Summary Basis of Decision for Tygacil ™
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:
TygacilTM
Tigecycline, 50 mg/vial, Powder for solution, Intravenous
Wyeth Canada
Submission control no: 094870
Date issued: 2007-03-12
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), PrTYGACILMD, Tygécycline, 50 mg/flacon, poudre pour solution, Wyeth Canada, N° de contrôle de la présentation 094870.
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):
- 02285401
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On September 14, 2006, Health Canada issued a Notice of Compliance to Wyeth Canada for the drug product Tygacil.
Tygacil contains the medicinal ingredient tigecycline, a glycylcycline, which belongs to the tetracycline class of antibacterials. Tigecycline acts by inhibiting protein synthesis at the level of the bacterial ribosome.
Tygacil is indicated for the treatment of the following infections when caused by susceptible strains of the designated microorganisms in patients 18 years of age and older:
- Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible strains only), Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus agalactiae, Streptococcus anginosus, Streptococcus pyogenes and Bacteroides fragilis.
- Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible strains only), Staphylococcus aureus (methicillin-susceptible strains only), Streptococcus anginosus group(includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.
Tigecycline has decreased in vitro activity against Proteus spp., Providencia spp., and Morganella spp. Pseudomonas aeruginosa is inherently resistant to tigecycline.
The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from non-clinical and clinical studies. Overall, there were four pivotal Phase III double-blind, randomized, multicentre, multinational, active control clinical studies involving 1129 patients with complicated skin infections and 1658 patients with complicated intra-abdominal infections. Cure rates for tigecycline were shown to be non-inferior to the comparators.
Tygacil (50 mg/vial, tigecycline) is presented as sterile, lyophilized powder for intravenous use. The recommended dosage regimen of Tygacil is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous infusions should be administered over approximately 30 to 60 minutes every 12 hours. The recommended duration of treatment is 5 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.
Tygacil is contraindicated for use in patients who have known hypersensitivity to tigecycline or to the tetracycline class of antibacterials. Tygacil 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 Tygacil 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 Tygacil 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)
Manufacturing Process and Process Controls
Materials used in the manufacture of tigecycline are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.
Characterisation
The structure of tigecycline was elucidated. The batches manufactured were shown to consistently yield the same desired polymorphic form.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits were considered satisfactorily qualified (e.g., within recommended ICH limits, toxicological studies). Control of impurities in the drug substance is therefore considered to be acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were considered satisfactory for all analytical procedures used for release and stability testing of tigecycline.
Batch analysis results were reviewed and are within the proposed acceptance criteria.
The tigecycline packaging is considered to be acceptable.
Stability
Based on the long-term and accelerated stability study data submitted, the proposed re-test period, storage, and shipping conditions for tigecycline were supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Tygacil (50 mg/vial) is a sterile, lyophilized powder for intravenous infusion. The product is supplied in single-dose 5 mL Type 1 glass vials sealed with rubber stoppers under a blanket of nitrogen. Ten vials are packaged per box. Each vial contains 53 mg of tigecycline and is reconstituted with 5.3 mL of 0.9% sodium chloride injection or 5% dextrose injection to achieve a concentration of 10 mg/mL of tigecycline. This 6% overage facilitates withdrawal and administration of the labelled quantity (50 mg in 5 mL) of tigecycline. Prior to reconstitution, tigecycline is an orange powder or cake while the reconstituted solution is a clear and yellow-to-orange solution, essentially free of particulate matter. Tygacil contains no non-medicinal ingredients, however, two processing agents, water for injection and nitrogen, are used. Certificates of analysis were provided.
Pharmaceutical Development
Several studies were conducted to establish that Tygacil and its formulation composition, manufacturing process, container closure system, microbiological attributes and usage instructions were appropriate for their intended purpose. Changes made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and were deemed acceptable. Tigecycline is filled into vials using proper aseptic process techniques. The equipment and facilities are considered suitable for the products manufactured. The process is considered adequately controlled within justified limits.
Control of Drug Product
Tygacil is tested to verify that its identity, appearance, strength, purity, weight uniformity, pH, particle size, water content, and levels of degradation products and microbiological impurities are within acceptance criteria. The test specifications are considered acceptable to control the drug product and the proposed limits for degradation products are considered satisfactorily qualified (e.g., within recommended ICH limits, toxicological studies).
