Summary Basis of Decision for Brilinta ®
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:
Brilinta®
Ticagrelor, 90 mg, Tablet, Oral
AstraZeneca Canada Inc.
Submission control no: 132218
Date issued: 2011-11-29
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):
- 02368544
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
BRILINTA® is a registered trademark of the AstraZeneca group of companies.
2 Notice of decision
On May 30, 2011, Health Canada issued a Notice of Compliance to AstraZeneca Canada Inc. for the drug product Brilinta.
Brilinta contains the medicinal ingredient ticagrelor which is a platelet aggregation inhibitor.
Brilinta, co-administered with acetylsalicylic acid (ASA), is indicated for the secondary prevention of atherothrombotic events in patients with Acute Coronary Syndromes (ACS) (unstable angina, non ST elevation Myocardial Infarction or ST elevation Myocardial Infarction) who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) and/or coronary artery by-pass graft. Based on a relationship observed in the Phase III study [that is (i.e.) PLATO, study of PLATelet inhibition and patient Outcomes] between maintenance ASA dose and relative efficacy of ticagrelor compared to clopidogrel, Brilinta is recommended to be co-administered with low maintenance dose ASA (75-150 mg).
Brilinta belongs to the chemical class of cyclopentyltriazolopyrimidines. The primary mechanism of action of Brilinta results in the inhibition of adenosine diphosphate (ADP)- induced platelet aggregation.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Brilinta was primarily based on one Phase III, multicentre, international, randomized, double-blind, parallel-group study known as PLATO. A total of 18,624 ACS patients were enrolled and randomized to receive either Brilinta or clopidogrel (standard therapy) and were assessed for the prevention of vascular events. Brilinta was statistically superior to clopidogrel in the prevention of thrombotic events in the composite efficacy endpoint of cardiovascular death, myocardial infarction, and stroke over 12 months in patients with ACS.
Brilinta (90 mg, ticagrelor) is presented in tablet form. The initial dose of Brilinta is a single 180 mg (two 90 mg tablets) loading dose. Following this initial dose, treatment continues at 90 mg twice daily. Treatment is recommended for at least 12 months unless discontinuation of Brilinta is clinically indicated. Additional dosing guidelines are available in the Product Monograph.
Brilinta is contraindicated for patients with a known hypersensitivity to ticagrelor or to any ingredient in the formulation. Brilinta is also contraindicated for patients who have active pathological bleeding such as peptic ulcer or intracranial hemorrhage. Brilinta is also contraindicated in patients who have either a history of intracranial hemorrhage, moderate to severe hepatic impairment, or who are also taking strong cytochrome P450 3A4 (CYP3A4) inhibitors.
Brilinta 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 Brilinta are described in the Product Monograph.
Priority Review Status was granted for the evaluation of Brilinta as it appeared to provide substantial evidence of increased clinical efficacy such that the overall benefit/risk profile is improved over existing therapies.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Brilinta is favourable for the indication stated above.
3 Scientific and Regulatory Basis for Decision
Brilinta was granted Priority Review Status on January 11, 2010, based on data submitted by the sponsor in support of the Priority Review application. It was judged that Brilinta offered substantial evidence of increased clinical efficacy over existing treatments in the treatment of a life-threatening illness.
The New Drug Submission (NDS) for Brilinta was issued a Notice of Deficiency (NOD) on August 10, 2010 as further clinical and non-clinical data were required to clarify the mechanistic and biological interactions observed between Brilinta and concomitant use of high-dose acetylsalicylic acid (ASA) in the pivotal Phase III study, specifically for the North American (NA) population, given overall regional discrepancies were noted in regards to efficacy. The sponsor subsequently addressed all of the requirements in the NOD. A Notice of Compliance (NOC) was issued for Brilinta on May 30, 2011.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Ticagrelor, the medicinal ingredient of Brilinta, is a new chemical class of anti-platelet agents, the cyclopentyltriazolopyrimidines (CPTP), which selectively antagonizes the P2Y12 adenosine diphosphate (ADP) receptor and prevents ADP-mediated platelet activation and aggregation. Unlike thienopyridines and ASA, which irreversibly bind to the P2Y12 receptor for the lifetime of the platelet, ticagrelor reversibly inhibits platelet reactivity and exhibits rapid onset and offset of effect.
