Summary Basis of Decision for Effient ™
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:
EffientTM
Prasugrel hydrochloride, 10 mg, Tablet, Oral
Eli Lilly Canada Inc.
Submission control no: 121143
Date issued: 2010-07-13
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):
- 02349124
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Control Number: 121143
Date of Submission:
Date of authorization:
2 Notice of decision
On April 16, 2010, Health Canada issued a Notice of Compliance to Eli Lilly Canada Inc. for the drug product Effient.
Effient contains the medicinal ingredient prasugrel (as prasugrel hydrochloride) which is a platelet aggregation inhibitor.
Effient co-administered with acetylsalicylic acid, is indicated for the early and long-term secondary prevention of atherothrombotic events in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) as follows:
- unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI) managed with PCI.
- ST-segment elevation myocardial infarction (STEMI) managed with primary or delayed PCI.
Effient is an inhibitor of platelet activation and aggregation. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function can result in the reduction of the rate of cardiovascular (CV) events.
The market authorization was based on quality, non-clinical, and clinical information submitted. A Phase III multicentre, international, randomized, double-blind, parallel-group study compared the efficacy and safety of Effient to clopidogrel in 13,608 patients that had moderate to high risk UA, NSTEMI, or STEMI, managed with PCI. Both drugs were given in combination with acetylsalicylic acid. Other standard therapies were given according to the investigator's discretion. Compared to clopidogrel, Effient demonstrated an 18% relative risk reduction (1.0% absolute risk reduction) in the primary composite endpoint of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke, from 0-3 days; and a 20% relative risk reduction (1.2% absolute risk reduction) in the primary composite endpoint from 3 days to the end of the 15-month follow-up period. These differences were primarily due to the reduction in the component of nonfatal MI. Neither CV death nor nonfatal stroke were statistically significant. Bleeding was the main safety concern with Effient. In the Effient-treatment group, there was a 31.5% relative increase (0.5% absolute risk increase) in the risk of Thrombolysis in Myocardial Infarction (TIMI) major Non-Coronary Artery Bypass Graft (non-CABG) related bleeding compared to clopidogrel.
Effient [10 mg prasugrel (as prasugrel hydrochloride)] is presented as a tablet. Effient should be initiated with a single 60 mg loading dose and then continued at a 10 mg once daily dose for long-term treatment. Patients taking Effient should also take acetylsalicylic acid (75 mg to 325 mg) daily. Dosing guidelines are available in the Product Monograph.
Effient is contraindicated in:
- patients with a known history of transient ischemic attack or stroke.
- patients with active pathological bleeding, such as peptic ulcer or intracranial haemorrhage.
- patients with severe hepatic impairment (Child-Pugh Class C).
- patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.
A Black Box Warning in the Product Monograph outlines the safety concerns related to the increased risk of bleeding in the populations of:
- elderly patients ≥75 years old; and
- patients with low body weights <60 kg.
Effient 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 Effient 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 Effient is favourable for the indications stated above.
3 Scientific and Regulatory Basis for Decision
The New Drug Submission (NDS) for Effient was filed with Health Canada on April 3, 2008. Due to quality, non-clinical, and clinical issues, a Notice of Non-Compliance (NON) was issued on July 2, 2009. In the sponsor's response to the NON, the quality, non-clinical, efficacy and safety issues were addressed. Many of the Sponsor's responses to the NON were inadequate and the original indication was revised to be consistent with the efficacy and safety data as reflected in the approved Effient Product Monograph. These changes were accepted by the Sponsor, and on April 16, 2010 a Notice of Compliance (NOC) was issued for Effient. The timeline of this submission review is reported in section 4 Submission Milestones. A discussion regarding the safety concerns appears in section 3.3.4 Clinical Safety.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Prasugrel (as prasugrel hydrochloride) is the medicinal ingredient of Effient. Effient is an inhibitor of platelet activation and aggregation. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function can prevent atherothrombotic events and impact the occurrence of cardiovascular events.
