Summary Basis of Decision for Vibativ
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:
Vibativ
Telavancin hydrochloride, 250 mg/vial, 750 mg/vial, Powder for solution, Intravenous
Astellas Pharma Canada Inc.
Submission control no: 107792
Date issued: 2010-01-07
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):
- 02330717 - 250 mg/vial
- 02330725 - 750 mg/vial
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On September 29, 2009, Health Canada issued a Notice of Compliance to Astellas Pharma Canada, Inc. for the drug product Vibativ. Vibativ contains the medicinal ingredient telavancin which is a lipoglycopeptide antibiotic.
Vibativ is indicated for the treatment of patients with complicated skin and skin structure infections (cSSSI) caused by susceptible strains of the following Gram-positive microorganisms: Staphylococcus aureus (methicillin-resistant [MRSA] and -susceptible strains [MSSA]), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), and Enterococcus faecalis (vancomycin-susceptible isolates only). Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative organisms.
The bactericidal activity of telavancin results from a multifunctional mechanism of action that contributes to a low potential for selection of resistant mutants of Gram-positive bacteria. The multifunctional mechanism of action of telavancin includes the inhibition of bacterial cell wall synthesis and the disruption of the functional integrity of the bacterial membrane.
The market authorization was based on quality, non-clinical, and clinical information submitted. The safety and efficacy were assessed in two large, randomized, multicentre, double-blind, active-controlled studies in adult patients with clinically documented cSSSI. Vibativ was shown to be non-inferior and as effective as vancomycin for the treatment of cSSSI due to the susceptible strains. Vibativ was not studied in patients with diabetic foot ulcers, ischaemic ulcers/wounds, necrotizing fasciitis, gas gangrene, burns involving >20% of body surface area or those that are third degree/full-thickness in nature, prosthetic materials, osteomyelitis, endocarditis, mediastinitis or other deep site tissue infection (other than skin and skin structure infection). Three major safety issues were identified in this drug submission: 1) teratogenicity, 2) renal toxicity, and 3) QT prolongation. These issues have been addressed through appropriate labelling in the Product Monograph.
Vibativ (250 mg telavancin/vial and 750 mg telavancin/vial, telavancin as telavancin hydrochloride) is presented as a powder for solution. The recommended dosing for Vibativ is 10 mg/kg administered over a 60-minute period by intravenous infusion once every 24 hours for 7 to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patient's clinical and bacteriological progress. Dosing guidelines are available in the Product Monograph.
Vibativ is contraindicated for use in patients who have known hypersensitivity to this drug or to other glycopeptides or to any ingredient in the formulation or component of the container. Developmental and reproductive toxicology studies in both rats and rabbits demonstrated a low incidence of limb defects. There are no adequate and well-controlled studies in pregnant women with Vibativ. Vibativ should not be used during pregnancy unless the benefit to the mother outweighs the risk to the foetus. Detailed conditions for the use of Vibativ are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Vibativ is favourable for the indications stated above.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Telavancin, as telavancin hydrochloride, is the medicinal ingredient of Vibativ. Vibativ is a lipoglycopeptide antibiotic that has shown multiple mechanisms of action against clinically important Gram-positive bacteria. Telavancin inhibits bacterial cell wall synthesis and disrupts the functional integrity of the bacterial membrane.
.
Manufacturing Process and Process Controls
Telavancin hydrochloride is manufactured via a multi-step synthesis. In-process controls performed during manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
Detailed characterization studies were performed to provide assurance that telavancin hydrochloride consistently exhibits the proposed chemical structure.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits are considered adequately qualified [that is (i.e.) within International Conference on Harmonisation (ICH) limits or qualified from batch analysis or toxicological studies]. Control of the impurities and degradation products is therefore considered acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of telavancin hydrochloride are considered acceptable. Data from batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed retest period for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Vibativ is presented as 250 mg/vial or 750 mg/vial.
Vibativ is a sterile, white to pale pink lyophilized powder containing telavancin hydrochloride (equivalent to either 250 mg or 750 mg of telavancin as the free base). The inactive ingredients are hydroxypropylbetadex (hydroxypropyl-beta-cyclodextrin), mannitol, and sodium hydroxide and hydrochloric acid used in minimal quantities for pH adjustment. The lyophilized powder for injection is contained in a glass vial with a rubber stopper and a flip-off seal.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of telavancin hydrochloride 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 pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Vibativ is tested to verify that its identity, appearance, content uniformity, assay, pH, particulate matter, sterility, moisture content, levels of degradation products, and bacterial endotoxins are within acceptance criteria. The test specifications are within acceptable limits.