Manufacturing Process and Process Controls
The drug substance is synthetically derived. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The structure of ticagrelor has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within proposed limits. Appropriate tests are adequately controlling the levels of product- and process-related impurities.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of ticagrelor are considered acceptable. Data from batch analyses were reviewed and are within the proposed acceptance criteria.
The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicated that the impurities of the drug substance were adequately under control. The level of impurities reported for the drug substance was found to be within the established limits.
Data from the batch chosen to serve as a suitable reference standard and from consistency batches are considered acceptable according to the specifications of the drug substance.
The drug substance packaging is considered acceptable.
Stability
Stability study results based on accelerated, long-term, and stress testing show that ticagrelor is a stable compound when packaged as proposed over the proposed storage period. The bulk drug is also stable under the proposed storage conditions.
3.1.2 Drug Product
Description and Composition
Brilinta (ticagrelor) is supplied as a round, biconvex, yellow film-coated tablet. One side of the tablet is embossed with 90/T while the other side is plain. Each tablet contains 90 mg of ticagrelor and the following excipients: dibasic calcium phosphate; ferric oxide yellow; hydroxypropyl cellulose; hypromellose; magnesium stearate; mannitol; polyethylene glycol 400; sodium starch glycolate; talc; and titanium dioxide. The product is packaged in blister packs of 60 tablets (4 x 15 tablets) or in bottles of 60 tablets for institutional use only.
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 ticagrelor with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The manufacturing process uses conventional manufacturing techniques, namely: dry mixing; granulation; milling; lubrication; tableting; and film-coating.
The validated process is capable of consistently generating product that meets release specifications. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Brilinta is tested to verify that its identity, appearance, content uniformity, assay, dissolution, levels of degradation products and drug-related impurities are within acceptance criteria.
Validation results of the analytical methods used for the determination of ticagrelor and the drug-related impurities are considered acceptable.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on real-time, accelerated, and long-term stability data submitted, the proposed 24-month shelf-life for Brilinta stored between 2°C-30°C is considered acceptable.
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 facility and equipment that are involved in the production of Brilinta are considered suitable for the activities and products manufactured. The sites are compliant with Good Manufacturing Practices (GMP).
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 Brilinta 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
Primary Pharmacology
Pharmacodynamic studies conducted in vitro demonstrated that the primary mechanism of action of ticagrelor is through the non-competitive antagonism of platelet P2Y12-receptors which results in the inhibition of ADP-induced platelet aggregation. In vitro studies also indicated that the binding of ticagrelor to the P2Y12-receptor is reversible, but shows a slow dissociation rate.
Ticagrelor was shown to inhibit ADP-induced platelet aggregation in vitro in different species with almost complete inhibition reached at nanomolar concentrations. Furthermore, intravenous infusion of ticagrelor in dogs produced dose-dependent inhibition of ADP-induced platelet aggregation ex vivo and reduced platelet-mediated thrombosis in damaged femoral artery.
Secondary Pharmacology
The specificity of ticagrelor for the P2Y12-receptors was established through in vitro screening against a variety of receptors, enzymes, and transporters. Inhibitory effects seen with half maximal inhibitory concentration (IC50) values less than 10 µM were phospholipase C, adenosine transporters, platelet activating factor and phosphodiesterases (PDE 3 and 5). Ticagrelor also reversibly inhibited the human ether-a-go-go-related gene (hERG) potassium channel with an IC50 of 1.72 µM. In addition, ticagrelor also demonstrated potent inhibition of GPR17, a G-protein coupled receptor activated by both uracil nucleotides and cysteinyl-leukotrienes.
In a range of functional assays, ticagrelor did not show significant activity against any other P2-receptor types.