Copies of the analytical methods and, where appropriate, validation reports were considered satisfactory for all analytical procedures used for release and stability testing of tigecycline.
Stability
Based on the long-term and accelerated stability study data submitted, the proposed shelf life of 18 months is considered acceptable when the product is packaged in the commercial container/closure system and stored at controlled room temperature (20-25°C). The in-use period for the reconstituted solution is 6 hours when stored at room temperature or under refrigeration (2-8°C).
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 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Tygacil 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
Non-clinical pharmacodynamic (PD) studies are not directly applicable to antibacterials. Antibacterial agents differ from other drugs by exerting their pharmacological effects on susceptible bacteria, not animal or human cells. Therefore, microbiology studies were conducted to assess the antibacterial activity of tigecycline.
Microbiology
Tigecycline inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. Tigecycline has been shown to be active against a wide spectrum of gram-positive and gram-negative aerobic, anaerobic, and facultative anaerobic bacteria including those bacteria harbouring classical tetracycline resistance mechanisms. Tigecycline has demonstrated no in vitro activity against Pseudomonas aeruginosa and decreased activity against bacteria of genera Proteeae (Proteus spp., Providencia spp. and Morganella spp). No antagonism was observed between tigecycline and other commonly used antibiotics. In general, tigecycline is considered bacteriostatic.
Quantitative methods to determine the antimicrobial minimum inhibitory concentrations (MICs) of tigecycline were assessed. Aged aerobically stored media demonstrated a 3-to 8- fold increase in MIC values of tigecycline. Further studies concluded that tigecycline was susceptible to oxidative degradation. Clinical laboratories should use Mueller-Hinton broth if the prepared microtitre plates are stored frozen within 12 hours of the preparation of the broth.
Tigecycline demonstrated in vivo efficacy in acute murine lethal infections with S. aureus and S. pneumoniae; inmousethigh infections with E. coli, S. aureus, S. pneumoniae, E. coli & K. pneumoniae isolates; in mouse peritonitis infections with E. faecalis and E. faecium strains; and in a rat intra-abdominal abscess model.
Data from the mouse thigh infection model demonstrated that the time above MIC or the drug exposure parameter (AUC) correlates best with the efficacy of tigecycline. The tigecycline in vitro susceptibility test profile, and the in vitro MIC data and Quality Control range for susceptibility testing range documented in the Microbiology section of the Product Monograph is considered acceptable.
3.2.2 Pharmacokinetics
Absorption
Tigecycline was not absorbed systemically after oral administration in rats and monkeys. When the drug was administered intravenously, the volume of distribution of tigecycline in different species of animals was large and in excess of the volume of total body water, suggesting that tigecycline is distributed to various tissues and organs.
Distribution
In rats that received a single intravenous dose, the highest concentrations of tigecycline were detected in the kidneys and liver which are the main organs for the excretion of tigecycline. The tissue which had the highest exposure was bone. The tissue:plasma ratios for some of the organs which accumulated tigecycline were bone (255); bone marrow (19); and thyroid, spleen and salivary gland (12). The elimination half-life of radioactivity was much higher in bone (208 hours) as compared to blood (44 hours). After repeated administration of tigecycline, the accumulation of the drug in bone and thyroid escalated by an additional 3- to 4-fold increase before attaining equilibrium. A substantial accumulation of tigecycline could take place in the bone, thyroid and bone marrow of humans.
The in vitro binding of tigecycline to human plasma proteins ranged from 72-96%. The percentage increased as the drug concentration increased, and was more evident at 250C as compared to 370C.
In pregnant rats, tigecycline was rapidly distributed to the placenta, fetuses and amniotic fluid after intravenous administration. Due to the fact that tigecycline accumulated in the fetus, Tygacil should not be given to pregnant women.
Tigecycline was secreted in the breast milk of rats. Although substantial levels of tigecycline were present in milk, the serum concentrations attained in the suckling pups were very low probably due to poor oral bioavailability. The systemic exposure of nursing pups to tigecycline via the maternal milk was low.