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of Vibativ. Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed
24-month shelf-life is considered acceptable when Vibativ is contained in the proposed container and is stored at 2°C to 8°C. 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 of Vibativ are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Vibativ 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 Microbiology
Telavancin is a lipoglycopeptide antibiotic with multiple mechanisms of action against clinically important Gram-positive pathogens. Telavancin inhibits cell wall synthesis by inhibition of peptidoglycan biosynthesis. Telavancin also interacts with the bacterial membranes dissipating the membrane potential and effecting changes in permeability.
In vitro studies show telavancin is bactericidal against the principal target organisms of complicated skin and skin structure infection, staphylococci and streptococci. The bactericidal activity of telavancin at both plasma peak and trough concentrations against staphylococci has been demonstrated in vitro. In vitro studies have been performed to assess the potential for the emergence of resistance to telavancin. The results from single-step and serial-passage experiments suggest that there is a low potential for emergence of telavancin resistance against staphylococci and streptococci as well as against vancomycin-susceptible and VanB-type enterococci.
The antibacterial efficacy of telavancin has been demonstrated in vivo against infections caused by clinically important Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, in several relevant animal models of infections either with or without an intact host immune system.
3.2.2 Pharmacodynamics
Several pharmacology studies were conducted to determine if telavancin had the potential to delay ventricular repolarization (QT interval prolongation). In a study of the effects on hERG potassium currents, telavancin significantly inhibited the hERG tail current at concentrations of 15 μg/mL and greater when compared to placebo. However, in a study of the effect on action potential parameters using sheep cardiac Purkinje fibres, telavancin at concentrations up to 150 μg/mL had no effect on action potential duration or other action potential parameters when the fibres were paced at a stimulation frequency of 1 Hz. Therefore, telavancin is not expected to have a direct effect on the QRS complex duration or the QT interval. In dogs, administration of telavancin by intravenous (IV) infusion at doses up to 100 mg/kg also did not result in any cardiovascular changes.
3.2.3 Pharmacokinetics
Absorption
In mice and rats, telavancin showed a dose-proportional increase in the maximum plasma concentration (Cmax) and area under the curve (AUC) values with doses 1 mg/kg to 25 mg/kg by IV infusion. The drug exposure parameters (Cmax and AUC) also appeared to increase in a linear dose-dependant manner in rabbits, following the IV infusion of 10 mg/kg and 50 mg/kg telavancin.
Distribution
Telavancin was highly (>90%) protein bound in mouse, rat, dog, rabbit, and human plasma. In mice, rats, and dogs, telavancin was widely distributed in tissues following IV administration. The highest concentrations were found in the liver and kidney.
Metabolism
In vitro metabolism studies indicated that telavancin was stable in rat, dog, and human: liver microsomes, liver and renal S9 fractions, and liver and kidney slices. None of the following recombinant cytochrome P450 (CYP) isoforms were shown to metabolize telavancin: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and CYP4A11. The activities of CYP2D6 and CYP3A in human liver microsomes were unaltered by co-incubation with telavancin at a concentration of 10 μg/mL. However, at higher concentrations (100 μg/mL), a weak inhibitory effect was noted towards both CYPs. The inhibitory effect of 100 μg/mL of telavancin on CYP3A activity in human liver microsomes was slightly greater than vancomycin. This suggests that telavancin may be a moderate inhibitor of CYP3A and CYP2D6.
Hydroxylated metabolites were recovered from the urine of mice, rats, and dogs. In the radiolabelled studies conducted in mice, the majority of the radioactivity in urine was primarily the unchanged drug (78.6%), with metabolites accounting for the other 21.4% of the total radioactivity. Similar results were seen with rats. From male and female dog urine samples, the metabolites accounted for 15.5% and 22% of the total radioactivity, respectively.
Excretion
Urinary excretion was the major route of elimination for telavancin in the animals studied.