3.2.2 Pharmacokinetics
Absorption
The pharmacokinetics of ticagrelor was investigated in rats, marmosets, dogs, and monkeys. Following oral dosing, absorption of ticagrelor was rapid and the time to reach peak plasma concentrations (Tmax) ranged between 1.5 to 6 hours depending on the species studied. The major active metabolite, O-deethylated AR-C124910XX (hereon referred to as AR-C124910XX) was also rapidly absorbed with a median Tmax ranging from 2 to 4 hours. The oral bioavailability of ticagrelor ranged between 27% to 41%, with the exception of an 88% bioavailability shown in rats.
Distribution
Ticagrelor and its active metabolite were both shown to be widely distributed along with a high plasma protein binding capacity (>98%). Organs which showed highest concentrations were those associated with the metabolism and excretion of ticagrelor, such as the liver, pancreas and kidneys. High concentrations were also noted in glandular tissues, such as adrenal and pituitary glands. Lowest concentrations were observed in the brain and spinal cord. The elimination half-life (t1/2) within tissues was approximately 3 to 10 hours post-dose administration.
Metabolism
The metabolic pathway for ticagrelor was found to be qualitatively similar across all species and no human specific metabolites were detected. The majority of ticagrelor metabolism was through oxidation with AR-C124910XX and AR-C133913 being the main metabolites identified. In vitro, the major cytochrome enzymes involved in the metabolism of ticagrelor were cytochrome P450 3A4 (CYP3A4) and CYP3A45. Other CYP isoforms were also investigated, but their contributions to the metabolism of ticagrelor were considered less significant.
Excretion
In the animal species tested, the major route of elimination was through the faeces and to a much lesser extent the urine. The major components identified in the faeces were ticagrelor and its active metabolite. The inactive metabolite was mainly excreted through the urine. The mean t1/2 for ticagrelor ranged from 1.5 to 7.5 hours and from 2.6 to 12.6 hours for the active metabolite, depending on the species studied.
3.2.3 Toxicology
Single-Dose Toxicity
The acute single-dose studies in mice and rats showed that ticagrelor was well-tolerated. No deaths were observed following administration of up to 2,000 mg/kg (550 times the times the recommended human daily dose on a mg/kg basis). The primary observation noted at higher doses in rats was a transient body weight loss.
Repeat-Dose Toxicity
Repeat-dose studies were conducted in mice, rats, and marmosets. The primary target organ of toxicity seen across all species was the gastrointestinal tract, although the location and type of effect seen varied across the species tested. In mice, abdominal distension was observed. In rats, increased stomach weights, and effects generally in the upper gastrointestinal tract, including mucosal erosion, squamous hyperplasia, oedema, and inflammation were observed. Marmosets inconsistently demonstrated effects in the small and/or large intestine consistent with enteritis frequently seen in this species. The gastrointestinal effects observed were mainly reversible. Indications of subclinical bleeding were also observed across all of the species tested.
Increased liver weight occurred in rodents with high doses. In rats, this was accompanied by centrilobular hypertrophy and induction of CYP450 liver enzymes, and was reversible upon withdrawal of treatment.
Adrenal weights increased at higher doses in the repeat-dose studies in rodents, and were reversible upon withdrawal of treatment.
Genotoxicity
Ticagrelor and its metabolite AR-C124910XX have shown no genotoxic potential in vitro in the Ames and mouse lymphoma tests, nor in vivo in the rat micronucleus test.
Carcinogenicity
The carcinogenicity studies conducted in mice and rats have provided adequate evidence that ticagrelor has no or limited carcinogenic potential.
Reproductive and Developmental Toxicity
In reproductive studies, ticagrelor was found to have no effect on the fertility of female rats at oral doses up to 200 mg/kg/day (approximately 20-times the proposed human therapeutic exposure). In male rats, ticagrelor had no effect on fertility at doses up to 180 mg/kg/day (15.7 times the proposed human therapeutic exposure).
