Summary Basis of Decision for Vasovist ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
VasovistTM
Gadofosveset trisodium, 244 mg/mL (0.25 mmol/mL), Solution, Intravenous
Berlex Canada Inc.
Submission control no: 096420
Date issued: 2008-01-30
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), VASOVISTMD, gadofosveset trisodique, 244 mg/mL , solution, Berlex Canada Inc. No de contrôle de la présentation 096420
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02286319
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Control No. 096420
Date of Submission:
Date of authorization:
2 Notice of decision
On October 31, 2006, Health Canada issued a Notice of Compliance to Berlex Canada Inc. for the drug product Vasovist.
Vasovist contains the medicinal ingredient gadofosveset trisodium which is an intravenous contrast enhancement agent for magnetic resonance imaging (MRI).
Vasovist is indicated for contrast-enhanced magnetic resonance angiography (MRA) for visualization of abdominal or limb vessels in patients with suspected or known vascular disease. Vasovist binds reversibly to plasma protein. This protein binding extends the residence time of the drug in the vascular space and, consequently, extends the period available for imaging.
The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from preclinical and clinical studies. A total of 759 patients were evaluated in four controlled Phase III clinical trials using Vasovist. In all four trials, Vasovist provided a significant improvement in diagnostic efficacy compared to unenhanced MRA.
Vasovist (gadofosveset trisodium injection, 244 mg/mL) is presented as a solution for intravenous injection. The recommended dose for adults is 0.12 mL/kg of body weight (equivalent to 0.03 mmol/kg). Vasovist doses higher than 0.03 mmol/kg are not recommended. Vasovist should be administered as an intravenous bolus injection, manually or by power injection, over a period of up to 30 seconds, followed by a 25-30 mL normal saline flush. The rate of injection should not exceed 1.5 mL/sec. Dosing guidelines are available in the Product Monograph.
Vasovist is contraindicated in patients who are hypersensitive to gadofosveset trisodium or to any ingredient in the formulation, or component of the container. Vasovist should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Vasovist are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Vasovist is favourable for contrast-enhanced magnetic resonance angiography (MRA) for visualization of abdominal or limb vessels in patients with suspected or known vascular disease.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Gadofosveset trisodium, the medicinal ingredient of Vasovist is a contrast enhancement agent for magnetic resonance imaging (MRI). Gadofosveset binds reversibly to the plasma protein, albumin. This protein binding extends the residence time of the drug in the vascular space and, consequently, extends the period available for imaging.
Manufacturing Process and Process Controls
Gadofosveset trisodium is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet ICH requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
Detailed characterization studies were performed to provide assurance that gadofosveset trisodium consistently exhibits the desired characteristic structure. Results from process validation studies also indicate that the methods used during processing adequately control the levels of product and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of gadofosveset trisodium.
The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and were within the proposed acceptance criteria.
The drug substance packaging is considered to be acceptable.
Stability
Based on the real-time and accelerated stability data submitted, the proposed retest period, storage and shipping conditions for gadofosveset trisodium are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Vasovist is provided as a sterile, non-pyrogenic, clear, colourless-to-pale yellow aqueous solution containing 244 mg/mL of gadofosveset trisodium, 268 µg/mL of fosveset, and water for injection. Sodium hydroxide and/or hydrochloric acid are added as needed for pH adjustment.
Vasovist is packaged in clear, glass, 10-mL single-use vials containing 10 mL of solution, and in 20-mL single-use vials containing 15 mL or 20 mL of solution. The vials are sealed with rubber stoppers and aluminum flip-and-tear type seals. The drug product is supplied in cartons of one, five, and ten vials.
All excipients (non-medicinal ingredients) found in Vasovist are acceptable for use in drugs by the Food and Drug Regulations. The compatibility of gadofosveset trisodium with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the development were considered acceptable upon review.
Manufacturing Process and Process Controls
The drug product is formulated, mixed, filtered, filled, sterilized, labelled and packaged. The specifications for all the ingredients are either approved in accordance with USP/NF or Ph. Eur. standards.
The manufacturing process for Vasovist uses a standard method of manufacture for aqueous solutions and complies with Ph. Eur. requirements for sterilization procedures. The in-process control tests and specifications are considered adequate to control the quality of the product.