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 route of synthesis of prasugrel hydrochloride supports the chemical structure assigned. Confirmation of the chemical structure was provided by elemental analysis and spectroscopic analysis.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within International Conference on Harmonisation established limits and/or were qualified from toxicological studies or batch studies and therefore, are considered to be acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of prasugrel hydrochloride are considered acceptable.
Data from the 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, shelf-life, and storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Effient (prasugrel hydrochloride, 10 mg) is a beige, double-arrow-shaped, film-coated tablet debossed with "10 MG" on one side and "4759" on the other side.
Each 10 mg tablet is manufactured with 10.98 mg prasugrel hydrochloride, equivalent to 10 mg of prasugrel. Other ingredients include croscarmellose sodium, hypromellose, mannitol, microcrystalline cellulose, and vegetable magnesium stearate. The colour coating contains hypromellose, iron oxide red, iron oxide yellow, lactose, titanium dioxide, and triacetin.
Effient tablets are contained in blister packages of 28 (2×14) tablets or 30 (5×6) tablets.
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 prasugrel 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
Effient is tested to verify that its identity, appearance, content uniformity, assay, dye identity test, dissolution, tablet-form conversion, moisture content, and levels of degradation products, and drug-related impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products are within acceptable limits.
Validation results of the analytical methods used for the determination of prasugrel hydrochloride 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 the real-time, long-term, and accelerated stability data submitted, the proposed 24-month shelf-life for Effient is considered acceptable when the drug product is stored in the original blister packaging at a controlled room temperature of 15-30°C.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Effient are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
The only excipient of animal origin is lactose monohydrate which is used in the colour mixture. The lactose is sourced from healthy animals in the United States, under the same conditions that milk is collected for human consumption. Therefore, the excipient is considered acceptable.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Effient 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
Prasugrel is a pro-drug whose active metabolite inhibits the P2Y12 class of platelet adenosine-diphosphate (ADP) receptors. This inhibition is selective for P2Y12 and is irreversible. As a result of this inhibition, numerous ADP-mediated platelet activities are inhibited including aggregation, secretion, fibrinogen binding, procoagulant activities, P-selectin expression, platelet-leukocyte aggregation, and adenylate cyclase inhibition
The concentration-dependent inhibition of platelet aggregation by the active metabolite was demonstrated in vitro in several species including: human, monkey, dog, rabbit, and rat. The parent prodrug, prasugrel, showed minimal effects on rat and human platelet aggregation even at the highest concentration (300 µM). The specificity of the active metabolite for P2Y12 was demonstrated in binding experiments using the human P2Y12 receptor expressed in Chinese hamster ovary (CHO) K-1 cells, and further demonstrated in binding studies with intact human platelets. Inhibition of the platelet activities listed above by prasugrel's active metabolite were demonstrated in a series of in vitro experiments using preparations of human platelets.
Oral administration of prasugrel resulted in time- and dose-dependent inhibition of ex vivo platelet aggregation in rats, dogs, and monkeys and inhibition of in vivo thrombus formation and prolongation of the bleeding time in rats. Inhibitory effects on platelet aggregation and thrombus formation were enhanced in the presence of acetylsalicylic acid.
Based on the non-clinical safety pharmacology studies, clinical doses of prasugrel are not expected to produce secondary pharmacodynamic effects related to the central nervous system, cardiovascular (including QT interval), respiratory, renal, or gastrointestinal function. At higher doses, prasugrel may decrease paradoxical sleep, and decrease gastric acid content and gastric volume.
3.2.2 Pharmacokinetics
Absorption, distribution, metabolism, and excretion characteristics of prasugrel have been investigated in mice, rats, and dogs; the same species used in the toxicological evaluation of the compound. Appropriate methodology was used to detect the presence of prasugrel metabolites in plasma, urine, and bile. The limits of quantitation in the assays were appropriate for the animal studies and allowed appropriate evaluation of the pharmacokinetics (PK) of prasugrel and its metabolites.