Administration of ticagrelor during the period of organogenesis had no effects on foetal development at oral doses up to 100 mg/kg/day in rats (5.1 times the proposed human therapeutic exposure) and up to 42 mg/kg/day in rabbits (equivalent to the proposed human therapeutic exposure). Developmental effects on foetuses of female rats were noted at 300 mg/kg (decreased body weight, defects in the vertebral arch, extra 14th ribs, and incomplete ossification of various skeletal structures). Foetal development delays were also seen in rabbits administered 63 mg/kg (increased incidences of clear gall bladder contents, incompletely ossified hyoid and pubis, and one or more incomplete ossification of various skeletal structures).
Ticagrelor had no effects on parturition or postnatal development in rats at doses up to 60 mg/kg/day (4.6 times the proposed human therapeutic exposure). However, ticagrelor and its metabolites were transferred to the milk of lactating rats reaching maximum concentrations 4 hours post-dose. Unchanged ticagrelor and its two metabolites (AR-C124910XX and AR-C133913) were the major components found in the rat milk. Analysis of the suckling young showed that these molecules were well absorbed and widely distributed throughout the pup tissues.
3.2.4 Summary and Conclusion
The non-clinical profile of ticagrelor was established in a comprehensive investigational program that included studies of in vitro and in vivo pharmacodynamics, safety pharmacology, pharmacokinetics, and toxicology. Based on these non-clinical studies, there are no major safety concerns that would predict unexpected adverse effects in patients treated with ticagrelor at the recommended therapeutic dose. Thus, from the perspective of the non-clinical studies ticagrelor is recommended for approval for the proposed indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The primary mechanism of action of ticagrelor is the antagonism of platelet P2Y12 receptors resulting in the inhibition of ADP-induced platelet aggregation. Ticagrelor and its active metabolite AR-C124910XX were shown to similarly displace a specific P2Y12 receptor radioligand from the P2Y12 receptors on the surface of human washed platelets in vitro, with a Ki of 2.0 nM and 2.5 nM, respectively. Ticagrelor concentration-dependently inhibited ADP-induced platelet aggregation in suspensions of human washed platelets and also inhibited ADP-induced platelet aggregation in human platelet rich plasma, as well as, in human whole blood.
Binding assays showed that ticagrelor had low affinities for the adenosine A1, A2A and A2B receptors, but high affinity for the adenosine A3 receptor. Moreover, functional assays characterized ticagrelor as an antagonist of the A1, A2B, and A3 receptors and as an agonist of the A2A receptor. Ticagrelor was also shown to inhibit the adenosine transporter, and thereby adenosine uptake in human breast cancer cell line [(Michigan Cancer Foundation - 7 (MCF7)] and human erythrocytes, besides being a weak inhibitor of adenosine deaminase. The active metabolite of ticagrelor was shown to have similar effects to that of the parent compound, although with less potency. Taken together, these data suggest that ticagrelor and its active metabolite may potentiate the effects of endogenous adenosine in vivo. Furthermore, these mechanisms may well be one of those leading to the increased occurrence of dyspnoea in patients treated with ticagrelor.
Ticagrelor and its two metabolites (AR-C124910XX and AR-C133913) were shown to have an inhibitory effect on organic anion transporter-3 (OAT-3)-dependent uric acid uptake. They also had a weak inhibitory effect on uric acid transporter-1 (URAT-1) - mediated uric acid uptake. These results suggest that ticagrelor and its metabolites may interfere with the renal transport of uric acid which is consistent with the observation that patients on ticagrelor had a higher risk of hyperuricemia.
3.3.2 Pharmacokinetics
Absorption
Ticagrelor undergoes rapid absorption with a median Tmax of 1.5 hours following oral administration. The formation of the major circulating active metabolite AR-C124910XX was rapid with a median Tmax of approximately 2.5 hours. The Cmax and area under the curve (AUC) of ticagrelor and its active metabolite increased in a dose-proportional manner over the dose range of 30-1,260 mg.
Ticagrelor absorption occurs along the gastrointestinal tract. Ingestion of a high-fat meal had no effect on ticagrelor Cmax or the AUC of the active metabolite, but resulted in a 21% increase in ticagrelor AUC and a 22% decrease in the active metabolite Cmax. These small changes are considered of minimal clinical significance; therefore, ticagrelor can be given with or without food.