Metabolism
In dogs and rats, the unchanged tigecycline was the predominant form (≥ 80%) detected in plasma and urine. The remainder consisted of minor metabolites plus degradation products of tigecycline. In humans, two additional metabolites [tigecycline glucuronide (M7) and N-acetyl 9-aminominocycline (M9)] of tigecycline were identified in plasma and urine samples.
Tigecycline metabolism was investigated with microsomal preparations (from various species, including humans) as well as with human hepatocytes. In the in vitro metabolic systems investigated, the most abundant compound-related component detected was unchanged tigecycline. A degradation product, an epimer of tigecycline, was observed in each of the metabolic systems. The studies done with microsomal preparations were validated and the studies with human hepatocytes were questionable. It is not known if tigecycline is metabolized by other tissues such as lungs, kidney or brain.
Excretion
Rapid excretion of radiolabelled tigecycline was demonstrated after a single intravenous administration in animals. Both the faecal and urinary routes are important for the elimination of tigecycline. In the urine and bile, the majority of the recovery was in the form of unchanged tigecycline.
Drug-Drug Interactions
To evaluate the drug-drug interaction potential, the effect of tigecycline on the activities of the major human liver cytochrome P450 isozymes were investigated. No significant inhibition was demonstrated with CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2C8, or CYP1A2 with 1-100 uM of tigecycline. Therefore, the probability of interactions with co-administered drugs is low based on its effect on enzyme activity. However, the effect of tigecycline on microsomal enzyme induction has not been examined in animal studies.
Administration of tigecycline at 10 or 30 mg/kg prolonged thiopental-induced sleeping time by 3- to 15-fold in mice. In the animal studies, exposure to a dose of 5 mg/kg is equivalent to the clinically effective dose in humans. The Product Monograph provides information on the interaction of tigecycline and thiopental in the Detailed Pharmacology section.
Safety Pharmacology
The safety pharmacology of tigecycline was well investigated in several animal species and the doses used were appropriate. The low dose (5 mg/kg) provided exposure equivalent to the clinically effective dose, and exposure from the high dose was 10-fold greater than that obtained with the clinically effective dose.
At low doses, there were no neurological effects in mice. At higher doses, tigecycline suppressed spontaneous motility and irritability.
A slight decrease in blood pressure was reported with high doses of tigecycline in dogs and rabbits. The mechanism for this decrease in blood pressure is unknown.
No major changes in ECG or prolongation of QT interval were reported in the animal studies. The hERG channel assay was not performed as part of the non-clinical studies to assess the possible effect of tigecycline on QT.
In mice, tigecycline had no effect on gastrointestinal transit.
Intravenous bolus administration of high doses of tigecycline in guinea pigs increased bronchoresistance. This effect was minimized by slow infusion. This action of tigecycline in guinea pigs may be related to histamine release as the increase in bronchoresistance with tigecycline is blocked with histamine antagonists. In human polymorphonuclear leukocytes, tigecycline did not induce histamine release. Therefore, histamine release with tigecycline may not be a concern with low concentrations for clinical use when administered slowly.
3.2.3 Toxicology
Acute Toxicity
High single doses of tigecycline were studied in mice and rats. After intravenous bolus administration of high single doses, the lethal doses that killed 50% of the tested animals (LD50) were 124 mg/kg and 98 mg/kg for male and female mice, respectively. In rats, the LD50 was 106 mg/kg. These LD50s were approximately 33 times or more the recommended human therapeutic dose by intravenous infusion (30 to 60 minutes), indicating a satisfactory therapeutic index. The value 33 was based on the therapeutic dose of 150 mg received in the first 24 hours by a 50 kg patient.
Long-Term Toxicity
The following tigecycline-related effects were observed in the repeat-dose studies in rats and/or dogs. Treatment durations ranged from 2 to 13 weeks, at doses up to 70 and 20 mg/kg/day, respectively.
- Changes in the immune system and hematopoietic tissues: bone marrow myelosuppression and hypocellularity; lymphoid atrophy and/or depletion with the lymph nodes, spleen, and thymus; decreased extramedullary hematopoiesis in rats; decreases in the hematology parameters (red blood cells, white blood cells, platelets and globulin).
- Increased plasma histamine levels in dogs.
- Clinical signs consistent with histamine release (erythema, edema, pruritis).
