Summary Basis of Decision for Coversyl ®
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:
Coversyl®
Perindopril arginine, 2.5 mg, 5 mg, 10 mg, Tablet, Oral
Servier Canada Inc.
Submission control no: 092251
Date issued: 2006-03-10
Health Products and Food Branch
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Health Canada
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), COVERSYLMD , périndopril arginine, comprimés de 2,5 mg, 5 mg et 10 mg, Servier Canada Inc. , No de contrôle de la présentation 092251
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):
- 02270552 - 2.5 mg
- 02270560 - 5 mg
- 02270579 - 10 mg
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On August 23, 2005 , Health Canada issued a Notice of Compliance to Servier Canada Inc. for the new drug product Coversyl® (perindopril arginine). Market authorization was based on the demonstration of bioequivalence of perindopril arginine to the previously authorized product, perindopril erbumine.
Perindopril is an Angiotensin Converting Enzyme (ACE) inhibitor. Inhibition of ACE activity leads to decreased levels of angiotensin II, resulting in decreased vasoconstriction and, thereby, lower blood pressure.
Coversyl® is indicated in:
- Treatment of mild to moderate essential hypertension. It may be used alone or in association with other drugs, particularly thiazide diuretics. In using Coversyl®, consideration should be given to the risk of angioedema. The safety and efficacy of Coversyl® in renovascular hypertension have not been established and therefore, its use in this condition is not recommended. The safety and efficacy of concurrent use of Coversyl® with antihypertensive agents other than thiazide diuretics have not been established.
- Treatment of mild to moderate congestive heart failure, generally as adjunctive therapy to diuretics, and where appropriate a digitalis glycoside. Treatment should be initiated under close medical supervision.
Coversyl® (2.5 mg, 5 mg, and 10 mg perindopril arginine) is presented in tablet form. Dosing instructions must be individualized and adjustments are required in the elderly, and in cases of renal impairment. Dosing guidelines are available in the Product Monograph.
Coversyl® is contraindicated in patients with a history of angioedema related to previous treatment with an ACE inhibitor or patients with known hypersensitivity to any components of this product.
Detailed conditions for the use of Coversyl® 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 Coversyl® is favourable for the indication 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 the drug substance, perindopril arginine, 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. The specifications given for the starting materials, reagents, and solvents are considered satisfactory.
Characterisation
The drug substance specifications include testing for the stereochemical purity of perindopril. Perindopril arginine is highly soluble. The manufacturing process consistently gives a product which is stable under ambient conditions. Dissolution profiles obtained from tablets manufactured using drug substance batches with different particle size distributions (PSDs) showed that the drug substance release kinetics is not influenced by variability in PSD.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterised. These products were found to be within ICH established limits and/or were qualified from batch analysis and therefore, considered acceptable.
Control of Drug Substance
Validation reports were satisfactorily submitted for all analytical procedures used for in-process and release testing of p erindopril arginine, and to justify the specification of the drug substance.
Data from batch analyses were reviewed and considered to be acceptable according to the specifications of perindopril arginine.
Stability
Based upon the real-time and accelerated stability study data submitted, the proposed re-test period, storage, and shipping conditions for perindopril arginine were supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Coversyl® (perindopril arginine) is manufactured in three tablet strengths:
- 2.5 mg , white, round, convex, film-coated tablets.
- 5 mg, light green, rod- shaped, film-coated tablets engraved on one face and scored on both edges.
- 10 mg, green, round, biconvex, film-coated tablets engraved on both faces.
The formulations are proportional and contain commonly used tablet excipients: glycerol, hydrophobic colloidal silica, lactose monohydrate, magnesium stearate, maltodextrin, sodium starch glycolate (type A), and titanium dioxide.
Each tablet strength is packaged in a polypropylene white tube equipped with a low density polyethylene flow reducer and a low density polyethylene green opaque stopper containing 2.0 g of white desiccant gel. Each tube contains 30 film-coated tablets.
Pharmaceutical Development
Servier Canada Inc. developed a new salt form, perindopril arginine, for the current drug product Coversyl®. Coversyl® is presently marketed as 2, 4 and 8 mg tablets of perindopril erbumine. A change of the salt form, from erbumine to arginine, was developed in order to optimize stability. The pharmaceutical development essentially consisted of the demonstration of the bioequivalence between the two salts. The new salt of perindopril contains 2.5 mg, 5 mg and 10 mg of perindopril arginine and is equimolar to 2, 4 and 8 mg of perindopril erbumine, respectively. Changes to the manufacturing process and formulation made throughout the development are considered acceptable upon review.
Manufacturing Process and Process Controls
The product is manufactured employing standard wet granulation techniques followed by film-coating.
The manufacturing process is considered to be adequately controlled within justified limits. The trade formulations are identical to the batches used in the bioequivalence studies.
Control of Drug Product
Coversyl® (perindopril arginine) was tested to verify its identity, appearance, average mass, uniformity of content, disintegration time, dissolution, microbial quality, and presence of degradation products. Hardness and water content were monitored in the stability testing. The test specifications are considered acceptable and are within the ICH recommended limits.