Distribution
Ticagrelor and its active metabolite extensively bind to human plasma proteins (>99%). The steady state volume of distribution of ticagrelor was 87.5 L.
Metabolism
The primary route of ticagrelor metabolism was through the hepatic system. Cytochrome P450 3A (CYP3A) was the major enzyme responsible for ticagrelor metabolism and the formation of its active metabolite.
There is also a complex interaction between ticagrelor and CYP3A4/5, depending on the substrate used, ranging from activation through to inhibition. Moreover, interactions with strong CYP3A4 inhibitors have been identified as these drugs significantly increase the exposure to ticagrelor.
In vitro studies have shown that ticagrelor and its active metabolite also affect (weakly or moderately) the activities of other CYP isoforms, such as CYP2C9, CYP2C19, CYP2B6, and CYP1A2. The impact of these findings on potential drug-drug interactions remains unclear. Nevertheless, co-administration of ticagrelor with tolbutamide, a CYP2C9 substrate, was shown to result in no change in the plasma levels of either drug.
Ticagrelor and its active metabolite are weak p-glycoprotein (P-gp) inhibitors. Different p-glycoprotein substrates [for example (e.g.) digoxin, erythromycin, verapamil, vinblastine, and vincristine] were found to inhibit ticagrelor efflux in vitro. Both ticagrelor and its active metabolite inhibited the p-glycoprotein mediated transport of digoxin in vitro. In support of this concept, concomitant administration of ticagrelor was shown to increase the digoxin Cmax by 75% and AUC by 28% and therefore, caution should be taken while administering ticagrelor with P-gp substrates with narrow therapeutic index like digoxin.
Elimination
The primary route of ticagrelor elimination is via hepatic metabolism. When radiolabelled ticagrelor was administered, the mean recovery of radioactivity was approximately 84% (57.8% in feces, 26.5% in urine). Recoveries of ticagrelor and the active metabolite in urine were both <1% of the dose. The primary route of elimination for the active metabolite is most likely via biliary secretion.
The mean ticagrelor terminal elimination half-life (t1/2) was 6.9 (range 4.5 to 12.8 hours) for ticagrelor and 8.6 hours (range 6.5 to 12.8 hours) for the active metabolite.
3.3.3 Clinical Efficacy
The clinical program for Brilinta consisted of several Phase I and II studies, and a single major Phase III pivotal study named PLATO (PLATelet Inhibition and Patient Outcomes). The PLATO study was a multinational, double blind, randomized-comparative, clinical study conducted over a 12-month period in 18,624 patients with Acute Coronary Syndromes (ASA) with or without ST-segment elevation. The primary objective of PLATO was to determine whether Brilinta was superior to clopidogrel for the prevention of vascular events in ACS patients with unstable angina (UA), non-ST elevation myocardial infarction (non-STEMI) or ST elevation myocardial infarction (STEMI). The composite efficacy endpoint (primary endpoint) of this study was the time to first event of cardiovascular (CV) death, myocardial infarction (MI), and stroke. Patients randomized to the Brilinta treatment group received a loading dose of Brilinta 180 mg followed by Brilinta 90 mg twice daily administered concomitantly with ASA (actual ASA dose range used in PLATO: 75 to 325 mg). Patients randomized to clopidogrel treatment group received a ≤600 mg clopidogrel loading dose followed by 75 mg clopidogrel once daily administered concomitantly with ASA (actual ASA dose range used in PLATO: 75 to 325 mg). All patients also received a background of standard post-ACS therapies. The two treatment groups were well balanced with regard to all baseline characteristics, non-study medication and procedures.
The study PLATO included ACS patients with planned invasive management strategies [that is (i.e.) percutaneous coronary intervention (PCI) and/or coronary artery by-pass graft (CABG)] or medically managed strategies, at the discretion of the investigators. Note that these patients were not stratified at randomization in terms of management strategy.