- Lesions associated with inflammation and consistent with histamine release were observed in the heart, joint, gastric mucosa and prostate. The heart lesions secondary to the tygecycline-induced histamine effects suggest a potential for serious, less frequent sequelae.
- Renal tubular degeneration in rats.
- Bone discoloration and persistent association of tigecycline with bone and fetal ossification sites.
- Injection site lesions in the rat.
In both rats and dogs with drug exposures 0.7 to 2.8 times the exposure observed in humans at the proposed dosage (100 mg/day), the primary toxicological determinant was bone marrow myelotoxicity and its hematologic correlates.
Evidence of reversibility for the tigecycline-related effects reported in the rat and dog studies were seen by the end of three week recovery period, except for heart lesions and bone discoloration which persisted in rats. The data on reversibility of heart lesions were indeterminate.
Functional immunotoxicity was not evaluated. Cross-sensitization with structurally-related tetracyclines was not evaluated. Tigecycline, but not two of its human metabolites [tigecycline glucuronide (M7) and N-acetyl 9-aminominocycline (M9)], was evaluated in an extensive toxicology program, excluding carcinogenic and immunotoxic potential. Elevated levels of tigecycline drug product impurities were not directly evaluated for genotoxic potential.
For the evaluation of the potential toxicity of the M7 and M9 human metabolites, the following indirect evidence was submitted for the two metabolites:
- Human systemic exposures to each metabolite were ≤15% of the
drug-related material.
- Human excretion of each metabolite was <10% of the administered dose.
- The identification of M7 as an ether glucuronide which is relatively stable and generally not associated with toxicity.
- The similarity of the toxicity profile of tigecycline to structurally-related marketed tetracyclines.
- The short recommended duration of clinical therapy with Tygacil (5 to 14 days).
- The clinical data supporting tigecycline therapy for patients with serious infections.
The supporting information listed above together with labelling to convey the limited nature of the evaluation is considered sufficient at this time to address the potential toxicological risk of metabolites M7 and M9. The sponsor has planned additional studies that evaluate potential effects on immune function and the toxicology of the M7 and M9 human metabolites and has committed to submitting the final reports when available.
Mutagenicity/Genotoxicity
Tigecycline was not mutagenic or genotoxic in standard mammalian assays but was not evaluated in bacterial reverse mutation assays. Elevated levels of the tigecycline impurities and the two human metabolites M7 and M9 were not directly evaluated for genotoxic potential. The sponsor committed to submitting the final reports of additional planned genotoxicity studies when available.
Carcinogenicity
Animal carcinogenicity studies with tigecycline were not conducted on the basis of negative genotoxicity findings and the short recommended duration of clinical therapy for life-threatening conditions.
Reproductive Toxicity
Effects on embryofetal development were observed in mice, rats and/or rabbits (reduced fetal weight, increased incidence of minor skeletal anomalies, differences in ossification rates, increased fetal loss). A warning and precautionary statement is included in the Product Monograph.
Other Toxicity Studies
Phototoxicity potential (ocular and skin) was evaluated in rats using a typical assay. No evidence of phototoxicity was observed following single-dose intravenous (IV) administration of 70 mg/kg tigecycline. The photogenotoxic and photoallergy potentials of tigecycline were not evaluated.
Tigecycline was negative for the following toxicity tests: antigenicity in mice/rats [passive cutaneous anaphylaxis (PCA)], in vitro cellular protein synthesis, and in vitro blood compatibility.
3.2.4 Summary and Conclusion
Tigecycline has demonstrated in vivo and in vitro antibacterial activity against a wide spectrum of bacteria. Acceptable criteria for susceptibility testing are documented in the Product Monograph.
The safety pharmacology and pharmacokinetics of tigecycline have been well investigated in various animal species. Tigecycline is well distributed to various tissues and organs. Intravenous bolus administration of high doses of tigecycline leads to release of histamine and increases bronchoresistance but this effect was not observed during slow infusion. The non-clinical studies demonstrated the safety of tigecycline in the animal studies. There were no major changes in ECG or prolongation of QT interval identified.