Validation reports were satisfactorily submitted for all analytical procedures used for in-process and release testing of the drug product, and to justify the specification of the drug product.
Data from final batch analyses were reviewed and considered to be acceptable according to the specification of the drug product.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized, and were found to be within the ICH established limits and/or were qualified from batch analysis and therefore, considered acceptable.
Stability
Based upon the real-time and accelerated stability study data submitted, the proposed 24-month shelf-life for Coversyl® (perindopril arginine) is considered acceptable when the product packaged in a polypropylene white tube equipped with a low density polyethylene flow reducer and a low density polyethylene green opaque stopper containing white desiccant gel is stored at 15-30oC.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facility and equipment are considered to be 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
This New Drug Submission is considered to meet the requirements of Division C.08.002 of the Food and Drug Regulations insofar as the Quality (Chemistry and Manufacturing) information is concerned.
The Chemistry and Manufacturing information submitted for Coversyl® (perindopril arginine) has demonstrated that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
Coversyl® has been marketed as a perindopril erbumine salt. This new drug submission is for a new perindopril formulation that has been developed; a perindopril arginine salt which was shown to be more stable and easier to protect against humidity. As a result, a number of non-clinical studies were performed and the main observations are summarized in the following sections.
3.2.1 Pharmacodynamics
Animal studies to compare the effects of perindopril erbumine salt and perindopril arginine salt on blood pressure response and renin-angiotensin-aldosterone parameters were not considered relevant for this submission. The pharmacokinetics of both salts were demonstrated in rats and dogs, and both salts showed comparative bioavailability in therapeutic conditions, for all doses studied.
3.2.2 Pharmacokinetics
The pharmacokinetic properties of perindopril arginine and perindopril erbumine were compared after single and repeated oral administration in the Wistar rat and the Beagle dog. In each of the species tested, both salts were found to be essentially similar regarding their absorption, distribution, metabolism and elimination characteristics.
Absorption
For both perindopril salts, the absorption of perindopril was rapid in both species studied. Peak concentrations of the metabolite, perindoprilat, occurred after its glucuronide. The same delay in maximal plasma concentrations was observed in humans for perindoprilat and its glucuronide.
Distribution
No accumulation was observed after repeated oral administration for 7 days for perindopril, perindoprilat and their respective glucuronides after repeated oral administration of perindopril erbumine or perindopril arginine.
The mean bioavailability was similar for both salts, 15% for the arginine salt and 19% for the erbumine salt. The volume of distribution at steady-state was small (Vd = 0.4 L/kg).
Metabolism
In the Wistar rat irrespective of the salt administered, perindoprilat was the main metabolite identified in both plasma and urine, with up to 40% and 46% of the dose eliminated in the urine after oral and intravenous administration, respectively. These results show the importance of the hydrolytic route in the metabolism of perindopril in the rat, as compared to the minor glucuronidation pathway represented by perindoprilat glucuronide.
In the Beagle dog, the hydrolytic and glucuronidation pathways were quantitatively comparable. Perindoprilat and perindoprilat glucuronide were the predominant metabolites in plasma and urine. These results are similar to those found in man; perindoprilat and perindopril glucuronide are the major circulating metabolites followed by perindoprilat glucuronide and perindopril .
In the male Beagle dog, perindopril elimination was characterized by a short half-life (0.25 hours) and an intermediate plasma clearance (26 mL/min/kg).
The plasma concentration time profile of perindoprilat was characterised by two half-lives. The first and rapid half-life of 0.6 hours in the male Wistar rat and 1.3 hours in the Beagle dog, corresponds to the main part of its elimination. The longer terminal half-life (at least 26 hours in each species) is mostly attributed to the binding of perindoprilat to the ACE, as seen in humans. The two glucuronides (perindopril glucuronide and perindoprilat glucuronide) were shown to have a rapid elimination phase.
3.2.3 Toxicology
Single-Dose Toxicity
Acute toxicity of perindopril arginine (2000 mg/kg) was studied in Wistar rats and Swiss mice. No mortality, no changes in body weight and food consumption, and no lesions at the necropsy were observed. The only finding was sialism (hypersalivation) in all of the treated rats. Perindopril arginine was devoid of acute toxicity after single-dose administration and was shown to be comparable to perindopril erbumine.
Repeat-Dose Toxicity
Two four-week studies were performed in Wistar rats and Beagle dogs to compare the safety profile of perindopril arginine to perindopril erbumine . In summary, gastric lesions and a slight decrease in blood glucose levels were observed at high doses of perindopril arginine. No deaths and no change in target organs were seen. The safety and toxicokinetic profiles were similar for both perindopril salts. The results were also consistent with previous studies carried out for the registration and for the post market development of perindropil erbumine.
Reproductive and Development Toxicity
Reproductive and development toxicity studies were performed on mouse, rat, rabbit and monkey for perindopril erbumine and the results have been extrapolated to perindopril arginine. The results were negative and need not be repeated. This extrapolation is indicated as such in the Product Monograph.
Genotoxic/Mutagenic Toxicity
No mutagenic potential was observed with perindopril arginine. Chromosomal aberrations were found after prolonged (20 hours) treatment of human lymphocytes from 1924 μg /mL but the test was considered inappropriate since the accurate assessment of toxicity was not possible .