Results of the PLATO study confirmed that Brilinta showed a clinically meaningful and a statistically significant benefit in the efficacy compared to clopidogrel for the primary endpoint of death from vascular causes, MI or stroke (P <0.001) over a 12-month period. These results were derived mainly from the reduction in both CV death (P = 0.005) and MI (P = 0.001), with no reduction or contribution from strokes (P = 0.22). Brilinta demonstrated a statistically significant relative risk reduction (RRR) of 21% [absolute risk reduction (ARR) 1.1%] for CV death and a RRR of 16% (ARR 1.1%) for MI, as compared to clopidogrel. Brilinta reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the unstable angina non-STEMI and STEMI population.
The treatment effect of Brilinta was apparent within the first 30 days and the degree of benefit continued to increase throughout the 12-month period. Within the first 30 days of treatment, Brilinta showed a statistically significant early benefit (ARR 0.6%, RRR 12%), with a constant treatment effect over the entire 12-month period, yielding ARR 1.9% per year with RRR of 16%. Together, these findings demonstrated that the benefit of Brilinta treatment continues to accrue over 1 to 12 months, suggesting it is appropriate to treat ACS patient with Brilinta for at least 12 months.
Post-hoc analyses also showed that Brilinta was effective in treating both subgroups of non-invasively (medically managed) and invasively (PCI and/or CABG) patients.
An analysis by global regions did however demonstrate a treatment interaction in the NA region demonstrating a lower efficacy for Brilinta [United States of America and Canada]. Specifically, the hazard ratio (HR) point estimate for the primary endpoint numerically favoured clopidogrel in the NA region, and favoured Brilinta in the other regions. Consequently, results from the PLATO study did not demonstrate a superior outcome for Brilinta within the NA population. Further evaluation indicated the HR point estimate for the primary endpoint within the United States was not statistically significant at 1.27 (95% CI 0.92, 1.75) compared to 0.81 (95% CI 0.74, 0.90) for the non-United States region. The overall HR for the primary endpoint of the study, including all regions, demonstrated a statistically significant difference, HR 0.85 (95% CI 0.77, 0.92).
The noted difference in efficacy based on regional location was raised through the issuance of an NOD, whereby the sponsor was requested to clarify the mechanistic and biological interactions observed between Brilinta and the concomitant use of high-dose ASA seen in the PLATO study. In addition, further clarification was also sought in identifying the main factor responsible for the lower efficacy of Brilinta observed within the NA population.
Through the conduct of a post-hoc multivariate analysis of the primary endpoint, the factor most likely associated with the observed treatment difference between regions was determined to be the median dose of ASA. This observation was supported by a univariate analysis that examined ASA doses in categories of ≤100 mg, >100 to <300 mg, and ≥300 mg, which produced HRs of 0.78, 1.13, and 1.21, respectively. This suggests a possible link between the increased ASA dose and decreased efficacy of Brilinta. In addition, it should also be noted that the ASA dose was a highly unbalanced factor between the NA region and non-NA regions, with most high-dose ASA use (≥300 mg) occurring within the NA region. As such, a higher ASA dose was identified as the main factor to account for the lower efficacy observed with use of Brilinta in the NA population. Given the noted interaction between Brilinta and high-dose ASA, this risk was mitigated by restricting the use of Brilinta with concomitant low-dose ASA, 75 to 150 mg per day.
3.3.4 Clinical Safety
The safety data set consisted of 9,235 patients who received at least one dose of ticagrelor and 9,186 patients who received at least one dose of clopidogrel, in study PLATO, which constituted the primary data set for the safety assessment. Pooled data from the Phase II studies were also reviewed to further support results observed in the PLATO study.
In the PLATO study, patients in the Brilinta-treatment group reported slightly higher adverse events (AEs) than those in the clopidogrel-treatment group, whether including bleeding events [73% versus (vs.) 70%], or excluding them (69% vs. 67%). The Phase II pooled AE data confirmed similar results. The most commonly reported AEs in Brilinta-treated patients were dyspnoea (12.0%), headache (6.5%), and epistaxis (6.0%) which occurred at higher rates than clopidogrel-treated patients (6.5%, 5.8%, and 3.4%, respectively). The level of severity of these AEs was generally mild to moderate in nature. Serious adverse events (SAEs) were reported with similar frequency between the Brilinta group (20.2%) and clopidogrel group (20.3%). The most frequent SAEs observed were cardiac failure (1.1% vs. 1.0%), non-cardiac chest pain (0.9% vs. 0.9%), and dyspnoea (0.7% vs. 0.4%). Fewer deaths occurred in the Brilinta group (2.4%) versus the clopidogrel group (3.1%).