Control of Drug Product
Vasovist is tested to verify that the identity, appearance, content uniformity, pH, sterility, and the levels of degradation products and impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of Vasovist.
Data from final batch analyses were reviewed and considered to be acceptable according to the specification of the drug product.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH established limits and/or were qualified from batch analysis and therefore, considered to be acceptable.
Stability
Based on the stability data provided, the proposed 36-month shelf-life for the drug product is considered acceptable when stored between 15-30°C and protected from light.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured. All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Vasovist has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
The non-clinical pharmacodynamic (PD) studies included in vitro and in vivo studies to assess the protein binding of gadofosveset and its effects on contrast imaging. The in vitro binding experiments indicated that gadofosveset binds exclusively to human serum albumin (HSA) and not to other plasma proteins. The protein binding was concentration dependent; the binding decreased as the concentration of the drug increased. At clinically relevant plasma concentrations (0 to 2 mM), the fraction of gadofosveset bound to HSA was high (75-96%). The binding of gadofosveset to serum albumin of different animal species and humans caused a distinct increase in the relaxivity of the contrast agent (5-10 times greater than that of the non-albumin binding standard contrast agent, gadopentetate), using the RIME (receptor-induced magnetization enhancement) strategy.
The ability of gadofosveset to enhance the imaging of stenotic vessels was evaluated in a pig model of renal artery stenosis after the administration of 0.05 mmol/kg gadofosveset. Dynamic (during or immediately after contrast agent administration) and steady-state gadofosveset-enhanced three-dimensional magnetic resonance angiogram images (3D MRA) were compared against the standard clinical techniques of contrast X-ray angiography and pre-contrast two-dimensional (2D) MRA in the presence of gradually increasing stenosis. The 2D pre-contrast MRA was not able to consistently depict stenotic vessels (6 out of 21). The gadofosveset-enhanced dynamic 3D MRA was able to depict stenosis in all cases (21 out of 21), and steady-state 3D MRA with gadofosveset depicted stenosis in most cases (18 out of 21). There was no significant difference in measured diameters between the dynamic contrast 3D MRA imaging and the x-ray angiography. Whereas there was a significant overestimation of stenotic lumen diameter as measured by steady state 3D MRA with gadofosveset as compared to contrast x-ray angiography.
The PD studies also investigated the effects of gadofosveset on the central nervous system (CNS), the cardiovascular system, renal function, and the blood coagulation system in animals.
CNS function of mice and rats was studied and only transient and short lasting effects at doses ≥ 1 mmol/kg were observed (e.g. CNS hyperexcitability in mice and slightly depressed respiration in rats). A dose of 1 mmol/kg gadofosveset decreased the threshold dose in pentylenetetrazole-treated rats for 30 minutes as a sign of a transient proconvulsive activity at this high dose.
Cardiovascular effects were studied in Beagle dogs and cynomolgus monkeys. The intravenous administration of gadofosveset to anesthetized Beagle dogs at doses ranging from 0.1 to 1 mmol/kg led to transient hemodynamic changes (e.g. decreases in mean arterial pressure, total peripheral resistance, pulmonary vascular resistance and increases in cardiac output, stroke volume, and central venous pressure) immediately after treatment which were significant and most pronounced at the 1 mmol/kg dose. Cardiovascular studies in anesthetized and conscious cynomolgus monkeys at doses ranging from 0.1 to 3 mmol/kg did not alter arterial pressure, heart rate or ECG rhythm. At the highest dose of 3 mmol/kg, the conscious monkeys had vomiting episodes but appeared normal thereafter.
The risk of QT interval prolongation was studied in the HERG-potassium channel assay, in isolated guinea pig papillary muscle preparations, and in ECG time intervals of dogs and monkeys. Study results demonstrated no significant risk of QT prolongation.
The impact on renal function was investigated in a series of in vitro and in vivo studies. It was determined that gadofosveset did not impair human kidney proximal tubule cell viability at concentrations up to 25 mM. In rats that received 1 mmol/kg, some alterations of renal function were observed. These included increased urine volume at 1 hour, increased urinary sodium and potassium at 2 hours, while the excretion of chloride was decreased for 4-6 hours after administration. Total excretion of sodium for 6 hours was increased, but potassium and chloride remained unchanged. In a monkey study with intravenous single doses of 0.03 and 2 mmol/kg, gadofosveset did not alter renal function or induce renal vacuolation.
