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Name:Ablavar
Manufacturer:Lantheus Medical Imaging, Inc.
Category:Prescription Marketed Drugs


These highlights do not include all the information needed to use ABLAVAR® safely and effectively. See full prescribing information for ABLAVAR. ABLAVAR (gadofosveset trisodium) Injection for intravenous use Initial U.S. Approval: 2008

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

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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ABLAVAR® safely and effectively. See full prescribing information for ABLAVAR.
ABLAVAR (gadofosveset trisodium) Injection for intravenous use
Initial U.S. Approval: 2008


WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

See full prescribing information for complete boxed warning.

Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities.

  • The risk for NSF appears highest among patients with:
    • chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or
    • acute kidney injury.
  • Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age >60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.1)

RECENT MAJOR CHANGES

Boxed Warning 12/2010
Warnings and Precautions (5.1) 12/2010
Patient Counseling Information (17) 12/2010

INDICATIONS AND USAGE

ABLAVAR Injection is a gadolinium-based contrast agent 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.


DOSAGE AND ADMINISTRATION

Administer ABLAVAR Injection by an intravenous bolus, 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.

Imaging is performed in two stages, the dynamic stage which begins immediately following ABLAVAR Injection and the steady-state stage, which begins following dynamic imaging; generally 5 to 7 minutes after ABLAVAR Injection.


DOSAGE FORMS AND STRENGTHS

Each mL of ABLAVAR Injection contains 244 mg gadofosveset trisodium (equivalent to 0.25 mmol/mL) and is available in single-use vials (3).


CONTRAINDICATIONS

  • History of a prior allergic reaction to a gadolinium-based contrast agent (4).

WARNINGS AND PRECAUTIONS

  • Nephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeated dosing appears to increase the risk (5.1).
  • Hypersensitivity reactions, including anaphylactoid and/or anaphylactic reactions may result from ABLAVAR 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 ABLAVAR may increase the risk for acute renal failure in patients with a history of renal insufficiency (5.3).
  • QTc prolongation has been reported following ABLAVAR administration. Assess patients for a history of underlying conditions that may predispose to arrhythmias due to QTc prolongation (5.4).

ADVERSE REACTIONS

The most common (>2%) adverse reactions are pruritis, headache, nausea, vasodilatation, and paresthesia (6.1, 6.2)

 

To report SUSPECTED ADVERSE REACTIONS, contact Lantheus Medical Imaging, Inc. at 1-978-667-9531/1-800-362-2668 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch



See 17 for PATIENT COUNSELING INFORMATION

Revised: 12/2010

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

RECENT MAJOR CHANGES

1  INDICATIONS AND USAGE

2  DOSAGE AND ADMINISTRATION

2.1  Dosing Guidelines

2.2  Imaging Guidelines

3  DOSAGE FORMS AND STRENGTHS

4  CONTRAINDICATIONS

5  WARNINGS AND PRECAUTIONS

5.1  Nephrogenic Systemic Fibrosis (NSF)

5.2  Hypersensitivity Reactions

5.3   Acute Renal Failure

5.4  QTc Prolongation and Risk for Arrhythmias

6  ADVERSE REACTIONS

6.1  Clinical Studies Experience

6.2  Post-marketing Experience

7  DRUG INTERACTIONS

7.1  Warfarin

8  USE IN SPECIFIC POPULATIONS

8.1  Pregnancy

8.3  Nursing Mothers

8.4  Pediatric Use

8.5  Geriatric Use

10  OVERDOSAGE

11  DESCRIPTION

12  CLINICAL PHARMACOLOGY

12.1  Mechanism of Action

12.2  Pharmacodynamics

12.3  Pharmacokinetics

13  NONCLINICAL TOXICOLOGY

13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility

14  CLINICAL STUDIES

16  HOW SUPPLIED/STORAGE AND HANDLING

17  PATIENT COUNSELING INFORMATION


FULL PRESCRIBING INFORMATION

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs.

