Vasovist

Name: Vasovist

Indications and Usage for Vasovist

Vasovist 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)].

Use in specific populations

Pregnancy

Pregnancy Category C

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

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 Vasovist 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 Vasovist. Avoid Vasovist administration to women who are breastfeeding unless the diagnostic information is essential and not obtainable with non-contrast MRA.

Less than 1% of gadofosveset at doses up to 0.3 mmol/kg was secreted in the milk of lactating rats.

Pediatric Use

The safety and effectiveness of Vasovist in patients under 18 years of age have not been established. The risks associated with Vasovist administration to pediatric patients are unknown and insufficient data are available to establish a dose. Because Vasovist is eliminated predominantly by the kidneys, pediatric patients with immature renal function may be at particular risk for adverse reactions.

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.

Vasovist Description

Vasovist (gadofosveset trisodium) Injection is a sterile, nonpyrogenic, formulation of a stable gadolinium diethylenetriaminepentaacetic acid (GdDTPA) chelate derivative with a diphenylcyclohexylphosphate group. Each mL of Vasovist Injection contains 244 mg of gadofosveset trisodium (0.25 mmol), 0.27 mg of fosveset, and water for injection.

It contains no preservative and the solution pH ranges between 6.5 to 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:

Pertinent physiochemical data of Vasovist 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

Vasovist - Clinical Pharmacology

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.

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.

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. 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 approximately 83.5% of an injected dose excreted in the urine over 14 days. Ninety-four percent (94%) of urinary excretion occurs in 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 Vasovist 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 Vasovist 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 Vasovist at a dose of 0.01 mmol/kg to 0.02 mmol/kg. Consider follow-up renal function assessments following Vasovist 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: Studies of gadofosveset in pediatric patients have not been performed.

Clinical Studies

Safety and efficacy of Vasovist 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 Vasovist as well as catheter-based X-ray arteriography. Diagnostic efficacy was based upon comparisons of sensitivity and specificity between MRA with and without Vasovist, 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 Vasovist-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 Vasovist-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 Vasovist administration. Specifically, the sensitivity and specificity for these Vasovist 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 Vasovist-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 Vasovist-MRA and Non-contrast MRA
Reader SENSITIVITY SPECIFICITY
Vasovist-MRA [A] Non-contrast MRA [B] [A] – [B]
(95% CI)*
Vasovist MRA [A] Non-contrast MRA [B] [A] – [B]
(95% CI)*
* (Based on cluster-corrected McNemar Test)
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 Vasovist-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%)].

Before receiving Vasovist

Vasovist can cause a life-threatening condition in people with advanced kidney disease who are undergoing an MRI. The symptoms of this condition include:

  • burning, itching, swelling, and tightening or hardening of your skin;

  • muscle weakness;

  • pain or stiffness in your arms, hands, legs, or feet;

  • deep bone pain in your ribs or your hips;

  • yellow patches on the whites of your eyes; or

  • skin redness or discoloration.

Before receiving Vasovist, tell your doctor if you have kidney disease. You may not be able to receive an MRI using this medicine.

Before receiving Vasovist, tell your doctor if you have ever had any type of reaction to another contrast agent, or if you have:

  • a heart rhythm disorder;

  • a personal or family history of "Long QT Syndrome";

  • liver disease;

  • asthma, hay fever, or a history of food or drug allergies; or

  • if you are on dialysis.

If you have any of these conditions, you may not be able to receive Vasovist, or you may need a dose adjustment or special tests during treatment.

FDA pregnancy category C. It is not known whether Vasovist is harmful to an unborn baby. Before you receive Vasovist, tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether gadofosveset trisodium passes into breast milk or if it could harm a nursing baby. Do not receive this medication without telling your doctor if you are breast-feeding a baby.

How is Vasovist given?

Vasovist is given as an injection through a needle placed into a vein. You will receive this injection in a clinic or hospital setting during your MRA.

Your doctor or other healthcare provider may want to watch you for a short time after your test is over. This is to make sure you do not have any unwanted side effects or delayed reactions.

What happens if I overdose?

Seek emergency medical attention if you think you have received too much of this medicine. Symptoms of an overdose are not known.

What other drugs will affect Vasovist?

There may be other drugs that can affect Vasovist. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

For the Consumer

Applies to gadofosveset trisodium: injection solution

Along with its needed effects, gadofosveset trisodium (the active ingredient contained in Vasovist) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking gadofosveset trisodium:

More common
  • Cough
  • difficulty with swallowing
  • dizziness
  • fast heartbeat
  • hives
  • itching
  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
  • shortness of breath
  • skin rash
  • tightness in the chest
  • unusual tiredness or weakness
  • wheezing
Less common
  • Blurred vision
  • burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
  • feeling faint, dizzy, or lightheaded
  • feeling of warmth or heat
  • flushing or redness of the skin, especially on the face and neck
  • headache
  • nervousness
  • pounding in the ears
  • slow or fast heartbeat
  • sweating

Some side effects of gadofosveset trisodium may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common
  • Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
  • change in taste
  • feeling cold
  • loss of taste
  • nausea

(web3)