Carcinogenicity Toxicity
Carcinogenicity studies were performed on mouse and rat for perindopril erbumine and results have been extrapolated to perindopril arginine. The results were negative and need not be repeated. This extrapolation is indicated as such in the Product Monograph.
3.2.4 Summary and Conclusion
The preclinical studies that were performed for New Drug Submission, Control No. 092251 for Coversyl® (perindopril arginine) are acceptable. No data from the preclinical studies submitted indicate that perindopril arginine could have different pharmacological properties different from that of perindopril erbumine.
3.3 Clinical basis for decision
The New Drug Submission, Control No. 092251, for Coversyl® (perindopril arginine) does not include studies for efficacy and safety of perindopril since the efficacy and safety were previously established with the market authorization of Coversyl® (perindopril erbumine). The objective of this drug submission was to show the comparative bioavailability of both perindopril salts from the submitted pharmacokinetic (PK) data.
3.3.1 Pharmacodynamics
Perindopril is a prodrug that is partly rapidly de-esterified after oral administration to its diacid active metabolite perindoprilat. Perindoprilat inhibits ACE activity and thus prevents the conversion of angiotensin I, which is pharmacologically inactive to a vasoconstrictive product.
3.3.2 Pharmacokinetics
The bioavailability between the arginine salt and the erbumine salt of perindopril was demonstrated in the pharmacokinetic drug exposure parameters, AUC and C max , not only for perindopril but also for its active metabolite perindoprilat. Only one dose was chosen for the bioequivalence study as linearity between dose and AUC was demonstrated. Both salts of perindopril were compared following a single oral administration in 36 healthy male volunteers (one tablet containing 10 mg of the arginine salt [6.78 mg of free])This study was an open randomized two-way crossover study with a washout of at least 8 days between the two periods. Perindopril and perindoprilat plasma concentrations, measured by Liquid Chromatography-Mass Spectrometry-Mass Spectrometry (LC-MS-MS), were followed for 120 hours after dosing.
The comparative bioavailability study of the 1 x 10 mg perindopril arginine salt and 2 x 4 mg perindopril erbumine salt formulations was reviewed in detail in accordance with the guidelines for bioavailability of oral dosage formulations of drugs used for systemic effects. The subject selection was satisfactory and the clinical portion of the study was conducted in an acceptable fashion. The data provided from both the assay validation and the subject sample analysis show that the analytical method is capable of producing reliable data for measuring perindopril concentrations in human plasma. The data and graphs presented in the submission are adequate and the statistical results presented in the submission agree with those of the reviewer.
Based on the data from the comparative bioavailability study comparing perindoporil arginine 1 x 10 mg immediate release tablets to the perindopril erbumine 2 x 4 mg tablets, it can be concluded that the proposed product, Coversyl® (perindopril arginine), demonstrates similar rate and extent of absorption to the erbumine salt of perindopril. The results of the submitted study meet the recommended standards for bioequivalence based on both measured data and potency-corrected data; i.e., the 90% confidence interval of the relative mean of AUC T and the relative mean Cmax of the test to that of the reference was within 80 to 125%.
3.3.3 Clinical Efficacy
Clinical efficacy studies were not submitted for Coversyl® (perindopril arginine), New Drug Submission, Control No. 092251. The efficacy of perindopril was previously established with the market authorization of Coversyl® (perindopril erbumine). Perindopril arginine demonstrated comparable bioavailability to perindopril erbumine in the PK studies for perindopril exposure.
3.3.4 Clinical Safety
Clinical safety studies were not submitted for Coversyl® (perindopril arginine), New Drug Submission, Control No. 092251. The safety of perindopril was previously established with the market authorization of Coversyl® (perindopril erbumine). Perindopril arginine demonstrated comparable bioavailability to perindopril erbumine in the PK studies for perindopril exposure. In the PK studies, there were no safety issues observed.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The submitted data demonstrate similar pharmacokinetics and comparable bioavailability (AUC and Cmax) between the two salts of perindopril (erbumine and arginine salts) for perindopril exposure. The preclinical data demonstrate that the arginine salt did not present any additional toxicity as compared to the erbumine salt. Therefore, the benefit/risk ratio of perindopril arginine is not different from that of perindopril erbumine.
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 Coversyl® (perindopril arginine) is favourable in the treatment of mild to moderate hypertension and the treatment of mild to moderate congestive heart failure. 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: Coversyl®
| Submission Milestone | Date |
|---|---|
| Submission filed | 2004-06-15 |
| Screening 1 | |
| Screening Deficiency Notice issued | 2004-07-29 |
| Response filed | 2004-09-13 |
| Screening Acceptance Letter issued | 2004-10-27 |
| Review 1 | |
| Biopharmaceutics Evaluation complete | 2005-05-10 |
| Clinical Evaluation complete | 2005-08-08 |
| Quality Evaluation complete | 2005-07-04 |
| Labelling Evaluation complete | 2005-08-16 |
| NOC issued by Director General | 2005-08-23 |