic reactions, including life-threatening or fatal reactions. In clinical trials, anaphylactoid and/or anaphylactic reactions occurred in two of 1676 subjects. If anaphylactic or anaphylactoid reactions occur, stop VASOVIST Injection and immediately begin appropriate therapy. Observe patients closely, particularly those with a history of drug reactions, asthma, allergy or other hypersensitivity disorders, during and up to several hours after VASOVIST administration. Have emergency resuscitative equipment available prior to and during VASOVIST administration.

5.3 Acute Renal Failure

In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred with the use of other gadolinium agents. The risk of renal failure may increase with increasing dose of gadolinium contrast. 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. No reports of acute renal failure were observed in clinical trials of VASOVIST [see Clinical Pharmacology (12.3)].

5.4 QTc Prolongation and Risk for Arrhythmias

In clinical trials, a small increase (2.8 msec) in the average change from baseline in QTc was observed at 45 minutes following VASOVIST administration; no increase was observed at 24 and 72 hours. A QTc change of 30 to 60 msec from baseline was observed in 39/702 (6%) patients at 45 min following VASOVIST administration. At this time point, 3/702 (0.4%) patients experienced a QTc increase of > 60 msec. These QTc prolongations were not associated with arrhythmias or symptoms. In patients at high risk for arrhythmias due to QTc prolongation (e.g., concomitant medications, underlying cardiac conditions) consider obtaining baseline electrocardiograms to help assess the risks for VASOVIST administration. If VASOVIST is administered to these patients, consider follow-up electrocardiograms and risk reduction measures (e.g., patient counseling or intensive electrocardiography monitoring) until most VASOVIST has been eliminated from the blood. In patients with normal renal function, most VASOVIST was eliminated from the blood by 72 hours following injection [see Clinical Pharmacology (12.3)].

6.1 Clinical Studies Experience

Anaphylaxis and anaphylactoid reactions were the most common serious reactions observed following VASOVIST injection administration [see Warnings and Precautions (5.2)].

In all clinical trials evaluating VASOVIST with MRA, a total of 1,676 (1379 patients and 297 healthy subjects) were exposed to various doses VASOVIST. The mean age of the 1379 patients who received VASOVIST was 63 years (range 18 to 91 years); 66% (903) were men and 34% (476) were women. In this population, there were 80% (1100) Caucasian, 8% (107) Black, 12% (159) Hispanic, 1% (7) Asian, and < 1% (6) patients of other racial or ethnic groups. Table 2 shows the most common adverse reactions (≥1%) experienced by subjects receiving VASOVIST at a dose of 0.03 mmol/kg.

6.2 Post-marketing Experience

Because post-marketing 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 profile of adverse reactions identified during the post-marketing experience outside the United States was similar to that observed during the clinical studies experience.

7.1 Warfarin

In a clinical trial of 10 patients receiving a stable dose of warfarin, a single dose of VASOVIST (0.05 mmol/kg) did not alter the anticoagulant activity of warfarin as measured by the International Normalized Ratio (INR).

8.1 Pregnancy

8.3 Nursing Mothers

It is not known whether gadofosveset is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when VASOVIST is administered to a woman who is breastfeeding. The risks associated with exposure of infants to gadolinium-based contrast agents in breast milk are unknown. Limited case reports indicate that 0.01 to 0.04% of the maternal gadolinium dose is excreted in human breast milk. Studies of other gadolinium products have shown limited gastrointestinal absorption. These studies were conducted with gadolinium products with shorter half-lives than VASOVIST. Avoid VASOVIST administration to women who are breastfeeding unless the diagnostic information is essential and not obtainable with non-contrast MRA.

Less than 1% of gadofosveset at doses up to 0.3 mmol/kg was secreted in the milk of lactating rats.

8.4 Pediatric Use

The safety and effectiveness of VASOVIST in patients under 18 years of age have not been established. The risks associated with VASOVIST administration to pediatric patients are unknown and insufficient data are available to establish a dose. Because VASOVIST is eliminated predominantly by the kidneys, pediatric patients with immature renal function may be at particular risk for adverse reactions.

8.5 Geriatric Use

In clinical trials, no overall differences in safety and efficacy were observed between subjects 65 years and older and younger subjects. Whereas current clinical experience has not identified differences in responses between elderly and younger patients, greater susceptibility to adverse experiences of some older individuals cannot be ruled out.

12.1 Mechanism of Action

Following intravenous injection, gadofosveset binds reversibly to endogenous serum albumin resulting in longer vascular residence time than non-protein binding contrast agents. The binding to serum albumin also increases the magnetic resonance relaxivity of gadofosveset and decreases the relaxation time (T1) of water protons resulting in an increase in signal intensity (brightness) of blood.

12.2 Pharmacodynamics

In human studies, gadofosveset substantially shortened blood T1 values for up to 4 hours after intravenous bolus injection. Relaxivity in plasma was measured to be 33.4 to 45.7 mM-1s-1 (0.47 T) over the dose range of up to 0.05 mmol/kg.

12.3 Pharmacokinetics

The pharmacokinetics of intravenously administered gadofosveset conforms to a two-compartment open model with mean plasma concentrations (reported as mean ±SD) of 0.43 ± 0.04 mmol/L at 3 minutes post-injection, and 0.24 ± 0.03 mmol/L at one hour post-injection. The mean half-life of the distribution phase is 0.48 ± 0.11 hours and the mean half-life of the elimination phase is 16.3 ± 2.6 hours. The mean total clearance of gadofosveset is 6.57 ± 0.97 mL/h/kg following the administration of 0.03 mmol/kg.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadofosveset. Gadofosveset was negative in the in vitro bacterial reverse mutation assay, in vitro CHO chromosome aberration assay, and the in vivo mouse micronucleus assay. Administration of up to 1.5 mmol/kg (8.3 times the human dose) to female rats for 2 weeks and to male rats for 4 weeks did not impair fertility [see Use in Specific Populations (8.1)].

Store VASOVIST Injection at 25°C (77°F: excursions permitted to 15 to 30°C [59 to 86°F]). Protect from light and freezing.