Absorption
Prasugrel was rapidly absorbed after oral administration in mice, rats, rabbits, and dogs. In the species studied, the time to achieve maximum plasma concentration (Tmax) was <1 hour.
The absolute oral bioavailability of prasugrel was high. In rats that were administered single oral and intravenous doses of radiolabelled prasugrel, the oral bioavailability was estimated to be approximately 77%.
Distribution
The maximum concentrations of radiolabelled prasugrel occurred at 1-hour post dose in most tissues involved in the absorption and elimination of the compound and its metabolites, including the stomach, intestines, liver, kidneys, and urinary bladder.
Placental transfer of the prasugrel metabolites to the foetus of pregnant rats was low. However, transfer of radiolabelled prasugrel into the milk of lactating rats was demonstrated.
In general, protein binding of the prasugrel metabolites was high (>80%) in rat, dog, and human plasma. Binding of the active metabolite was estimated to be 98% in a human serum albumin solution.
Metabolism
Prasugrel is rapidly hydrolyzed in vivo by esterases to a thiolactone which is subsequently metabolized by several cytochrome P450 (CYP) enzymes, mainly CYP3A and CYP2B6, to a thiol-containing active metabolite.
The prasugrel metabolites that were identified in the human plasma, urine, and faeces were also identified in mice, rats, and dogs. Exposure of the measured metabolites increased as the prasugrel dose was increased. After multiple doses, exposure of the metabolites generally decreased in comparison to exposure after the first dose, indicating enzyme induction. Those results occurred at high doses in mice (≥100 mg/kg/day), rats (100 and 300 mg/kg/day), and dogs (≥20 mg/kg/day).
Exposure to the prasugrel metabolites was generally comparable for prasugrel base and prasugrel hydrochloride in mice, rats, and dogs; however, exposure was higher following doses of prasugrel hydrochloride ≥500 mg/kg in the rat and at 100 mg/kg in the dog.
Excretion
In rats and dogs, biliary excretion was the major route of elimination for the prasugrel metabolites. Approximately 73 to 79% of the oral dose was excreted in the faeces. In mice, approximately 52% of the dose was eliminated in the urine, and 37% was eliminated in the faeces.
3.2.3 Toxicology
Pivotal toxicology studies were all conducted in accordance with current regulatory guidelines and in compliance with Good Laboratory Practice. The majority of the studies were conducted using prasugrel base, while some studies compared the toxicity of prasugrel base to its hydrochloride salt. Animals were exposed to the same metabolites regardless of whether the prasugrel base or prasugrel hydrochloride was administered. The safety margins were appropriately based on exposure to the metabolites of prasugrel and not on the administered dose.
Single-Dose Toxicity
In general, prasugrel demonstrated low single-dose toxicity in mice, rats, and dogs. In female rats that were administered 2000 mg/kg, irregular respiration, reduction of locomotor activity, ptosis (drooping of eyelids), staggering gait, and lacrimation (increased production of tears) were reported. All these clinical signs disappeared within 3 days of drug administration.
Repeat-Dose Toxicity
The repeat-dose studies with prasugrel were conducted in mice, rats, and dogs for a duration of up to 3, 6, and 9 months, respectively. The major toxicological issues associated with prasugrel included: decreased body weight (mice and rats); significant histologic changes to the liver (mice, rats, and dogs); increased serum alkaline phosphatase activity (dogs); increased prothrombin time, increased activated partial thromboplastin time, and increased platelet counts (rats); and decreases in red blood cell parameters (mice and rats). The No Observed Adverse Effect Level (NOAEL) in the rat was 30 mg/kg (24-fold the clinical maintenance dose of 10 mg on a mg/m2 basis). The NOAEL in the dog was 4 mg/kg (11-fold the clinical maintenance dose of 10 mg on a mg/m2 basis).
Genotoxicity
Prasugrel was not genotoxic in the Ames bacterial gene mutation test, the in vitro chromosome aberration tests, and the micronucleus test in mice.