In rat studies that assessed the impact of gadofosveset on blood coagulation, a dose of 1 mmol/kg transiently prolonged the prothrombin time and the activated partial thromboplastin time, for 30 and 10 minutes, respectively. These effects are most likely caused by the prolonged blood residence time of gadofosveset trisodium and the high dose given.
3.2.2 Pharmacokinetics
The pharmacokinetics of gadofosveset were studied in rats, rabbits, dogs, and monkeys.
Absorption
After intravenous administration of gadofosveset, plasma gadolinium levels declined in a biexponential manner in all species, with a rapid distribution phase followed by a slower elimination phase. However , in one study in rabbits and one study in dogs, declines following a tri-exponential pattern were reported. At the same dosages, the mean terminal half-life ranged from 23 minutes in rats to approximately 3 hours in monkeys.
Distribution
Gadofosveset binds exclusively to human serum albumin (HSA). The in vitro binding studies in multiple species indicated a wide range of binding across the various species. Differences observed in volume of distribution and clearance were related to the differences in plasma protein binding. At 0.1 mM gadofosveset, the extent of binding was greater in human, monkey and rabbit plasma (approx. 95%) and less in the dog, rat and mouse (77 to 67%).
Radiolabelled gadofosveset was found in low levels in the breast milk of rats 1 to 2 hours post-injection. This level was transient, and by 4 hours post-injection and beyond, levels were not detectable in rat breast milk.
Metabolism
Metabolism studies were carried out in rat, monkey and human liver microsomes. Within the detection limits of the HPLC assay used there appeared to be no evidence of metabolism of gadofosveset in rats and monkeys. Human microsome preparations also did not appear to show any evidence of biotransformation of gadofosveset. Therefore, no studies on the induction or inhibition of drug-metabolizing enzymes were performed.
Elimination
Renal elimination appeared to be the main route of excretion in rats, dogs and monkeys. In monkeys, greater than 90% recovery of gadofosveset in the urine was achieved within 72 hours. In dogs, approximately 68% was eliminated by the kidneys and 25% via the feces. In rats, approximately 80% was recovered in the urine and approximately 17% was recovered in the feces within 24 hours post-injection.
Gadofosveset appears to be dialyzable, but also appears to be dependent on the type of dialysis filter used and the type of dialyzer used. Only high flux dialyzers should be used to remove gadofosveset from patients during hemodialysis.
Drug Interactions
Binding interaction studies measured the effects of common protein-binding drugs (warfarin, ibuprofen, digitoxin, diazepam, ketoprofen, naproxen, diclofenac, and piroxicam) on the relaxation rates. All drugs tested caused some decrease in the plasma relaxation rate (1/T1) effect of gadofosveset at the highest concentrations tested (100x). However, only ibuprofen and naproxen reduced the 1/T1 value by 10% or more, at clinically relevant concentrations. The other protein binding studies focussed on the effect of gadofosveset on the binding of the other interacting drug (digitoxin, propranolol, verapamil, and warfarin) in human plasma. Initially warfarin was shown to have a statistically significant increase in free fraction in the presence of gadofosveset. This interaction was unexpected since gadofosvest binds primarily to site II on subdomain IIIA of HSA and warfarin binds to site I on subdomain IIA of HSA. However, a second in vitro protein binding study did not confirm this finding. A reason for this discrepancy was not obvious. The unbound fraction of 0.53% warfarin without gadofosveset in the first study may have been erroneously low. Since, warfarin and gadofosveset are expected to bind at separate binding sites this explanation seems reasonable, however, caution is still advised as there is no definitive data to support this claim.
3.2.3 Toxicology
Single-Dose Toxicity
The kidney was identified as the major target organ of gadofosveset. In rats that received high doses of the test drug, increases of urea nitrogen and creatinine along with increases in absolute and relative kidney weights were reported. Results also included minimal and moderate tubular vacuolation of the kidneys, as well as necrosis of the tubular epithelium and tubular lesions.