The toxicological evaluation of tigecycline is considered acceptable at this time, based on the submitted information, to support the recommended clinical use of Tygacil. Appropriate statements are included in the Product Monograph to convey the risks and to address the issues of completeness. Should clinical treatment durations in excess of 1 month be proposed in the future, a re-evaluation of the need for carcinogenicity studies and of the appropriate duration of repeat-dose general toxicology studies is recommended.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Clinical pharmacodynamic (PD) studies are not directly applicable to antibacterials. Antibacterial agents differ from other drugs by exerting their pharmacological effects exclusively on susceptible bacteria, not on human cells.
3.3.2 Pharmacokinetics
The pharmacokinetic (PK) profile of tigecycline was studied in clinical Phase I studies with healthy volunteers. After IV infusion, the decline in serum drug concentrations followed a polyphasic pattern. Tigecycline had a low systemic clearance (0.27 to 0.40 L/h/kg), and a relatively long half-life (26 to 30h). Following repeated administration, the serum levels of tigecycline attained steady-state by day 7 of administration. However in a different study it was observed that the trough levels of tigecycline were not significantly different among days 3, 4 and 5. This suggests that steady-state may be reached by day 3 of administration.
The maximum concentration and drug exposure (Cmax and AUC) of tigecycline increased proportionately with the dose. Food had no effect on the AUC of tigecycline. Animal studies indicated that AUC was reasonably predictive of tigecycline efficacy and an AUC of 1.5 ug h/mL to 8 ug h/mL was effective against most organisms tested in animal models. A single dose of 100 mg tigecycline gave an AUC of approximately 6.4 ug h/mL, therefore, a total dose of 100 mg tigecycline per day as a clinically effective dose is reasonable. Higher levels of Cmax were obtained when tigecycline was infused over a period of 30 minutes as compared to 60 minutes, without causing an increase in the incidence of adverse events.
Tigecycline demonstrated a high volume of distribution which suggests an extensive distribution into the tissues. The highest tigecycline concentrations were seen in the gallbladder and lung. Levels in the gallbladder and lung were 28- and 10-fold higher, respectively, when compared to levels attained in the serum. Levels in the colon were 2-fold higher, while levels in the synovial fluid and bone were less than the serum levels. The low concentrations found in human bone are in contrast with the animal studies which demonstrated very high concentrations in bone.
Studies with radiolabelled tigecycline in healthy men indicated that 33% of the dose administered was recovered in urine and 59% was in the faeces. Unchanged tigecycline was the major drug-related compound found in serum, urine and faeces. Other drug-related compounds were also present. The primary route of elimination for tigecycline appears to be the hepatic mechanism of biliary excretion. The secondary elimination pathway is renal excretion.
Special Populations
Age, Gender, and Race - Dosage adjustment based upon age, sex, or race is not necessary. Drug exposure levels obtained in elderly subjects were not markedly different from that of young men. Young women had exposure levels approximately 21% higher than young men. This difference is considered minimal from a PK point of view. Chinese subjects had a similar PK profile to non-Chinese subjects.
Renal Impairment - Differences in drug exposure and tigecycline clearance between patients with severe renal impairment and healthy subjects were minimal. No dosage adjustment based upon renal function is warranted. Tigecycline did not decrease renal function and the tigecycline PK profile was not affected by haemodialysis (HD).
Hepatic Impairment - The clearance of tigecycline was reduced by 55% in severe hepatic impairment (Child-Pugh-C) subjects. The reduced clearance increased systemic exposure by approximately 105% in the Child-Pugh-C subjects. With multiple-dose administration, patients with severe hepatic impairment receiving the standard therapeutic regimen would be exposed to approximately twice the steady-state serum concentrations of tigecycline. A 50% reduction in the maintenance dose of tigecycline in subjects with severe hepatic impairment is acceptable.
Drug Interactions
Warfarin - Tigecycline co-administration did not significantly affect the overall prothrombin ratio (INR) and pharmacodynamic profile of warfarin, and therefore no warfarin dosage adjustment should be required with the initiation of concomitant tigecycline therapy. However, consistent with good medical practice, the proper level of anticoagulant activity should be monitored when initiating treatment with another drug.
Digoxin - Tigecycline did not affect digoxin exposure or clearance, nor is it expected to alter the PD effect of digoxin. Co-administration of tigecycline did not produce significant changes in steady-state digoxin PD as measured by changes from baseline in ECG parameters. Based on the PK parameters and the bioequivalence analysis, as well as the linear PK theory, digoxin did not affect the exposure or clearance of tigecycline.
