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ABLAVAR- gadofosveset trisodium injection, solution
Lantheus Medical Imaging, Inc.

1  INDICATIONS AND USAGE

ABLAVAR is indicated for use as a contrast agent in magnetic resonance angiography (MRA) to evaluate aortoiliac occlusive disease (AIOD) in adults with known or suspected peripheral vascular disease [see Clinical Studies (14)].

2  DOSAGE AND ADMINISTRATION

2.1  Dosing Guidelines

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

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

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

2.2  Imaging Guidelines

ABLAVAR 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, ABLAVAR within the venous system may limit or confound the detection of arterial lesions.

To assess the initial distribution of ABLAVAR 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 ABLAVAR administration. At this time point, ABLAVAR is generally distributed throughout the blood. In clinical trials, steady-state imaging was completed within approximately one hour following ABLAVAR injection.

3  DOSAGE FORMS AND STRENGTHS

ABLAVAR is a sterile solution for intravenous injection containing 244 mg/mL (0.25 mmol/mL) gadofosveset trisodium [see How Supplied/Storage and Handling (16)]

4  CONTRAINDICATIONS

History of a prior allergic reaction to a gadolinium-based contrast agent.

5  WARNINGS AND PRECAUTIONS

5.1  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 ABLAVAR administration to Lantheus Medical Imaging, Inc. (1-978-667-9531)/(1-800-362-2668) 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 drug-induced 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 ABLAVAR 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 Clinical Pharmacology (12) and Dosage and Administration (2)]

5.2  Hypersensitivity Reactions

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.

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 ABLAVAR [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 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)].

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.

6.1  Clinical Studies Experience

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

In all clinical trials evaluating ABLAVAR with MRA, a total of 1,676 (1379 patients and 297 healthy subjects) were exposed to various doses ABLAVAR. The mean age of the 1379 patients who received ABLAVAR 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 ABLAVAR 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  DRUG INTERACTIONS

Following injection, ABLAVAR binds to blood albumin and has the potential to alter the binding of other drugs that also bind to albumin. No drug interaction reactions were observed in clinical trials. Consider the possibility of ABLAVAR interaction with concomitantly administered medications that bind to albumin. An interaction may enhance or decrease the activity of the concomitant medication [see Clinical Pharmacology (12.3)].

7.1  Warfarin

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

8  USE IN SPECIFIC POPULATIONS

8.1  Pregnancy

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.

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 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.

8.4  Pediatric Use

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.

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.