Carcinogenicity
Carcinogenicity studies were conducted with prasugrel hydrochloride in mice and rats for two years.
Changes in the liver in terms of increased nodules, raised focus, white or red foci, centrilobular hypertrophy of the hepatocytes, and incidence of eosinophilic altered cell foci were observed in some mice from the 100 and 300 mg/kg groups. Hepatocellular adenoma was observed in males and females in the 300 mg/kg group, and females in the 100 mg/kg group. One male from the 300 mg/kg group and one female from the 100 mg/kg had a hepatoblastoma. Hypertrophy and pigmentation of the thyroid follicular cells also occurred in mice from the 300 mg/kg groups (both sexes).
In rats, changes in the liver in terms of increased red foci, hypertrophy of hepatocytes and eosinophilic altered cell foci were observed in males from the 100 mg/kg group. In addition, some males and female rats in the 30 and 100 mg/kg groups had changes in their lungs including increased white foci and accumulation of foamy cells. In rats, no treatment-related changes in tumours were observed.
The occurrence of tumours in mice was attributed to an induction of liver enzymes. The rodent-specific association of liver tumours and drug-induced enzyme induction is well-documented in past literature. Therefore, the increase in liver tumours with prasugrel administration in mice is not considered a relevant human risk.
Reproductive and Developmental Toxicity
Oral doses of prasugrel up to 300 mg/kg did not appear to have any effects on fertility, early embryonic development, and pre- and post-natal development in rats. Prasugrel hydrochloride did not exhibit any adverse effects in pre- and post-natal toxicity studies in rats.
3.2.4 Conclusion
The non-clinical studies for this drug submission are considered suitable and support the use of Effient for the proposed indication. Overall, the results of the toxicology studies demonstrate no evidence of risk to the health of humans at the recommended dosage and duration of administration, provided adequate safety precautions are taken.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The pharmacodynamic (PD) effects of Effient on platelet function were assessed by inducing platelet aggregation with various concentrations of ADP (20 µM and 5 µM). The ADP-induced platelet aggregation was measured by light transmission aggregometry in healthy subjects and patients with atherosclerotic disease, who were administered Effient or the active comparator, clopidogrel.
The mean maximum platelet inhibition after a 60-mg loading dose (LD) of Effient was 79% and 83% for 20 µM and 5 µM ADP, respectively, with ≥89% of all subjects achieving at least 50% inhibition of platelet aggregation (IPA) by 1 hour for both ADP concentrations.
Mean steady-state IPA was 69% and 74% for 20 µM and 5 µM ADP, respectively, and was achieved following 3 to 5 days of 10-mg maintenance dosing with a preceding loading dose of Effient. Greater than 98% of the subjects had an IPA of ≥20% during maintenance dosing. The levels of IPA were dependent on the dose of Effient and exposure of the active metabolite.
Effient-mediated IPA exhibited low between-subject (9%) and within-subject (12%) variability with both 20 µM and 5 µM ADP. Platelet aggregation values gradually returned to baseline after treatment in 7 to 9 days following a single 60-mg LD of Effient and in 5 days following discontinuation of maintenance dosing at steady-state.
The IPA achieved in response to Effient was significantly higher than that observed for clopidogrel responders. An Effient LD of 60 mg followed by a daily maintenance dose (MD) of 10 mg consistently achieved a faster onset of action, a greater mean IPA, lower between- and within-subject variability in IPA, and a lower incidence of PD (pharmacodynamic) poor responders (defined as those with an IPA of <20% for 20 µM ADP at 4 or 24 hours post dose) compared to the clopidogrel 300-mg LD/daily 75-mg MD regimen. In addition, in direct crossover studies, almost all PD poor responders to clopidogrel achieved high levels of platelet inhibition with Effient LD and MD administration.