QTc Prolongation
A thorough QT/QTc study to determine whether tigecycline has a threshold pharmacologic effect on cardiac repolarization was not conducted in the clinical Phase I studies. In one of the clinical Phase I studies, there were four elderly subjects of >70 years of age who had QTc prolongation and one of the ascending dose studies indicates a significant increase in QT/QTc interval near the maximum drug concentration. In the absence of a thorough QT/QTc study, the results presented from the clinical Phase I studies are not considered as being negative.
3.3.3 Clinical Efficacy
Complicated Skin and Skin-Structure Infections
Two Phase III pivotal studies, one non-pivotal study, and information from three incomplete studies were submitted to support the claim for complicated skin and skin-structure infections (cSSI). Protocols for both pivotal studies were similar to each other, and both used vancomycin and aztreonam as the comparators, however aztreonam has not been authorized for the cSSI indication in Canada. A total of 1129 patients with cSSI were randomized in the two pivotal studies. Duration of therapy was up to 14 days. Clinical response at the test-of-cure assessment (12 to 92 days after the last dose) was the primary efficacy endpoint. The Clinical Evaluable (CE) population, which comprised of subjects who met all evaluability criteria for efficacy specified, was selected as one of two co-primary populations for determining clinical response. The clinical modified intent-to-treat (c-mITT) population, which consisted of all mITT subjects who received study drug and met the minimum disease criteria for cSSSI, was included as the other co-primary population for determining efficacy. Exclusion was noted for the following: infected diabetic foot ulcers or decubitus ulcers where the infection was present for greater than one week, and necrotizing fasciitis or gangrene. Patients with infections caused by Pseudomonas aeurginosa were not considered evaluable.
The clinical response was assessed from pooled data from the two pivotal studies. The cure rates for tigecycline were shown to be non-inferior to the comparator, for the CE and c-mITT populations at the test-of-cure assessment. For the CE population, the cure rates were 86.5% for tigecycline-treated subjects and 88.6% for vancomycin/aztreonam-treated subjects. The cure rates for the c-mITT population were 79.7% and 81.9% for the tigecycline-treated subjects and vancomycin/aztreonam-treated subjects, respectively.
With respect to the pathogens proposed for the indication of cSSI, the following eradication rates were noted for tigecycline: Bacteroides fragilis-8/8, Enterococcus faecalis (Non-VRE)-14/16, Escherichia coli-24/29, Staphylococcus aureus (MRSA)-24/31, Staphylococcus aureus (MSSA)-120/135, Streptococcus agalactiae-7/8, Streptococcus anginosus-14/16, andStreptococcus pyogenes-30/32.
Complicated Intra-Abdominal Infections
Two Phase III pivotal studies and one Phase II non-pivotal study were submitted to support the claim for complicated intra-abdominal infections (cIAI). The protocols of the two pivotal studies were similar and both used imipenem/cilastatin as the comparator. There was no oral antibiotic therapy as follow-up to the parenteral therapy. Duration of therapy was 5 to 14 days. The test-of-cure visit was at least 12 days but no more than 44 days after the last dose. Exclusion criteria of note included intra-abdominal infections known to be caused by one or more bacterial pathogens not susceptible to both of the study drugs (e.g., Pseudomonas aeruginosa, Proteus mirabilis) and which required treatment with an additional antibacterial agent, and patients with an APACHE II score greater than 30. Pseudomonas aeruginosa and Proteus mirabilis are resistant to tigecycline and both organisms are important pathogens in the hospitalized setting, which is the environment where many patients with complicated intra-abdominal infections will be treated. The lack of efficacy seen with Tygacil against Pseudomonas aeruginosa and Proteus mirabilis is documented in the Product Monograph and labelling.
