WARNING: 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/1.73m 2 ), 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 re-administration [ see Warnings and Precautions (5.1) ] WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF) See full prescribing information for complete boxed warning Gadolinium-based contrast agents increase the risk of nephrogenic systemic fibrosis (NSF) in patients with: acute or chronic severe renal insufficiency (glomerular filtration rate <30 mL/min/1.73m 2 ), 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 re-administration [ see Warnings and Precautions (5.1) ]
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Nephrogenic Systemic Fibrosis may result from administration of gadolinium-based contrast agents to certain patients ( 5.1 ). Hypersensitivity reactions, including anaphylactoid and/or anaphylactic reactions may result from VASOVIST administration. Assess patients for a history of allergic reactions to gadolinium-based contrast agents and monitor patients closely for need of emergency cardiorespiratory support ( 5.2 ) Gadolinium-based contrast agents, including VASOVIST may increase the risk for acute renal failure in patients with a history of renal insufficiency ( 5.3 ). QTc prolongation has been reported following VASOVIST administration. Assess patients for a history of underlying conditions that may predispose to arrhythmias due to QTc prolongation ( 5.4 ). 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/1.73m 2 ) 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 (Omniscan TM ), 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 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The most common (>2%) adverse reactions are pruritis, headache, nausea, vasodilatation, and paresthesia ( 6.1 , 6.2 ) 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. Table 2 Common Adverse Reactions in 802 Subjects Receiving VASOVIST at 0.03 mmol/kg Preferred Term n (%) Pruritis 42 (5) Headache 33 (4) Nausea 33 (4) Vasodilatation 26 (3) Paresthesia 25 (3) Injection site bruising 19 (2) Dysgeusia 18 (2) Burning sensation 17 (2) Venipuncture site bruise 17 (2) Hypertension 11 (1) Dizziness (excluding vertigo) 8 (1) Feeling cold 7 (1) 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.