3.3.2 Pharmacokinetics
Absorption
After oral administration, prasugrel was absorbed quickly, and rapidly metabolized to the pharmacologically active metabolite and inactive metabolites. The peak plasma concentration of the active metabolite occurred within approximately 30 minutes in the fasted state. At least 79% of the prasugrel dose was absorbed. Exposure to the active metabolite was dose-proportional.
Distribution
The apparent volume of distribution of the active metabolite ranged from 30 L to 84 L in healthy subjects and patients with stable atherosclerosis.
The active metabolite was found to be highly protein bound (98%) to human serum albumin.
Metabolism
Prasugrel is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step of CYP metabolism, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The active metabolite is further metabolized into two inactive compounds by S-methylation or conjugation with cysteine.
Excretion
Approximately 68% and 27% of the administered drug was excreted in the urine and faeces, respectively, in the form of inactive metabolites. The average terminal elimination half-life of the active metabolite in plasma was approximately 7.4 hours; the active metabolite was not detected in urine or faeces.
It is not known whether the prasugrel metabolites are excreted in human milk.
Drug Interactions
Effects of Elevated Gastric pH
An elevated gastric pH was shown to have significant effects on the PK of prasugrel in two studies in which healthy subjects were also administered ranitidine, a drug that reduces stomach acid production. A separate study where subjects were administered lansoprazole (another drug that prevents the stomach from producing gastric acid), also demonstrated an impact on the PK parameters of prasugrel. Adverse events (AEs) in the ranitidine studies were not different between the prasugrel and clopidogrel groups in general.
Inhibitor of CYP3A4
Ketoconazole, a potent inhibitor of CYP3A4, did not significantly affect the drug exposure of prasugrel's active metabolite after a LD or during the maintenance dosing. There was no affect of ketoconazole on IPA.
Inducers of Cytochrome P450 Enzymes
Coadministration of prasugrel with rifampicin, a potent inducer of CYP3A and CYP2B6 and also an inducer of CYP2C9, CYP2C19, and CYP2C8, did not significantly change the exposure to prasugrel's active metabolite. Therefore, other CYP inducers are not expected to significantly affect the PK of prasugrel's active metabolite.
Special Populations
Hepatic Impairment
The PD and PK of prasugrel were similar in patients with mild to moderate hepatic impairment compared with healthy control subjects. The PK and PD of prasugrel in patients with severe hepatic impairment have not been studied.
Renal Impairment
The PD and PK of prasugrel were similar in patients with moderate renal impairment compared to healthy control subjects. In patients with end-stage renal disease (ESRD), the maximum plasma concentration (Cmax) and mean exposure (AUC) of the active metabolite was decreased 51% and 42%, respectively; however the prasugrel-mediated platelet aggregation was similar in patients with moderate renal impairment, ESRD, and healthy controls.
Body Weight and Age
The data indicates that patients <60 kg had a higher exposure to prasugrel's active metabolite compared to the general population and were more likely to experience a bleeding episode.
An increase in exposure to the active metabolite was also reported for patients ≥75 years of age compared to patients <75 years of age. Due to this increase in exposure and a possibly greater sensitivity to bleeding in patients ≥75 years of age, Effient is not recommended for patients ≥75 years of age.
3.3.3 Clinical Efficacy
A Phase III multicentre, international, randomized, double-blind, parallel-group study (Study TAAL) compared the efficacy and safety of Effient to clopidogrel in 13,608 ACS patients that had moderate to high risk UA, NSTEMI, or STEMI, managed with PCI. Patients received Effient (60 mg LD followed by 10 mg once daily) or clopidogrel (300 mg LD followed by 75 mg once daily); 6813 patients were treated with Effient and 6795 patients were treated with clopidogrel. Both drugs were given in combination with acetylsalicylic acid (75 mg to 325 mg once daily). Other standard therapies were given according to the investigator's discretion. The maximum follow-up period was 15 months and the minimum was 6 months (actual median 14.5 months). The primary composite endpoint was the composite of CV death, nonfatal MI, or nonfatal stroke.