The rate of study drug discontinuation due to AEs was 7.4% for Brilinta and 5.4% for clopidogrel. Dyspnoea was the most common AE leading to study drug discontinuation for Brilinta (0.9%) vs. clopidogrel (0.1%).
Safety Issues of Interest
Bleeding Events
A primary safety concern associated with use of Brilinta is the possible risk of increased bleeding events; an AE occurrence commonly associated with antiplatelet therapy. In the PLATO study, Brilinta-treated patients experienced a few more major bleeding events than clopidogrel-treated patients, 11.6% vs. 11.2%, respectively. This observed difference was however not statistically significant. As for major/life-threatening or fatal bleeding events, no differences were noted within either treatment group. In regard to spontaneous bleeds and intracranial bleeding risk, more were noted within the Brilinta-treatment group than in the clopidogrel-treatment group. As such, Brilinta therapy should be used with caution in patients who have a propensity to bleed. Additionally, Brilinta therapy is contraindicated in patients with active pathological bleeding, or with a history of intracranial haemorrhage.
Dyspnoea
In the PLATO study, approximately 13.8% of patients in the Brilinta group vs. 7.8% in the clopidogrel group reported dyspnoea, including dyspnoea at rest, exertional dyspnoea, paroxysmal nocturnal dyspnoea, and nocturnal dyspnoea. Dyspnoea in Brilinta-treated patients resulted in more discontinuations than dyspnoea in clopidogrel-treated patients, 0.9% vs. 0.1%, respectively. Additionally, the onset of dyspnoea was considerably earlier in the Brilinta-treated patients compared to the clopidogrel-treated patients. The precise mechanism(s) by which Brilinta induces dyspnoea has not yet been identified.
Arrhythmia
Arrhythmic effects were monitored in a subset of nearly 3,000 patients, of whom approximately 2,000 had recordings both in the acute phase of their ACS and one month after. The primary variable of interest was the occurrence of ventricular pauses ≥3 seconds. Results showed that more patients had ventricular pauses with Brilinta (6.0%) than with clopidogrel (3.5%) in the acute phase; and 2.2% and 1.6% were reported, respectively, after 1 month. However, there were no adverse clinical consequences associated with this imbalance (including pacemaker insertions) for this patient population.
Renal Insufficiency
In the Phase I and II studies, observations of increased serum creatinine levels were noted during treatment with Brilinta. In the PLATO study, more Brilinta-treated patients than clopidogrel-treated patients experienced extreme decreases in Estimated Glomerular Filtration Rate (eGFR), identifying early kidney disease. There was however, no difference noted between the two treatment groups in the frequency of deaths or discontinuations for renal AEs. Nonetheless, more renal AEs and renal SAEs were reported in Brilinta-treated patients compared to the clopidogrel-treated patients; especially magnified in patients with pre-existing stage 4 renal insufficiency.
Uric Acid Increase
In the PLATO study, patients that were treated with Brilinta had a higher risk of hyperuricemia than those who were treated with clopidogrel. Therefore, caution should be exercised when administering Brilinta to patients with history of hyperuricemia or gouty arthritis. As a precautionary measure, the use of Brilinta in patients with uric acid nephropathy is discouraged.
Hepatic Insufficiency
Approximately 400 patients with mild hepatic impairment were enrolled in the PLATO study. It was observed that these patients were more likely to have major bleeds when treated with Brilinta (11.2%) compared to those treated with clopidogrel (8.7%). Also more deaths were reported for hepatically-impaired patients treated with Brilinta (3.2%) than for those treated with clopidogrel (0.9%). In addition, more AEs and SAEs were reported within this patient population who received treatment with Brilinta vs. clopidogrel. Therefore, patients with mild hepatic impairment who receive Brilinta therapy should be closely monitored as part of patient management. Brilinta therapy is contraindicated in patients with moderate to severe hepatic impairment.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Priority Review Status was granted for the evaluation of Brilinta as it appeared to provide substantial evidence of increased clinical efficacy such that the overall benefit/risk profile is improved over existing therapies.