Based on pooled data from both pivotal studies, the clinical cure rates for tigecycline were shown to be not inferior to the comparator for the microbiologically evaluable cohort at the test-of-cure assessment. The clinical cure rate was 86.1% for tigecycline-treated subjects and 86.2% for imipenem/cilastatin-treated subjects. With respect to the pathogens proposed for the cIAI indication, the following eradication rates were noted for tigecycline: Citrobacter freundii 12/16, Enterobacter cloacae 14/16, Escherichia coli 281/329, Klebsiella oxytoca 19/20, Klebsiella pneumonia 46/52, Enterococcus faecalis (vancomycin-susceptible strains only) 25/33, Staphylococcus aureus (methicillin-susceptible strains only) 26/29, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus) 102/120, Bacteroides fragilis 67/87, Bacteroides thetaiotaomicron 36/41, Bacteroides uniformis 12/17, Bacteroides vulgatus 14/16, Clostridium perfringens 19/20, and Peptostreptococcus micros 14/18.
3.3.4 Clinical Safety
The safety database for tigecycline comprised of 1415 tigecycline-treated subjects in Phase III studies, 328 tigecycline-treated subjects in Phase II studies, and 424 tigecycline-treated subjects in Phase I studies. All studies were conducted in adult subjects. In Phase III studies, the most common (≥ 10%) treatment-emergent adverse events with tigecycline were nausea (28.7%), vomiting (19.4%), and diarrhea (11.9%). Nausea and vomiting were generally scored as being mild to moderate in severity.
Phase III subjects treated with tigecycline demonstrated mean increases in blood urea nitrogen, increases in coagulation parameters (most notably prothrombin time) and decreases in mean total protein and albumin. Safety data also showed increases in amylase levels and drug-related pancreatitis, elevated liver function tests, and hyperbilirubinemia. Increased rates of infection-related serious adverse events (sepsis, pneumonia, surgical wound infection) were noted with Tygacil. When compared to the comparator drug, more tigecycline subjects reported sepsis/septic shock (1.5% vs 0.4%) as a serious adverse event.
The following serious adverse events were noted in the Phase III studies, without reference to causation.
| Tigecyline (N=1415) | Comparator (N=1382) | |
Heart arrest | 6 | 1 |
Syncope | 2 | 0 |
Ventricular tachycardia | 1 | 0 |
Hepatic failure | 1 | 1 |
Hepatitis | 3 | 0 |
Jaundice | 3 | 0 |
Liver damage | 2 | 0 |
Pancytopenia | 1 | 0 |
Hypoglycemia | 3 | 0 |
Acute kidney failure | 5 | 2 |
Toxic nephropathy | 1 | 0 |
Seven subjects died in the combined cSSSI pivotal studies: 6 in the tigecycline group and 1 in the vancomycin/aztreonam group. Forty-one subjects died in the combined cIAI pivotal studies: 24 in the tigecycline group and 17 in the imipenem/cilastatin group. One death in each test and comparator group was considered to be possibly related to tigecycline/comparator drug.
Cardiac Safety
A thorough QT/QTc study with a concurrent positive control group was not performed.The QTc interval was analyzed from the results of the pooled four pivotal studies, across both indications.
With the Linear Model Correction (L), the median change from baseline for the tigecycline group was 3.3 msec for the QTc interval, with an upper bound of a 2-sided 95% confidence interval of 5.0 msec. Comparable median change values from subjects treated with comparator agents were 0.6 msec and 3.0 msec, respectively.
QTc interval data corrected by the Fridericia's Correction (F) showed that the tigecycline group had a median change from baseline of 6 msec, with an upper bound of a 2-sided 95% confidence interval of 7 msec. Comparable median change values from subjects treated with comparator agents were 3 msec and 5 msec, respectively.
Categorical analyses of QTc(F) and QTc(L) changes in subjects from the cSSSI and cIAI studies did demonstrate some significant imbalances between the tigecycline group and the comparator group in those subjects with QTc(F) and QTc(L) values >60 msec from baseline, or >450 and >480 msec absolute value.
An effect on cardiac repolarization by tigecycline cannot be definitively excluded from the Phase II and Phase III data. The potential for a QT prolonging effect appears to be small, but has not been adequately characterized. Adequate justification has not been provided in support of the use of the log-linear correction method for the primary analysis of the QT/QTc data. The Fridericia correction may be the most appropriate correction for analysis of the QT data. Dose-response and exposure-response data are not yet available, nor are analyses by demographic subset and baseline potassium (or other pro-arrhythmic factors).
The most recent Periodic Safety Update Report (PSUR) dated March 24, 2006, includes one case of ventricular tachycardia confirmed by positive dechallenge and rechallenge.