The highest tested non-lethal dose of 3.0 mmol/kg gadofosveset in mice and monkeys represented approximately 100-times the envisaged diagnostic dose of 0.03 mmol/kg in a single intravenous administration in humans. For the more sensitive species: rat and rabbit, the lethal doses represented 67-times the human dose. On the basis of the results of the acute toxicity studies, a risk of acute intoxication with gadofosveset is highly unlikely in humans.
Repeat-Dose Toxicity
Studies with gadofosveset were conducted in rats and monkeys over a period of 2 to 4 weeks. The main toxicological finding was vacuoaltion of the proximal tubular cells of the kidneys. The occurrence of this change is regarded as not being relevant or prohibitive for the diagnostic use of gadofosveset in humans for the following reasons:
- After single administration of 0.03 mmol/kg in rats, a no observed effect was noticed and in the more relevant species: monkeys, vacuolation was not observed up to single doses of 3.0 mmol/kg representing multiples of 100 over the single human diagnostic dose in terms of body weight. The lowest dose in rats which provoked vacuolation (0.12 mmol/kg) exceeds the intended diagnostic dose of gadofosveset by a factor of 4.
- At the diagnostic dose of 0.03 mmol/kg, kidney tubular vacuolation only occurred in rats after repeated administration over 4 weeks. In monkeys, the dose to elicit renal vacuolation after repeated administration (2 or 4 weeks) was ≥0.1 mmol/kg. Drug exposure (AUC) values were lower in rats when compared to monkeys, and point towards a more rapid excretion rate due to a lower fraction of bound gadofosveset in plasma and a higher glomerular filtration rate (GFR) in rats. This supports the argument that the observed renal vacuolation results mainly from a higher local exposure of the tubules at comparably lower doses in this species. Since plasma binding in humans is higher and GFR lower than in monkeys, the local tubular concentration of gadofosveset trisodium in humans will be even lower at identical doses than in monkeys. The sponsor has further confirmed the assumption by the findings of higher AUC values in humans compared to monkeys. Therefore, tubular vacuolation is not expected in humans after a single administration of the clinically intended dose.
- Results obtained during the recovery phases strongly point towards reversibility of the effect.
- No functional impairment of kidney function was observed at doses where vacuolation had not progressed towards tubular necrosis.
- Investigations of rat kidneys indicate that the observed vacuolation is a storage phenomenon not accompanied by obvious signs of cytotoxicity or necrosis.
- In vitro investigation did not reveal cytotoxicity towards human kidney cells at doses/concentrations expected to occur after clinical use of 0.03 mmol/kg.
- Vacuolation of the renal proximal tubular epithelial cells is characteristic of several iodine-containing contrast agents, including the structurally-related gadolinium-containing MRI agent. It has been shown that this phenomenon is mainly due to the storage of the contrast agent, and no functionally significant impairment of tubular or cellular processes was associated.
The second most prominent finding in the repeat-dose toxicity studies was the vacuolation of the macrophages in different tissues of rats and monkeys. Again, this finding is not regarded as being relevant or prohibitive for the diagnostic use of gadofosveset in humans for the following reasons:
- After a single dose, the first observation of vacuolated macrophages occurred at 1.0 mmol/kg in lungs and lymph nodes of rats. This dose in rats exceeded the intended clinical dose by a factor of 33 times in terms of body weight. In monkeys, vacuolation of macrophages did not occur with a single dose of 0.2 mmol/kg, which is 7 times more than the clinical intended dose.
- After repeated administration for 4 weeks, no vacuolation of macrophages was observed up to doses of 0.21 mmol/kg in rats and 0.1 mmol/kg in monkeys. Again the dose in monkeys and rats exceeds the intended clinical dose by factors of 3 and 7, respectively.
- Reversibility of the observed macrophage and reticuloendothelial cell vacuolation (indicated by a decrease in both incidence and severity) occurred at a faster rate than the kidney tubule vacuolation. In rats, the effects were completely reversible after a recovery period of 4 weeks. In the 4-week monkey study the vacuolation of macrophages had completely disappeared in the lung and was reduced to minimal severity in the lymph nodes after a 12-week recovery period.
- Except for macrophage or reticuloendothelial cell vacuolation, no obvious signs potentially pointing towards an impaired immune function such as histopathological changes in lymphoid organs, changes in lymphoid organ weights, changes in differential blood count or in the bone marrow were observed in the repeat-dose toxicity studies. Furthermore, investigations into macrophage function in rats did not reveal any impairment up to repeated doses of 0.5 mmol/kg. This dose exceeds the clinical dose by a factor of 17. Only at a repeated administration of 2.0 mmol/kg was there a weak indication of a functional impairment of macrophages.