3.2.4 Toxicology
Single-Dose Toxicity
A single-dose toxicity study in mice found the minimum lethal dose to be 100 mg/kg, with the maximum tolerated dose for males being 50 mg/kg and 35 mg/kg for females. A similar study in rats found the minimum lethal dose to be 100 mg/kg for males and >150 mg/kg for females. The maximum tolerated dose was considered to be 50 mg/kg for male rats and 150 mg/kg for female rats.
Repeat-Dose Toxicity
Long-term toxicity studies of 2, 4, and 13 weeks were conducted in rats and dogs, and a 26-week study was conducted in rats. In the 2-week study with rats that received telavancin 25 mg/kg/day, an increased incidence of granular casts and positive urine occult blood tests were noted. Renal tubular vacuolation was also present. In the 2-week toxicity study in dogs, however, no clinical or anatomical pathology findings were seen with the dose of 25 mg/kg/day. After 4 weeks of 50 mg/kg/day in rats, telavancin was associated with increased levels of blood urea nitrogen (BUN) and creatinine. Renal tubular degeneration, renal tubular vacuolation, and urothelial cell vacuolation were also observed. These effects occurred at a drug exposure similar to those measured in the clinical trials. In the 4-week study in dogs using 50 mg/kg/day, hypersensitivity (histamine) reactions during the first week of dosing were seen. Pathologic changes were confined to multifocal bilateral renal (cortical) tubular dilatation. Renal tubular vacuolation and renal tubular degeneration/necrosis were also present, as well as vacuolation of the urothelium of the renal pelvis and urinary bladder.
After 13 weeks of 50 and 100 mg/kg/day in rats, the effects were consistent with the findings of hepatocyte degeneration and proximal tubular degeneration. The 13-week toxicity study in dogs resulted in histamine reactions during the first 3 weeks of dosing. Increases in aspartate aminotransferase (AST), alanine transaminase (ALT), BUN and creatinine were also noted. Hepatocellular degeneration/necrosis was seen, as well as macrophage vacuolation in a variety of tissues and organs (liver, kidneys, lungs, lymph nodes, spleen, oesophagus, heart, and salivary gland), parenchyma kidney lesions (tubular vacuolation, dilatation, necrosis, and eosinophilic cytoplasmic inclusions), urothelial vacuolation in the kidneys, prostatic urethra and urinary bladder, and tubular vacuolation in the epididymides. The 26-week study in rats resulted in lower red blood cell (RBC) counts, haemoglobin, and haematocrit, as well as increased BUN, creatinine, AST, and ALT. Microscopic alterations included vacuolation of diffuse cortical tubular epithelial cells, renal tubular dilation/casts, vacuolation of epididymal epithelial cells, vacuolation of epithelioid venules, and macrophage hypertrophy/hyperplasia.
Genotoxicity
Telavancin was not mutagenic in the Ames bacterial reverse mutation assay, and was not clastogenic in the in vitro chromosome aberration test and the micronucleus study in mice.
Carcinogenicity
Given that the dosing regimen is only 14 days, long-term carcinogenic studies in animals were not performed. Pharmaceuticals administered infrequently or for short duration of exposure do not need carcinogenicity studies unless there is cause for concern
Reproductive and Developmental Toxicity
After 10 weeks of dosing (50, 75, and 100 mg/kg/day) in rats, telavancin showed no effects on the fertility indices despite showing effects on sperm parameters (i.e., number, motility, and morphology).
Embryo-foetal developmental studies conducted in rats and rabbits suggest that telavancin is teratogenic. Malformations occurred in animals exposed to approximately 1 to 2-fold the clinical dose based on AUC.
The Product Monograph has a Serious Boxed Warning to warn about the teratogenic effects of telavancin based on the results of the animal studies, and the sponsor is committed to a risk mitigation strategy that includes a pregnancy registry.
Immunotoxicity
Telavancin produced immunomodulatory effects, as evidenced by changes in the antibody response to sheep RBCs and macrophage function. These effects included slight decreases in the antibody response to a T-cell dependent antigen, increases in macrophage phagocytosis, and decreases in macrophage respiratory burst activity.