  • The risk for NSF appears highest among patients with:
    • chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or
    • acute kidney injury.
  • Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.
  • 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 from the body prior to re-administration [see Warnings and Precautions (5.1)].

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).

TABLE 1. Weight-Adjusted Volumes for the 0.03 mmol/kg Dose
Body Weight Volume
Kilograms (kg) Pounds (lb) Milliliters (mL)
40 88 4.8
50 110 6.0
60 132 7.2
70 154 8.4
80 176 9.6
90 198 10.8
100 220 12.0
110 242 13.2
120 264 14.4
130 286 15.6
140 308 16.8
150 330 18.0
160 352 19.2

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.

Table 2 Common Adverse Reactions in 802 Subjects Receiving Ablavar 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.

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.

10  OVERDOSAGE

ABLAVAR Injection has been administered to humans up to a dose of 0.15 mmol/kg (5 times the clinical dose). No ABLAVAR overdoses were reported in clinical trials. In the event of an overdose, direct treatment toward the support of all vital functions and prompt institution of symptomatic therapy. Gadofosveset has been shown to be removed by hemodialysis using a high flux dialysis procedure [see Clinical Pharmacology (12.3)].

11  DESCRIPTION

ABLAVAR (gadofosveset trisodium) Injection is a sterile, nonpyrogenic, formulation of a stable gadolinium diethylenetriaminepentaacetic acid (GdDTPA) chelate derivative with a diphenylcyclohexylphosphate group. Each mL of ABLAVAR Injection contains 244 mg of gadofosveset trisodium (0.25 mmol), 0.268 mg of fosveset, and water for injection.

It contains no preservative and the solution pH ranges between 6.5 and 8.0.

Gadofosveset trisodium is chemically trisodium-{(2-(R)-[(4,4-diphenylcyclohexyl) phosphonooxymethyl]-diethylenetriaminepentaacetato)(aquo) gadolinium(III),with a molecular weight of 975.88 g/mol, and an empirical formula of C33H40GdN3Na3O15P. It has a structural formula:

Ablavar Structure

Pertinent physiochemical data of ABLAVAR Injection are provided below:

Table 3. Physiochemical Characteristics
Parameter Condition Value
Osmolality (mOsmol/kg water) @ 37°C 825
Viscosity (cP) @ 20°C 3.0
Density (g/mL) @ 25°C 1.1224

12  CLINICAL PHARMACOLOGY

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.

Distribution: The mean volume of distribution at steady state for gadofosveset was 148 ± 16 mL/kg, roughly equivalent to that of extracellular fluid. A significant portion of circulating gadofosveset is bound to plasma proteins, predominantly albumin. At 0.05, 0.5, 1 and 4 hours after injection of 0.03 mmol/kg the plasma protein binding of gadofosveset ranges from 79.8 to 87.4%.

Metabolism: Gadofosveset does not undergo measurable metabolism in humans.

Excretion: Gadofosveset is eliminated primarily in the urine, with between 79% and 94% (mean of 83.7%) of an injected dose recovered in the urine. Of the total gadofosveset recovered in urine, 94% is recovered within the first 72 hours. A small portion of gadofosveset dose is recovered in feces (approximately 4.7%).

Special Populations

Renal Insufficiency: Administration of gadolinium-based contrast agents, including ABLAVAR to patients with severe renal insufficiency increases the risk for NSF. Administration of these agents to patients with mild to moderate renal insufficiency may increase the risk for worsened renal function [see Warnings and Precautions (5.1 and 5.3)]. Prior to use of ABLAVAR in these patients, ensure that no satisfactory diagnostic alternatives are available. In patients with moderate to severe renal impairment (glomerular filtration rate < 60 mL/kg/m2), administer ABLAVAR at a dose of 0.01 mmol/kg to 0.02 mmol/kg. Consider follow-up renal function assessments following ABLAVAR administration to any patients with renal insufficiency.