Another effect that occurred in the repeat-dose toxicity studies was a slight decrease in red blood cell parameters (hemoglobin, hematocrit, erythrocyte count) occurring in rats at the dose 0.01 mmol/kg and in monkeys at 0.5 mmol/kg.
The observed effects on red blood cells in both species:
- Were slight, i.e., in no case exceeded 16% reduction of the measured parameters even at the highest doses tested of 2.0 mmol/kg.
- Were not accompanied by signs of hemolytic anemia (e.g., no increases in bilirubin). No hemolytic potential of gadofosveset trisodium was observed in vitro.
- Were fully reversible after a recovery period.
- Did not occur after a single administration even at a high dose of 3.0 mmol/kg.
The results of the systemic tolerance studies following the repeated daily intravenous administration produced no findings which oppose the diagnostic administration of gadofosveset to humans.
Genotoxicity
Results of the genotoxicity studies performed in vivo and in vitro demonstrated no evidence of genotoxic or mutagenic potential for gadofosveset.
Carcinogenicity
Carcinogenicity studies were not performed for gadofosveset. However, the results of the genotoxicity assays together with data from a carcinogenicity study for a structurally related compound do not indicate a carcinogenic potential of gadofosveset upon single use.
Reproductive and Developmental Toxicity
Reproduction and developmental studies demonstrated no risks of undesirable effects on the reproductive and developmental parameters, in particular, there was no risk of teratogenic effects which might arise from the diagnostic use of gadofosveset.
Local Tolerance
Good local tolerability of gadofosveset was observed after intravenous administration. Upon erroneous paravenous injection, a mild irritation of the skin might occur. Erroneous intraarterial administration may lead to a transient severe erythema, and moderate edema around the injection site. Inadvertent administration into the muscle might result in reversible effects such as hemorrhages, focal necrosis, and inflammatory reactions at the injection site.
Immunogenic Potential
Studies evaluating the sensitizing or immunogenic potential gave no indications for an antigenic or contact-sensitizing potential of gadofosveset in experimental animals. No evidence for a risk to the health of humans can be deduced for the impurities at their respective specification limits.
3.2.4 Conclusion
Gadofosveset was studied in a standard battery of pre-clinical pharmacodynamic and pharmacokinetic studies and no safety concerns were identified. Overall, the results of the toxicology studies performed with gadofosveset demonstrated no evidence of risk to the health of humans at the diagnostic dose of 0.03 mmol/kg.
3.3 Clinical basis for decision
3.3.1 Clinical Program
The 18 clinical studies included seven clinical pharmacology studies (two Phase I studies and five Phase II studies), six studies of the safety and efficacy of Vasovist in peripheral vascular disease (two Phase II studies and four Phase III studies), and five exploratory studies in other indications (one Phase I study and four Phase II studies).
The four Phase III studies of Vasovist for the magnetic resonance angiography (MRA) detection of vascular disease were conducted utilizing the same basic design across all studies. They were open-label, multicenter studies and were performed to evaluate safety and efficacy of Vasovist at the 0.03 mmol/kg dose (as well as the 0.05 mmol/kg dose in Study MS-325-15). These controlled trials enrolled 1,203 patients with various vascular diseases, including aorto-iliac occlusive disease, renal arterial disease and pedal arterial disease. The four Phase III studies and one Phase II study were considered pivotal. A total of 1,438 subjects (1,321 patients and 117 healthy volunteers) were administered Vasovist. Studies were also conducted in patients with renal and hepatic dysfunction, and with patients on renal dialysis.
3.3.2 Pharmacodynamics
The two Phase I studies demonstrated that gadofosveset binds to human serum albumin (HSA) causing an increase in plasma relaxation rate (1/T1). The change in 1/T1 kinetics (Δ1/T1) were similar to the plasma concentration kinetics. As the dose increased from 0.01 to 0.025 mmol/kg, the increase in Δ1/T1 was greater than when the dose increased from 0.025 to 0.05 mmol/kg. This resulted in significantly lower relaxivity (R1) levels for the 0.05 mmol/kg dose, as compared to the lower doses.