3.2.5 Conclusion
Telavancin has demonstrated in vitro and in vivo activity against the Gram-positive microorganisms listed in the indication. The non-clinical studies support its safe use in humans as described in the Product Monograph. Adequate statements are in place in the Product Monograph to address the identified safety concerns.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
A thorough Phase I randomized, placebo-controlled and active-controlled, parallel-group study examined the potential effects of Vibativ on the QT interval in 160 volunteers. All of the analyses, including the primary analysis (QTcF), indicated that both telavancin 7.5 mg/kg and telavancin 15 mg/kg prolonged the QT interval more than placebo, but less than 400 mg moxifloxacin. The Product Monograph states that Vibativ should be used with caution in patients taking concomitant medications with any risk of Torsades de pointes.
3.3.2 Pharmacokinetics
Absorption
Vibativ is administered intravenously, therefore absorption is not relevant.
Distribution
In the in vitro protein-binding studies, televancin was highly protein bound, with >90% bound in human plasma. Telavancin appeared to be a low clearance drug with a small volume of distribution. Linear pharmacokinetics for telavancin was demonstrated with both single and multiple dose administration in healthy volunteers.
Televancin is indicated for the treatment of patients with complicated skin and skin structure infections. Good penetration of telavancin into the skin blister fluid was observed in the study. At every time point throughout the 24-hour dosing interval, the concentration of free telavancin in the skin blister fluid exceeded the minimum inhibitory concentration required to inhibit the growth of 90% of organisms (MIC90) for strains of Staphylococcus aureus (0.5 μg/mL).
Metabolism
Telavancin is not extensively metabolized. The metabolic profile of urine samples from humans indicates the presence of three hydroxyl metabolites of telavancin. The metabolic route by which these three metabolites are formed is not known. The CYP450 system does not appear to be involved in the metabolism of telavancin.
Excretion
Renal excretion is the major route of elimination of telavancin. Less than 1% of the drug was recovered from faeces.
Drug Interactions
In vitro drug-drug interaction studies demonstrate that telavancin exhibited weak inhibitory effects on CYP3A4 in pooled human liver microsomes. However the pharmacokinetic disposition of midazolam, a well-characterized substrate for CYP3A4, was not affected with concurrent administration of telavancin.
Aztreonam and piperacillin/tazobactam are two antibiotics with complementary spectra of activity to that of telavancin, making them candidates for coadministration with telavancin. Drug interaction studies have been conducted and no clinical drug interactions are expected if these drugs are used in combination in clinical practice.
Special Populations
Renal Impairment
The effects of renal impairment on the pharmacokinetics of telavancin were studied. The pharmacokinetic disposition of telavancin was influenced in a graded fashion by the degree of renal impairment. Elimination half-life was approximately 2- to 2.5-fold higher in subjects with severe renal impairment and end-stage renal disease compared with subjects with normal renal function. Telavancin was not cleared to a significant degree by haemodialysis.
Hepatic Impairment
The pharmacokinetic parameters of telavancin were similar for subjects with mild and moderate hepatic impairment and normal subjects. The study presented did not include subjects with severe hepatic impairment.
3.3.3 Clinical Efficacy
Two Phase III studies (ATLAS 1 and ATLAS 2) assessed the safety and efficacy of Vibativ in adult patients with complicated skin and skin structure infections (cSSSI) due to Gram-positive bacteria with an emphasis in patients with infections due to methicillin-resistant Staphylococcus aureus (MRSA).The number of patients that were enrolled in ATLAS 1 and ATLAS 2 were 855 and 1012, respectively.
The two Phase III studies were multinational, multicentre, double-blind; active-controlled studies of Vibativ 10 mg/kg versus the comparator, vancomycin. Patients were randomized to receive either Vibativ 10 mg/kg IV once daily or vancomycin 1 g IV every 12 hours, for 7-14 days.The study design in both studies was identical; therefore data could be pooled to assess the superiority of Vibativ to vancomycin in MRSA patients. The primary objective of both studies was to demonstrate the non-inferiority of Vibativ to vancomycin in the primary efficacy endpoint: clinical cure rates at a follow-up [Test-of-Cure (TOC)] visit. The clinical response was determined by assessing the patient's clinical signs and symptoms at the specified evaluation compared with the signs and symptoms present at the baseline evaluation.
The analysis populations were defined as follows:
- All-Treated (AT), all enrolled patients who received any amount of study medication;
- Modified All-Treated (MAT), patients in the AT population with a pathogen isolated from pre-treatment cultures;
- Clinically Evaluable (CE), patients in the AT population who met all pre-specified criteria for evaluability;
- Microbiologically Evaluable (ME), patients in the CE population with a pathogen isolated from pre-treatment cultures.