Compared to clopidogrel, Effient demonstrated an 18% relative risk reduction (1.0% absolute risk reduction) in the primary composite endpoint of CV death, nonfatal MI, or nonfatal stroke, from 0-3 days; and a 20% relative risk reduction (1.2% absolute risk reduction) in the primary composite endpoint from 3 days to the end of the 15-month follow-up period. These differences were primarily due to the reduction in the component of nonfatal MI. The components of CV death [Effient 2.0% versus (vs.) clopidogrel 2.2%, p=0.31] and nonfatal stroke (Effient 0.9% vs. clopidogrel 0.9%, p=0.93] did not demonstrate statistical significance. Patients who were <75 years, ≥60 kg, and with no history of transient ischemic attack (TIA) or stroke that were treated with Effient had a significantly greater treatment benefit with respect to the primary composite efficacy endpoint when compared to those who were treated with clopidogrel
Compared to clopidogrel, Effient significantly reduced the following Clinical Endpoints Committee (CEC) adjudicated secondary composite endpoints in all study populations:
- CV death, nonfatal MI or nonfatal stroke through 30 days and 90 days;
- CV death, nonfatal MI, or urgent target vessel revascularization through 30 days and 90 days;
- All causes of death, nonfatal MI, or nonfatal stroke through study end.
3.3.4 Clinical Safety
Study TAAL served as the primary safety database. For a description of the study, see section 3.3.3 Clinical Efficacy. Supporting safety data was provided from two Phase II studies along with a number of Phase I studies.
In Study TAAL, the common AEs in the Effient-treatment group were primarily haemorrhagic. The three most frequently reported common haemorrhagic treatment-emergent AEs in both treatment groups were contusion, haematoma, and epistaxis; and all had statistically significant higher incidence in the Effient-treatment group compared to the clopidogrel-treatment group.
The most common non-haemorrhagic AEs included:
- Rash was reported in 2.8% of Effient and 2.4% of clopidogrel patients.
- Anaemia was reported in 2.2% of Effient and 2.0% of clopidogrel patients.
- Pyrexia and increased tendency to bruise were reported in at least 1% of Effient patients and the incidence of these AEs was significantly higher compared to the clopidogrel-treatment group.
Gastrointestinal haemorrhage was the most common haemorrhagic serious adverse event (SAE) reported in patients treated with Effient (1.3%) or clopidogrel (0.8%). The non-haemorrhagic SAEs included non-cardiac chest pain [Effient 2.0% versus (vs). clopidogrel 2.5%], coronary artery restenosis (Effient 1.6% vs. clopidogrel 1.6%), chest pain (Effient 1.4% vs. clopidogrel 1.1%), and angina pectoris (Effient 1.3% vs. clopidogrel 1.3%).
Safety endpoints included coronary artery bypass graft (CABG)-related bleeding and Non-CABG-related Thrombolysis in Myocardial Infarction (TIMI) bleeding.
Effient significantly increased the risk of bleeding compared to clopidogrel, including fatal events. In the Effient-treatment group, there was a 31.5% relative increase (0.5% absolute risk increase) in the risk of TIMI major bleeding non-CABG related compared to clopidogrel.
In the UA/NSTEMI, STEMI, and All ACS populations, CABG-related TIMI major bleeding was 3.2 to 3.7-fold higher with Effient compared to clopidogrel.
In all populations, Effient significantly increased bleeding compared to clopidogrel in the following categories:
- Non-CABG-related TIMI major bleed
- Non-CABG-related TIMI life-threatening bleed
- Non-CABG-related TIMI fatal bleed
- Non-CABG-related TIMI minor bleed
According to the Kaplan-Meier curves, the risk of non-CABG-related bleeding increased over time for the Effient-treatment group compared to the clopidogrel-treatment group.
The number of patients experiencing intracranial haemorrhages (ICH) was similar between treatment groups. However, there was a higher incidence of ICH in patients with a history of prior TIA or prior stroke treated with Effient compared to clopidogrel. The fatality rate for ICH was higher in the Effient-treatment group [9 of 6741 (0.13%)] compared to the clopidogrel-treatment group [5 of 6716 (0.07%)]. The primary risk factor for fatal ICH was age ≥75 years.