The decrease in relaxivity was most likely caused by a decrease in the percent of albumin-bound gadofosveset. Some sporadic changes in QTc were identified, indicating that additional evaluation is required. No clinically significant changes in ECG were reported.
3.3.3 Pharmacokinetics
Absorption
Within the dose range of 0.01-0.15 mmol/kg gadofosveset, the increase in plasma gadofosveset concentrations was less than dose proportional. This observation is consistent with the known protein binding characteristics of gadofosveset, in which the fraction bound decreases at plasma concentrations of gadofosveset greater than 0.15 mM. Although a non-linear trend is apparent at higher doses, near the clinical dose of 0.03 mmol/kg the pharmacokinetic parameters are nearly dose proportional. Study results showed that plasma concentrations after the 0.03 mmol/kg and 0.05 mmol/kg dose declined in a parallel manner.
Distribution
The steady-state volume of distribution (VSS), tended to increase slightly with an increase in dose >0.05 mmol/kg. The VSS values indicate that gadofosveset is distributed to the extracellular space.
Metabolism
Analyses of plasma and urine samples indicate that gadofosveset is not metabolized.
Excretion
Renal excretion is the principle route of elimination of gadofosveset. In healthy subjects, the mean percent of dose excreted in urine over a 14-day collection period was 83.7+4.2%. An additional 4.7% was recovered in the feces indicating a minor role of biliary excretion in the elimination of gadofosveset.
Drug Interactions
Interaction with other plasma protein bound drugs is theoretically possible. Large doses of highly protein bound drugs, (i.e., warfarin, S-ketoprofen, piroxicam, digitoxin, diazepam, ibuprofen, R-ketoprofen, naproxen, and diclofenac) would be required to make the decrease in 1/T1 clinically relevant. Warfarin therapy does not appear to affect the pharmacokinetics and pharmacodynamics (PK/PD) of gadofosveset. The effect of gadofosveset on warfarin PK/PD remains uncertain.
Special Populations
Age and gender had no significant effects on the PK parameters of gadofosveset.
Patients with increased renal impairment demonstrated no significant changes in plasma concentration or mean percent bound vs. time in the one hour post-administration window that will be used for imaging. However, the rate of elimination was influenced by the degree of renal insufficiency; the amount of drug excreted in the urine decreased while the amount excreted in the feces increased.
No significant PK differences were detected in patients with moderate hepatic impairment. A slight decrease in mean fecal excretion was reported with the hepatically impaired patients compared to those with normal hepatic function.
3.3.4 Clinical Efficacy
Four multicentre, open-label, Phase III studies evaluated the clinical efficacy of Vasovist as a contrast agent for magnetic resonance angiography (MRA) detection of vascular disease. These controlled trials enrolled 759 patients of which 672 patients received the 0.03 mmol/kg dose intravenously. The studies were designed to determine the sensitivity, specificity and overall accuracy of Vasovist-enhanced MRA compared to pre-contrast MRA using catheter X-ray angiography (XRA) as the standard of reference for the detection of vascular disease.
For the primary analysis in each Phase III study, a diagnosis for the presence or absence of disease in vascular beds was performed. In these vascular beds (aorto-iliac, femoral, renal, and pedal), clinically significant disease was defined as ≥50% diameter stenosis. In addition, other clinically relevant secondary endpoints were used to provide more data to compare post-contrast MRA with the clinical standard, catheter angiography, for the anatomic characterization of these lesions. The analyses included: a) a direct comparison of the percent stenosis measurement by MRA and by catheter-based angiography (XRA); (b) a receiver operator characteristic (ROC) analysis based on a grading of stenosis on a qualitative scale of 1-5 for the presence of disease; and (c) a separate interpretation of all the MRA and XRA data by interventionalists (vascular surgeons) to determine how the images would be used in patient management decisions.