The AT and CE populations were considered to be co-primary for the analysis of non-inferiority to vancomycin.
Both efficacy studies independently met their primary objectives. The results of the primary efficacy endpoint, clinical cure at TOC, in the AT and CE analysis populations, demonstrated that Vibativ 10 mg/kg is non-inferior to vancomycin using the pre-specified non-inferiority margin of 10%. The lower bound of the 95% confidence interval (CI) of the difference between Vibativ and vancomycin in all analysis populations was greater than -5%. In each of these studies (as well as in the combined population), cure rates were consistently in the 85-90% range in the CE population and in the 70-80% range in the AT population; and the 95% CI around the difference between treatments in cure rates included the value of zero. The overall therapeutic response in the combined ME population from both studies was 88.6% for the Vibativ group compared with 86.2% for the vancomycin group.
Staphylococcus aureus was the predominant pathogen at Baseline, isolated from the primary infection site in 82% of the Vibativ patients and 85% of the vancomycin patients in the pooled studies. The clinical cure rates were in the 85-90% range in the ME population and in the 70-80% range in the MAT population.
In the pooled studies, the clinical cure rates favoured Vibativ over vancomycin in the CE (MRSA) population, and were comparably high in the Vibativ and vancomycin groups in the AT (MRSA) population. While superiority analyses did not demonstrate statistical superiority of Vibativ 10 mg/kg over vancomycin at the 1-sided 0.025 levels, the p values of 0.053 for MRSA-specific microbiologic response and 0.032 for overall therapeutic response were favouring Vibativ.
The microbiologic eradication rates and overall therapeutic response rates correlate with the clinical response outcomes. For all efficacy parameters, Vibativ was demonstrated to be clinically non-inferior to vancomycin using the pre-specified non-inferiority margin of 10% in both the AT (MRSA) and CE (MRSA) populations, and the results favoured Vibativ over vancomycin.
The pathogen-specific clinical cure rates for patients infected with other Gram-positive pathogens (Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus and Enterococcus faecalis), in the efficacy and safety studies, individually and combined, were comparably high in the Vibativ 10 mg/kg and vancomycin groups, ranging from 72-100% in the MAT population and from 80-100% in the ME population for the combined studies. Similarly, microbiologic eradication rates for Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus and Enterococcus faecalis in the efficacy and safety studies individually and combined, were comparably high in the Vibativ 10 mg/kg and vancomycin groups, ranging from 80-100% in the MAT population and from 91-100% in the ME population for the combined studies.
Overall, patients with renal impairment with a creatinine clearance (CrCl) of <50 mL/min in the pooled ME and TOC analysis set had lower cure rates than those with no renal impairment and required a dosage adjustment to the study drug.
The results of a Phase II randomized, double-blind, multinational study of Vibativ 10 mg/kg versus standard therapy support the results of the Phase III studies. Clinical and microbiologic response rates were generally higher in the patients treated with Vibativ, although the differences were not statistically significant.
3.3.4 Clinical Safety
In the two Phase III studies, ATLAS 1 and ATLAS 2 (described in section 3.3.4 Clinical Efficacy), 929 patients were treated with the recommended dose of Vibativ 10 mg/kg. The most common adverse events were dysgeusia or taste disturbance (33%), nausea (22%), urine abnormality or foamy urine (12%), vomiting (11%), headache (9%), diarrhea (6%), and insomnia (5%). These events were generally mild to moderate in severity and transient in duration.
In the combined Phase II and Phase III clinical studies, 8% of patients treated with Vibativ discontinued treatment due to adverse events versus 5% of patients who received comparator. The most frequently reported treatment-emergent adverse events resulting in discontinuation of study medication among patients treated with Vibativ 10 mg/kg were nausea (1%), rash (0.9%), increased blood creatinine and vomiting (0.7% each), acute renal failure and osteomyelitis (0.6% each).
Serious adverse events were reported in 7% of patients treated with Vibativ and 4% of patients treated with comparator. Twenty-six patients (2%) in the Vibativ group experienced at least one possibly/probably related serious adverse event compared with 13 patients (1%) in the comparator group. The most frequent treatment-emergent adverse events reported in patients treated with Vibativ were renal failure acute (0.4%), myocardial infarction (0.4%), anaemia (0.3%), drug hypersensitivity (0.3%), mental status changes (0.3%), and renal insufficiency (0.3%).