Patients ≥75 years of age or those with a history of TIA/cerebrovascular accident, and patients with a body weight <60 kg had an increased risk of bleeding with Effient, compared to clopidogrel. Additional analysis found that patients ≥75 years of age and patients with a body weight <60 kg had a higher exposure to the active metabolite of the 10 mg MD of Effient compared to others in the study population, and a higher risk of bleeding. Effient is contraindicated for patients with a known history of TIA or stroke, and a Black Box Warning in the Product Monograph outlines the safety concerns related to the increased risk of bleeding for patients ≥75 years of age, as well as for patients who have a body weight <60 kg.
There was an increased rate of neoplasms in the Effient-treatment group compared to the clopidogrel-treatment group. Newly diagnosed malignancies were reported in 1.6% and 1.2% of patients treated with Effient and clopidogrel, respectively. The sites contributing to the differences were primarily colon and lung. Given the observational nature and the small absolute risk, adequate warnings have been added to the Product Monograph and a risk management post-marketing plan has been submitted for review.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Effient (prasugrel hydrochloride) is an inhibitor of platelet activation and aggregation, and has been shown to reduce the rate of the primary composite endpoint of CV death, nonfatal MI, or nonfatal stroke in ACS patients managed with PCI. This was primarily due to the reduction in the component of nonfatal MI. The component that drove the positive composite results was nonfatal MI. Neither CV death (Effient 2.0% vs. clopidogrel 2.2%, p=0.31) or nonfatal stroke (Effient 0.9% vs. clopidogrel 0.9%, p=0.93) were statistically significant. However, this anti-platelet effect is linked with an increased bleeding risk (TIMI major and minor bleeds).
The bleeding rate in Study TAAL was a serious safety concern. Patients with a history of TIA/stroke were at increased risk of serious/fatal bleeds, thus Effient is contraindicated for patients with a known history of TIA or stroke. Patient populations at increased risk of bleeding (elderly patients ≥75 years of age and low body weight patients <60 kg) were identified. As a result, a Black Box Warning has been added to the Product Monograph to strongly warn prescribers of this increased risk, and the Product Monograph has been written to reflect the extent and limitations of use. Moreover, an increased rate of all neoplasms, particularly solid tumours, in the Effient-treatment group compared to the clopidogrel-treatment group was observed. Given the observational nature and the small absolute risk, adequate warnings have been added to the Product Monograph and a risk management post-marketing plan has been submitted for review.
Overall, the benefit to risk profile is favourable and supports the use of Effient for the approved indication.
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 Effient co-administered with acetylsalicylic acid, is favourable for the early and long-term secondary prevention of atherothrombotic events in patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention (PCI) as follows:
- Unstable angina or non-ST-segment elevation myocardial infarction managed with PCI.
- ST-segment elevation myocardial infarction managed with primary or delayed PCI.
The NDS complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the NOC pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: EffientTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2008-02-22 |
| Request for priority status | |
| Filed: | 2008-02-28 |
| Rejection issued by Director, Cardio-Renal Division: | 2008-03-31 |
| Submission filed: | 2008-04-03 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2008-05-23 |
| Review 1 | |
| Biopharmaceutics Evaluation complete: | 2009-04-14 |
| Quality Evaluation complete: | 2009-03-16 |
| Clinical Evaluation complete: | 2009-03-19 |
| NON issued by Director General (safety, efficacy, quality issues): | 2009-07-02 |
| Response filed: | 2009-10-13 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2009-11-18 |
| Review 2 | |
| Biopharmaceutics Evaluation complete: | 2010-04-15 |
| Quality Evaluation complete: | 2010-04-16 |
| Clinical Evaluation complete: | 2010-04-16 |
| Labelling Review complete: | 2010-04-16 |
| NOC issued by Director General: | 2010-04-16 |