The potential risk of cardiovascular events/QTc prolongation has been identified for further evaluation. Cautionary statements with respect to the issue of QT prolongation have been provided in the Product Monograph and labelling.
Pancreatitis
Six serious adverse event reports of pancreatitis, necrotizing pancreatitis, or increased amylase were reported from the Phase II and III clinical trials for tigecycline (4 cases related, 2 unrelated). The Product Monograph has identified pancreatitis in the Warning and Precautions section.
Post-Marketing
The PSUR dated March 24, 2006 (covering the time-frame of June 15, 2005 to December 14, 2005) estimated that 208 000 vials of tigecycline were commercially distributed. The following serious/unexpected adverse reactions were reported:
- Pancreatitis: 6 spontaneous reports. In addition, there were already 6 serious adverse event reports of pancreatitis, necrotizing pancreatitis, or increased amylase reported from the Phase II and III clinical trials for tigecycline (4 related, 2 unrelated).
- Hepatic Events: 1 case of clinical hepatitis, 3 cases of increased hepatic enzyme levels, 2 cases of hyperbilirubinemia.
- Renal Function events: 1 case of azotemia, 1 case of renal failure. Both patients had underlying diabetes mellitus and some degree of pre-existing renal impairment.
- Ventricula tachycardia: 1 case with positive dechallenge and rechallenge.
- Thrombocytopenia: 4 cases.
On the basis of the data presented in the PSUR and the cumulative experience to date, acute pancreatitis was added to the Adverse Reactions section of the tigecycline reference safety information (RSI). The following adverse events will also be added based on re-review of the data from the pivotal clinical trials: increased amylase, hypoproteinemia, increased aspartate aminotransferase, increased alanine aminotransferase.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Tigecycline has shown acceptable efficacy for the following indications and the indicated pathogens, at a dose of 100 mg followed by 50 mg IV every 12 hours for 5-14 days:
- Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible strains only), Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus agalactiae, Streptococcus anginosus, Streptococcus pyogenes and Bacteroides fragilis, and
- Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible strains only), Staphylococcus aureus (methicillin-susceptible strains only), Streptococcus anginosus group(includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.
The data provided support the conclusion that the tigecycline dose regimen is generally safe and efficacious in adults for the treatment of complicated skin and skin structure infections and complicated intra-abdominal infections.
The following have been identified as risks requiring close monitoring: nausea/vomiting, diarrhea, hypersensitivity, prolonged prothrombin time, prolonged partial thromboplastin time, hyperbilirubinemia, increased blood urea nitrogen, increased aspartate aminotransferase, increased alanine aminotransferase, and pancreatitis. Safety issues raised during the course of the drug review have been documented in the Product Monograph.
The deficiencies in the submitted data with respect to QTc prolongation is a safety concern. Although the data and analyses from the compiled information for Phases I, II, and III suggest that the QTc(F) and QTc(L) may not be extremely large, it is unclear whether the QTc prolongation is less than or exceeds five milliseconds. In conclusion, the analyses do not clearly demonstrate QTc prolongation to be less than five milliseconds when used at the proposed maintenance dose of tigecycline, and QT data are not available for the 100 mg loading dose. To address this concern, warnings and precautionary statements with respect to QT prolongation have been provided in the Product Monograph and the labelling.
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 Tygacil is favourable for the treatment of the following infections when caused by susceptible strains of the designated microorganisms in patients 18 years of age and older:
- Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible strains only), Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus agalactiae, Streptococcus anginosus, Streptococcus pyogenes and Bacteroides fragilis.
- Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible strains only), Staphylococcus aureus (methicillin-susceptible strains only), Streptococcus anginosus group(includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.
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: TygacilTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2004-09-29 |
| Submission filed | 2005-05-18 |
| Screening | |
| Screening Acceptance Letter issued | 2005-08-17 |
| Review | |
| Quality Evaluation complete | 2006-07-24 |
| Clinical Evaluation complete | 2006-09-07 |
| Labelling Review complete | 2006-08-31 |
| NOC issued by Director General | 2006-09-14 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| TYGACIL | 02285401 | PFIZER CANADA ULC | TIGECYCLINE 50 MG / VIAL |