Eighteen deaths are known to have occurred during the entire cSSSI clinical development program. They were assessed as possibly/probably related to the study medication.Nine patients who received Vibativ died (one patient received 7.5 mg/kg, eight patients received 10 mg/kg), compared with nine patients who received the comparator.
Vibativ is associated with an increased risk of renal toxicity, primarily in patients receiving concomitant medications known to affect kidney function, or patients with baseline conditions known to predispose to kidney dysfunction. Therefore Vibativ is not recommended for use in patients with severe renal impairment (CrCl <30 mL/min) and in patients with end-stage renal disease requiring haemodialysis. Patients in this subgroup had decreased efficacy and had an increased incidence of renal adverse events, serious adverse events, and discontinuations due to adverse events.
Rapid intravenous infusions of the glycopeptide class of antimicrobial agents, and Vibativ, have been associated with reactions similar to "Red-man syndrome" including flushing of the upper body, urticaria, pruritus, or rash. Vibativ should be administered over a period of not less than 60 minutes as recommended in the Product Monograph.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Complicated skin and skin structure infections (cSSSI) caused by Gram-positive bacteria are of a clinical importance because of the epidemiological implication and the resultant capacity to cause serious and life-threatening diseases. Staphylococcus aureus is the most common pathogen isolated from cSSSI. Of particular concern is the methicillin-resistant Staphylococcus aureus (MRSA) and strains with diminished susceptibility to vancomycin. These strains are becoming increasingly prevalent, in the community as well as in the hospital setting; in Canada it is primarily hospital-acquired.
Vancomycin remains the first-line therapy for severe infections where MRSA is suspected or documented. However, there are now six recognized strains of MRSA that is resistant to vancomycin. Vibativ was developed as a bactericidal agent with multiple mechanisms of action that would provide an alternative to the conventional therapy for the treatment of serious infections.
Vibativ has shown efficacy for the treatment of cSSSI caused by susceptible strains of the following Gram-positive microorganisms: Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), and Enterococcus faecalis (vancomycin susceptible isolates). Vibativ has shown potent activity against drug-resistant strains of Gram-positive bacteria, including those resistant to linezolid, daptomycin, vancomycin and fluoroquinolones.
The results of the efficacy analysis demonstrated that Vibativ is at least as effective as vancomycin and consistently showed higher cure rates in all the primary analysis populations across primary and secondary endpoints. In addition, the results suggest potentially superior efficacy of Vibativ compared with vancomycin in patients who are infected with MRSA.Vibativ 10 mg/kg administered once daily (with dose adjustment for moderate renal impairment) demonstrated a safety profile compatible with treatment of complicated skin and skin structure infections due to Gram-positive pathogens, including resistant strains.
Overall, the data presented in this application demonstrate that Vibativ has a favourable benefit to risk profile for use in accordance with the proposed labelling. Considering the public health need for drugs to treat resistant pathogens, Vibativ represents an important therapeutic gain for the treatment of cSSSI.
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 Vibativ is favourable in the treatment patients with complicated skin and skin structure infections caused by susceptible strains of the following Gram-positive microorganisms: Staphylococcus aureus (methicillin-resistant and -susceptible strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), and Enterococcus faecalis (vancomycin-susceptible isolates only). Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative organisms. The New Drug Submission (NDS) complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Vibativ
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2007-06-20 |
| Submission filed: | 2007-10-03 |
| Screening 1 | |
| Screening Deficiency Notice issued: | 2007-11-15 |
| Response filed: | 2007-12-21 |
| Screening Acceptance Letter issued: | 2008-01-31 |
| Review | |
| Quality Evaluation complete: | 2008-11-12 |
| Clinical Evaluation complete: | 2009-09-03 |
| Labelling Review complete: | 2009-09-02 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| VIBATIV | 02330717 | PENDOPHARM DIVISION OF PHARMASCIENCE INC | TELAVANCIN (TELAVANCIN HYDROCHLORIDE) 250 MG / VIAL |
| VIBATIV | 02330725 | PENDOPHARM DIVISION OF PHARMASCIENCE INC | TELAVANCIN (TELAVANCIN HYDROCHLORIDE) 750 MG / VIAL |