A clinical study of gadofosveset, at a dose of 0.05 mmol/kg, was conducted in patients with mild, moderate, and severe renal impairment. The clearance decreased substantially as renal function decreased and the systemic exposure (AUC) increased almost 1.75-fold in patients with moderate (creatinine clearance: 30 to 50 mL/min) and 2.25-fold in patients with severe renal impairment (creatinine clearance < 30 mL/min). The elimination half-life increased from 19 hours in normal subjects to 49 hours in patients with moderate and 70 hours in patients with severe renal impairment. The volume of distribution at steady state and plasma protein binding of gadofosveset were not affected by renal impairment. Fecal elimination of gadofosveset increased as a function of increasing renal impairment (6.5% in normal subjects to 13.3% in patients with severe renal impairment).

Hemodialysis: Gadofosveset is removed from the body by hemodialysis using high-flux filters. Elimination of the total administered dose of gadolinium in dialysate over 3 dialysis sessions using high-flux filters averaged 46.8%, 12.9%, and 6.11% for the first, second, and third sessions, respectively.

Hepatic Insufficiency: The pharmacokinetics and plasma protein binding of gadofosveset was not significantly influenced by moderate hepatic impairment. A slight decrease in fecal elimination of gadofosveset was seen for the hepatic impaired subjects (2.7%) compared to normal subjects (4.8%).

Gender: No dosage adjustment is necessary based on gender. Gender had no meaningful effect on the pharmacokinetics of gadofosveset.

Geriatric: No dosage adjustment is necessary based on age. Age had no meaningful effect on the pharmacokinetics of gadofosveset.

Pediatric: of gadofosveset in pediatric patients have not been performed.

13  NONCLINICAL TOXICOLOGY

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, 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)].

14  CLINICAL STUDIES

Safety and efficacy of ABLAVAR were assessed in two multi-center, open-label, Phase 3 clinical trials. In both trials, patients with known or suspected peripheral vascular disease underwent MRA with and without ABLAVAR as well as catheter-based X-ray arteriography. Diagnostic efficacy was based upon comparisons of sensitivity and specificity between MRA with and without ABLAVAR, with X-ray arteriography as the reference standard.

Out of 493 patients enrolled in these two trials, 424 were included in the comparison of the diagnostic efficacy of ABLAVAR-MRA to that of non-contrast MRA in detection/exclusion of occlusive vascular disease (≥ 50% stenosis) in 7 vessel-segments in the aortoiliac region. The interpretation of MRA images from both trials was conducted by three independent radiologist readers who were blinded to clinical data, including the results of X-ray arteriography. In these 424 patients, the median age was 67 years with a range of 29 to 87 years; 58% of the patients were over 65 years of age; 83% were white and 68% were male.

The primary efficacy analyses were designed to demonstrate superiority in sensitivity and non-inferiority in specificity of ABLAVAR-MRA as compared to non-contrast MRA at the vessel-segment level. The uninterpretable images were assigned an outcome of “wrong diagnosis”. Additionally, success was also based upon acceptable performance characteristics for the uninterpretable non-contrast MRA vessel segments that became interpretable following ABLAVAR administration. Specifically, the sensitivity and specificity for these ABLAVAR images were required to exceed 50%. These pre-specified success criteria were to be achieved by at least the same two readers for all primary analyses.

Superiority in sensitivity and non-inferiority in specificity was demonstrated for ABLAVAR-MRA by all three blinded readers. On average, 316 vessel segments were assessed for sensitivity and 2230 for specificity, by each reader. Table 4 summarizes the efficacy results, by reader.