The primary analysis and secondary analysis demonstrated that overall, there is an increase in diagnostic capabilities after the use of Vasovist injection as a contrast agent. The detection of clinically significant stenosis in the 0.03mmol/kg Vasovist-enhanced MRA (post-contrast) exams is shown in the following table.
| Phase III Studies | Improvement pre-contrast MRA to Vasovist-enhanced (post-contrast) MRA, range, % | Statistically Significant for Three Readers |
|---|---|---|
| MS-325-12 | ||
| Sensitivity | 6-19% | 2/3 p<0.001 |
| Specificity | 8-20% | 3/3 p<0.001 |
| Accuracy | 8-20% | 3/3 p<0.001 |
| MS-325-13 | ||
| Sensitivity | 22-31% | 3/3 p<0.001 |
| Specificity | 9-12% | 3/3 p<0.001 |
| Accuracy | 11-13% | 3/3 p<0.001 |
| MS-325-14 | ||
| Sensitivity | 25-42% | 3/3 p<0.01 |
| Specificity | 23-29% | 3/3 p<0.01 |
| Accuracy | 23-29% | 3/3 p<0.001 |
| MS-325-15 | ||
| Sensitivity | * | 1/3 p<0.001 |
| Specificity | 21-35% | 3/3 p<0.01 |
| Accuracy | 7-18% | 2/3 p<0.005 |
* Reader B had a decrease in Sensitivity of -9% and Reader C had an increase of 0.5%
In the supportive efficacy analysis, combining the results of the three readers showed improvements in sensitivity (range of improvements pre- to post-contrast 15-28%, p<0.001%) in the Phase III studies MS-325-12, MS-325-13 and MS-325-14; improvements in specificity (range of improvements pre- to post-contrast 9-25%, p<0.001%) for all four Phase III studies; as well as improvements in accuracy (range of improvements pre- to post-contrast 12-27%, p<0.001%) for all four studies. There was a non-significant increase in sensitivity post-contrast of 1.3% in study MS-325-15.
In the secondary efficacy analysis, improvements were seen in the assessment of clinically significant disease with the Vasovist-enhanced MRA examinations. All of the readers showed improved confidence in diagnostic ability and these improvements were statistically significant except for one reader in study MS-325-15. For the pre-contrast MRA or unenhanced MRA, the average proportion of uninterpretable images (UIs) was 10-34%, which decreased to 1-3% post-contrast. With the use of XRA, the average proportion of UIs was between 3-8%. The Vasovist-enhanced MRA treatment plans were in agreement with XRA-based patient management decisions and the agreement was substantially increased compared to unenhanced MRA treatment plans. In all four studies, Vasovist provided a significant improvement in diagnostic efficacy compared to unenhanced MRA.
3.3.5 Clinical Safety
In the clinical studies, a total of 1,328 patients received doses of Vasovist ranging from 0.005-0.100 mmol/kg. Of the 767 patients who received the 0.03 mmol/kg dose, 176 (22.9%) reported at least one adverse event (AE) considered to be treatment-related. At the 0.03 mmol/kg dose, the most common treatment-related AEs were pruritus (4.4%), headache (2.2%), nausea (3.8%), vasodilatation (2.9%), paresthesia (2.6%), dysgeusia (2.2%), and burning sensation (2.0%). Most of the AEs were mild to moderate in intensity. The less common side effects are listed in the Product Monograph. Many of the serious AEs were not related to Vasovist. The one allergic reaction that occurred was considered mild and was resolved with treatment.
However, there is data suggesting that Vasovist might play some role in the prolongation of the QTc interval, both at the clinical dose as well as at higher doses. There was a statistically significant increase seen in QTc at the 45-minute time point following the 0.03 mmol/kg dose and the greater than 0.05 mmol/kg dose. The absolute value for the change in baseline was 2.8 msec for the proposed clinical dose 0.03 mmol/kg, which was less than the placebo change of 3.2 msec. However, at doses >0.05mmol/kg, (0.07 and 1.0 mmol/kg combined), the mean increase in QTc was 8.8 msec. Using Fredericia's correction (FC) for the same time points, a change of 3.6 msec for the 0.03 mmol/kg group at 45 minutes was observed, while the change for the placebo group at the same time point was 4.7 msec. The QTc change (FC) for the >0.05mmol/kg group was 8.5 msec.
Changes from baseline QTc of 30-60 msec at the 45-minute time point were seen in 2.6% of the placebo group, 5.6% of the 0.03 mmol/kg group, 4.5% of the 0.05 mmol/kg group, 2.7% of the 0.07 mmol/kg group and 10% of the 0.1 mmol/kg group. The highest rate of incidence was seen in the 0.1 mmol/kg group. This increase is not considered as dose related as there was a high incidence at the suggested dose (0.03 mmol/kg) and also at the highest dose.
