Ablavar

Overdose

%medicine_name% Injection has been administered to humans up to a dose of 0.15 mmol/kg (5 times the clinical dose). No %medicine_name% 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.

Contraindications

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

Undesirable effects

The following adverse reactions are discussed in greater detail in other sections of the label:

• Nephrogenic systemic fibrosis
• Hypersensitivity 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.

Anaphylaxis and anaphylactoid reactions were the most common serious reactions observed following %medicine_name% injection administration.

In all clinical trials evaluating %medicine_name% with MRA, a total of 1,676 (1379 patients and 297 healthy subjects) were exposed to various doses %medicine_name%. The mean age of the 1379 patients who received %medicine_name% 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 %medicine_name% at a dose of 0.03 mmol/kg.

Table 2 : Common Adverse Reactions in 802 Subjects Receiving %medicine_name% at 0.03 mmol/kg

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.

Therapeutic indications

%medicine_name% 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.

Pharmacodynamic properties

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-1 s-1 (0.47 T) over the dose range of up to 0.05 mmol/kg.

Pharmacokinetic properties

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.

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.

Gadofosveset does not undergo measurable metabolism in humans.

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%).

Date of revision of the text

Name of the medicinal product

Fertility, pregnancy and lactation

There are no adequate and well-controlled studies of %medicine_name% 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 %medicine_name% 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 %medicine_name%, their overall exposure was significantly higher than that achieved with a single dose administered to humans.

Qualitative and quantitative composition

%medicine_name% is a sterile solution for intravenous injection containing 244 mg/mL (0.25 mmol/mL) gadofosveset trisodium

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

Distributed by : Lantheus Medical Imaging, Inc., 331 Treble Cove Road, North Billerica, MA 01862, United States. Revised: Mar 2015

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

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 %medicine_name% 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 %medicine_name% 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 .

%medicine_name% 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 %medicine_name% 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 %medicine_name% administration. Have trained personnel and emergency resuscitative equipment available prior to and during %medicine_name% administration. If such a reaction occurs stop %medicine_name% and immediately begin appropriate therapy.

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 %medicine_name%.

In clinical trials, a small increase (2.8 msec) in the average change from baseline in QTc was observed at 45 minutes following %medicine_name% 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 %medicine_name% 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 %medicine_name% administration. If %medicine_name% is administered to these patients, consider follow-up electrocardiograms and risk reduction measures (e.g., patient counseling or intensive electrocardiography monitoring) until most %medicine_name% has been eliminated from the blood. In patients with normal renal function, most %medicine_name% was eliminated from the blood by 72 hours following injection.

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.

There are no adequate and well-controlled studies of %medicine_name% 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 %medicine_name% 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 %medicine_name%, 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 %medicine_name% 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 halflives than %medicine_name%. Avoid %medicine_name% 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 %medicine_name% in patients under 18 years of age have not been established. The risks associated with %medicine_name% administration to pediatric patients are unknown and insufficient data are available to establish a dose. Because %medicine_name% 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.

Dosage (Posology) and method of administration

Administer %medicine_name% 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

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

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

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

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

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

Interaction with other medicinal products and other forms of interaction

The following adverse reactions are discussed in greater detail in other sections of the label:

• Nephrogenic systemic fibrosis
• Hypersensitivity 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.

Anaphylaxis and anaphylactoid reactions were the most common serious reactions observed following %medicine_name% injection administration.

In all clinical trials evaluating %medicine_name% with MRA, a total of 1,676 (1379 patients and 297 healthy subjects) were exposed to various doses %medicine_name%. The mean age of the 1379 patients who received %medicine_name% 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 %medicine_name% at a dose of 0.03 mmol/kg.

Table 2 : Common Adverse Reactions in 802 Subjects Receiving %medicine_name% at 0.03 mmol/kg

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.

Following injection, %medicine_name% 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 %medicine_name% interaction with concomitantly administered medications that bind to albumin. An interaction may enhance or decrease the activity of the concomitant medication.

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