Table 4. Performance Characteristics of Ablavar-MRA and Non-contrast MRA
*(Based on cluster-corrected McNemar Test)
Reader SENSITIVITY SPECIFICITY
Ablavar- Non-contrast [A] – [B] Ablavar Non-contrast [A] – [B]
MRA [A] MRA [B] (95% CI)* MRA [A] MRA [B] (95% CI)*
1 89% 69% 20%
(15%, 25%)
72% 71% 1%
(-3%, 5%)
2 82% 70% 12%
(7%, 17%)
81% 73% 8%
(4%, 12%)
3 79% 64% 15%
(9%, 21%)
85% 85% 0%
(-2%, 2%)

Among the three readers, 5 to 12% of the vessel-segments were deemed uninterpretable by non-contrast MRA. For these vessel segments, sensitivity of ABLAVAR-MRA ranged from 72% [95% CI (54%, 90%)] to 97% [95% CI (93%, 100%)] and specificity ranged from 72% [95% CI (67%,76%)] to 84% [95% CI (81%, 88%)].

16  HOW SUPPLIED/STORAGE AND HANDLING

ABLAVAR Injection is a sterile, clear, colorless to pale yellow solution containing 244 mg/mL (0.25 mmol/mL) of gadofosveset trisodium in rubber-stoppered glass vials with an aluminum seal. ABLAVAR Injection is supplied as follows:

NDC 11994-012-01 - 10 mL fills in 10 mL single use vials packages of 10 vials
NDC 11994-012-02 - 15 mL fills in 20 mL single use vials in packages of 10 vials

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

17  PATIENT COUNSELING INFORMATION

Instruct patients receiving ABLAVAR Injection to inform their physician or healthcare provider if they:

  • are pregnant or breast feeding
  • have a history of allergic reaction to contrast media, a history of bronchial asthma or allergic respiratory disorder
  • have a history of kidney and/or liver disease
  • have recently received a gadolinium-based contrast agent
  • have a history of heart rhythm disturbances, or cardiac disease
  • are taking any prescription or over-the counter medications

GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF:

  • Describe the clinical manifestations of NSF
  • Describe procedures to screen for the detection of renal impairment

Instruct the patients to contact their physician if they develop signs or symptoms of NSF following ABLAVAR administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness.

Inform patients that they may experience:

  • reactions at the injection site, such as: redness, mild and transient burning or pain or feeling of warmth or coldness
  • side effects of itching or nausea

Distributed by Lantheus Medical Imaging, Inc., 331 Treble Cove Road, North Billerica, MA 01862, United States

US Patents: 7,060,250; 7,229,606; 5,919,967; 6,676,929; and 7,011,815

515862-0910


 
 

Ablavar 10mL label
11994-012-01

Ablavar 10mL label
Ablavar 10mL label

Ablavar 15mL label
11994-012-02

Ablavar 10mL label
Ablavar 10mL label

ABLAVAR 
gadofosveset trisodium injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:11994-012
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
GADOFOSVESET TRISODIUM (GADOFOSVESET) GADOFOSVESET TRISODIUM 244 mg  in 1 mL
Inactive Ingredients
Ingredient Name Strength
FOSVESET 0.268 mg  in 1 mL
SODIUM HYDROXIDE  
HYDROCHLORIC ACID  
WATER  
Product Characteristics
Color      Score     
Shape Size
Flavor Imprint Code
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:11994-012-01 10 VIAL ( VIAL) in 1 BOX contains a VIAL
1 10 mL in 1 VIAL This package is contained within the BOX (11994-012-01)
2 NDC:11994-012-02 10 VIAL ( VIAL) in 1 BOX contains a VIAL
2 15 mL in 1 VIAL This package is contained within the BOX (11994-012-02)

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021711 12/12/2008

Labeler - Lantheus Medical Imaging, Inc. (176786812)
Establishment
Name Address ID/FEI Operations
Lantheus Medical Imaging, Inc. 176786812 RELABEL, REPACK, MANUFACTURE
Establishment
Name Address ID/FEI Operations
Covidien 047021092 MANUFACTURE

Revised: 12/2010 Lantheus Medical Imaging, Inc.



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


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