WARNINGS AND PRECAUTIONS
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. Ablavar binds to blood albumin and use of a high-flux dialysis procedure is essential to optimize Ablavar 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 Ablavar, 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 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 Ablavar [ see Clinical Pharmacology (12) and Dosage and Administration (2)
Ablavar 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 Ablavar 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 Ablavar administration. Have emergency resuscitative equipment available prior to and during Ablavar administration.
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 Ablavar [ see Clinical Pharmacology (12.3)
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 Ablavar 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 Ablavar 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 Ablavar administration. If Ablavar is administered to these patients, consider follow-up electrocardiograms and risk reduction measures (e.g., patient counseling or intensive electrocardiography monitoring) until most Ablavar has been eliminated from the blood. In patients with normal renal function, most Ablavar was eliminated from the blood by 72 hours following injection [ see Clinical Pharmacology (12.3)
USE IN SPECIFIC POPULATIONS
Pregnancy Category C
There are no adequate and well-controlled studies of Ablavar in pregnant women. In animal studies, pregnant rabbits treated with gadofosveset trisodium at doses 3 times the human dose (based on body surface area) experienced higher rates of fetal loss and resorptions. Because animal reproduction studies are not always predictive of human response, only use Ablavar during pregnancy if the diagnostic benefit justifies the potential risks to the fetus.
In reproductive studies, pregnant rats and rabbits received gadofosveset trisodium at various doses up to approximately 11 (rats) and 21.5 (rabbits) times the human dose (based on body surface area). The highest dose resulted in maternal toxicity in both species. In rabbits that received gadofosveset trisodium at 3 times the human dose (based on body surface area), increased post-implantation loss, resorptions, and dead fetuses were observed. Fetal anomalies were not observed in the rat or rabbit offspring. Because pregnant animals received repeated daily doses of Ablavar, their overall exposure was significantly higher than that achieved with a single dose administered to humans.
It is not known whether gadofosveset is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ablavar 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 Ablavar. Avoid Ablavar administration to women who are breastfeeding unless the diagnostic information is essential and not obtainable with non-contrast MRA.
In animal studies, less than 1% of gadofosveset at doses up to 0.3 mmol/kg was secreted in the milk of lactating rats.
The safety and effectiveness of Ablavar in patients under 18 years of age have not been established. The risks associated with Ablavar administration to pediatric patients are unknown and insufficient data are available to establish a dose. Because Ablavar is eliminated predominantly by the kidneys, pediatric patients with immature renal function may be at particular risk for adverse reactions.
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.