QTc increases from baseline of >60 msec at the 45-minute time point were seen in 0% of the placebo group, 0.4% of the 0.03 mmol/kg group, 0% of the 0.05 mmol/kg, 0% of the 0.07 mmol/kg group, and 1.4% of the 0.1 mmol/kg group. These changes are not considered to be dose related, but there does seem to be some suggestion that the highest dose might contribute to the effect.
Some absolute values of QTc >500 msec at the 45-minute time point were seen in the different dosage groups. This occurred in none of the patients who received placebo, and in 6 (1.3%) of the patients who received the 0.03 mmol/kg dose.
While realizing that there is a wide variation in the QTc values in this patient population, it cannot be excluded that Vasovist plays no role in the changes observed. In the absence of a study specifically designed to examine QTc effects, it cannot be excluded that Vasovist may be associated with QTc prolongation. The Product Monograph reflects this concern and contains appropriate information in this regard.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Diseases of blood vessels can occur in many parts of the body. Atherosclerotic disease in vessels contributes to death caused by cardiac events, strokes, limb-ischemia and loss, and other morbidities. In order to know how best to treat the vascular disease problem, it is necessary to have an objective measurement of the severity and location of the vascular lesion in question. The goal of any method of angiography is to localize and characterize the lesion, so as to allow for planning of further treatment, either medical or surgical.
The Phase III clinical studies have shown that there is an increase in diagnostic capabilities after the use of Vasovist (gadofosveset trisodium injection) as a contrast agent in magnetic resonance angiography (MRA). After Vasovist administration, the MRA exams showed an improvement that was statistically significant. In terms of accuracy, sensitivity and specificity, all except the specificity in one study were within 10% or less of the "gold standard" of x-ray contrast angiography.
The binding of gadofosveset to albumin in the blood gives Vasovist three properties that enhance vascular imaging with magnetic resonance imaging (MRI): (a) increased plasma concentration of the contrast agent, (b) prolonged vascular residence time of the contrast agent, and (c) increased signal enhancement per mole of agent. When taken as a whole, these three factors should facilitate the acquisition of contrast-enhanced MRI scans of vascular structures for up to 60 minutes following Vasovist administration. The longer vascular imaging period allows for the acquisition of reliable, high resolution MRA images in order to aid in the characterization of vascular abnormalities such as stenosis or aneurysm.
Other advantages of Vasovist include a decrease in the incidence of contrast media nephropathy, the elimination of complications caused by arterial puncture, less severe allergic reactions, and the ability to obtain 3D images. The patient undergoing the procedure receives less ionizing radiation, a shorter acquisition time, and less need for conscious sedation.
The most common side effects of Vasovist were pruritus, headache, nausea, vasodilatation, paresthesia, dysgeusia, and burning sensation. Another disadvantage is the concern for QTc prolongation. At the highest doses studied (3.3x the recommended dose) there were signs of QTc prolongation. This topic is discussed in section 3.3.5 Clinical Safety. In the absence of a dedicated QTc study with placebo and active controls, it is not possible to conclude that Vasovist is free from QTc interval prolonging effects, therefore full QTc labelling was incorporated into the Product Monograph.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Vasovist is favourable for contrast-enhanced magnetic resonance angiography for visualization of abdominal or limb vessels in patients with suspected or known vascular disease. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: VasovistTM
| Submission Milestone | Date |
|---|---|
| Submission filed with BGTD in error | 2004-12-22 |
| Submission re-routed to TPD | 2005-01-26 |
| Submission filed with TPD | 2005-01-26 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2005-03-31 |
| Review 1 | |
| Quality Evaluation complete | 2006-01-11 |
| Clinical Evaluation complete | 2006-01-23 |
| Biostatistics Consult complete | 2006-01-23 |
| NON issued by Director General (labelling issues) | 2006-01-24 |
| Response filed | 2006-05-04 |
| Screening 2 | |
| Response filed | 2006-05-04 |
| Screening Acceptance Letter issued | 2006-06-15 |
| Review 2 | |
| NOC issued | 2006-10-30 |
| NOC/c issued by Director General | 2006-10-31 |