Brilinta demonstrated a clear beneficial treatment effect for the main contributors of the composite primary endpoint, CV and MI; yet no beneficial treatment effect was demonstrated for stroke. This beneficial treatment effect was apparent within the first 30-days of follow-up and remained consistent up to the end of the 12-month follow-up.
Post-hoc analyses showed that Brilinta is effective in treating both subgroups of non-invasively (medically managed) and invasively (PCI and/or CABG) patients. The benefit/risk evaluation in both STEMI and non-STEMI patient population also appeared equally effective.
A subgroup population analysis did reveal lower efficacy of Brilinta within the NA population. A higher ASA dose was identified as the main covariate for this effect observed within the NA population. Yet, in the final analysis, a benefit for Brilinta is recognized and overall regional discrepancies based on the observation of a high-dose ASA interaction can be mitigated by restricting the use of Brilinta with concomitant low dose ASA (75-150 mg/day).
The safety assessment was primarily based on data from the PLATO study. More AEs were reported within the Brilinta-treatment group, with most events being of moderate severity. More discontinuations also occurred within the Brilinta treatment group due to these AEs. Although treatment management was different for STEMI and non-STEMI diagnosed patients, there was no difference observed in major bleeding events among both patient populations. The bleeding risk was similar for STEMI and non-STEMI patients, but higher for those patients managed invasively compared to non-invasive treatment. In addition, several AEs of interest were identified (i.e., dyspnoea, arrhythmia, increased uric acid, and higher serum creatinine) which have been clearly identified within the Product Monograph and shall be followed-up as part of post-market pharmacovigilance activities.
Overall, the PLATO study demonstrated a clear reduction in MI and CV death, as well as, overall death compared to standard treatment with clopidogrel. Brilinta's beneficial treatment effect outweighs the slightly higher risk for major bleeds, given the indicated patient population. In addition, regional discrepancies based on the observation of a high-dose ASA interaction has been mitigated by restricting the use of Brilinta with concomitant low dose ASA (75-150 mg/day).
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 Brilinta co-administered with ASA is favourable for secondary prevention of atherothrombotic events in patients with Acute Coronary Syndromes (unstable angina, non ST elevation Myocardial Infraction, or ST elevation Myocardial Infarction) who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) and/or coronary artery by-pass graft. Based on the relationship observed in the Phase III PLATO study between maintenance ASA dose and the relative efficacy of Brilinta compared to clopidogrel, Brilinta is recommended to be co-administered with low maintenance dose ASA (75-150 mg/day). 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: Brilinta®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2009-10-15 |
| Request for priority status | |
| Filed: | 2009-10-10 |
| Approval issued by the Director of the Bureau of Cardiology, Allergy and Neurological Sciences (BCANS): | 2010-01-13 |
| Submission filed: | 2010-02-08 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2010-03-05 |
| Review 1 | |
| Biopharmaceutics Evaluation complete: | 2010-07-10 |
| Quality Evaluation complete: | 2010-07-15 |
| Clinical Evaluation complete: | 2010-08-13 |
| Biostatistics Evaluation complete: | 2010-08-12 |
| Notice of Deficiency (NOD) issued by Director General (efficacy and quality issues): | 2010-08-10 |
| Response filed: | 2010-11-05 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2010-12-02 |
| Review 2 | |
| Biopharmaceutics Evaluation complete: | 2011-04-05 |
| Quality Evaluation complete: | 2011-05-24 |
| Clinical Evaluation complete: | 2011-05-24 |
| Labelling Review complete: | 2011-05-26 |
| Notice of Compliance issued by Director General: | 2011-05-30 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| BRILINTA | 02368544 | ASTRAZENECA CANADA INC | TICAGRELOR 90 MG |