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PUBLIC ASSESSMENT REPORT
Scientific Discussion
Domanion (ex-Irpax) 2 and 4 mg, tablet
Perindopril tert-butylamine
FR/H/312/01-02/DC
Applicant: Les Laboratoires Servier
Date of the PAR: April 2009
PAR IRPAX – March 2009
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Information about the procedure:
Application/Legal Basis
Active substance
Pharmaceutical form
Strength
Applicant
EU-Procedure number
End of procedure
1.
Article 10c / informed consent application of
Directive 2001/83/EC
Perindopril tert-butylamine
Tablet
2 and 4 mg
Les Laboratoires Servier
FR/H/312/01-02/DC
12 August 2008
INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Afssaps has granted on August 12,
2008 a marketing authorisation for DOMANION 2 and 4 mg, tablet (perindopril tert-butylamine)
from Les Laboratoires Servier in the treatment of hypertension, symptomatic heart failure,
reduction of risk of cardiac events in patients with stable coronary artery disease with a history of
myocardial infarction and/or revascularisation. A comprehensive description of indications and
doses is given in the SPC.
The Marketing Authorisation Holder applied for the registration of a duplicate of Coversyl 2 and 4
mg in accordance with the article 10c “informed consent application” of Directive 2001/83/EC.
Coversyl 2 and 4 mg (perindopril tert-butylamine) is an ACE inhibitor and has been used in the
treatment of hypertension (2- 8 mg dose), the treatment of symptomatic heart failure (2-4 mg dose)
for many years and recently in the reduction of risk of cardiac events in patients with a history of
myocardial infarction and/or revascularisation (2-8 mg dose).
All preclinical data and clinical data concerning the perindopril tert-butylamine salt were part of
the Innovator file. The studies of this application were given for information only. These data were
already evaluated by national agencies within the framework of evaluation for Coversyl (which
was first registered in France through a national procedure in June 1988).
The clinical pharmacology and efficacy and safety of perindopril (tert-butylamine and arginine
salts) have already been extensively studied and characterized during the development of the
several drug products already marketed.
During the procedure, no potential serious risk to public health was raised.
The content of the SPC approved during the national procedure is in accordance with that accepted
for the reference product Coversyl 2 mg and 4 mg. The SPC is also in agreement with the MRPapproved SPCs from other procedures.
2.
QUALITY ASPECTS
Introduction
The DOMANION Servier products are presented in the form of tablets containing 2 mg and 4 mg of
perindopril tert-butylamine.
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The excipients are lactose monohydrate, microcrystalline cellulose, magnesium stearate, silica
colloidal hydrophobic and Aluminium copper complexes of chlorophyllins (E141 ii) lake only for the
4 mg.
The tablets are packed in blisters made of a thermoformed PVC film with a heat sealable lacquered
aluminium backing foil. The blisters are presented in cardboard boxes, which constitute the secondary
packaging.
2.1. Drug substance
Perindopril tert-butyalmine is a well-known drug substance belonging to the therapeutic family of the
angiotensin converting enzyme (ACE) inhibitors. Perindopril tert-butylamine is a stable compound
and its level quality is guarantied by its compliance to the Ph. Eur. Monograph.
The drug substance is a white to almost white powder that is freely soluble in water, freely soluble in
alcohol and sparingly soluble in methylene chloride. The CEP procedure is followed.
The manufacturing procedure has been assessed at the EDQM.
The Ph. Eur. specifications are completed by an additional test for the residual solvents
2.2. Drug product
The 2 mg drug product is a white, round, uncoated tablet of 5 mm diameter with a curvatus radius of 4
mm and a finished mass of 45 mg.
The 4 mg drug product is a light-green, breakable, rod-shaped, uncoated tablet, 8 mm long and 4 mm
wide, with a curvatus radius of 3.5 mm, scored on both edges, engraved on one face and has a finished
mass of 90 mg.
No bioequivalence study and no comparative dissolution profiles were performed as the application is
an informed consent application of the reference medicinal products marketed in France: Coversyl
marketed by Servier.
Chosen excipients are very common for tablet manufacture and commonly used in pharmaceutical
industry.
The manufacturing process consists of a direct compression.
For each strength, process validation data are provided for at least three industrial batches for each site
and each batch size.
The proposed specifications for the control of the drug product are adequate. The methods are
satisfactorily described and validated. The batch analysis results show that the drug product meet the
specifications proposed.
The packaging is sufficient to ensure the quality of the tablets.
The conditions used in the stability studies are according to the ICH stability guideline.
On the basis of the submitted stability data, a shelf life of 24 months with the storage condition ‘do not
store above 30°C’ has been granted.
3.
NON-CLINICAL ASPECTS
3.1 Discussion on the non-clinical aspects
Since this is an informed consent application which refers to Coversyl 2 mg and 4 mg (full dossier),
which is already on the European market, no new preclinical such data have been submitted.
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The non clinical dossier contains an overview of non clinical data previously submitted for the
registration of Coversyl. Moreover results of specific studies performed in support of the registration
of the arginine salt have also been provided.
Perindopril is a pro-drug that is hydrolysed after oral administration to the diacid active metabolite
perindoprilat. Perindoprilat is an inhibitor of the angiotensin converting enzyme which converts
angiotensin I to angiotensin II; in addition the enzyme stimulates the secretion of aldosterone by the
adrenal cortex and stimulates the degradation of bradykinin, a vasodilatory substance, into inactive
heptapeptides.
Pharmacokinetics of perindopril tert-butylamine was investigated in rats and dogs during the
development of Coversyl. The absorption of perindopril is rapid in both species. Perindopril is rapidly
distributed through the organism. No accumulation was observed in the main organs. Perindopril is
mainly metabolised in vivo by hydrolytic cleavage of its ester bond into perindoprilat. Perindoprilat
and its glucuronide were the main metabolites in rats and dogs.
Perindopril tert-butylamine has low acute toxicity. Target organ identified in repeat dose toxicity
studies was the kidney with reversible damage.
Perindopril and perindoprilat did not reveal genotoxic potential in a standard battery of tests.
Perindopril did not show carcinogenic potential in rats and mice.
No findings of embryotoxicity or teratogenicity were observed in studies performed in mice, rabbits
and monkeys.
Section 5.3 of the SPC correctly reflects the non clinical data and is in line with Coversyl’s SPC.
Environmental risk
As perindopril is a well-known substance, such an evaluation of the potential environmental risk is
deemed unnecessary. Approval of this product will indeed not result in an increase in the total quantity
of the active substance released into the environment, since it is intended as a duplicate of other
identical products on the market.
4.
CLINICAL ASPECTS
4.1 Introduction
The Marketing Authorisation Holder is applying for a marketing authorisation application according to
article 10c - informed consent application of Coversyl 2 and 4 mg in accordance with the article 10c
“informed consent application” of Directive 2001/83/EC.
The studies of this application were given for information only.
These data have already been evaluated by National Agencies within the framework of evaluation for
Coversyl.
Perindopril tert-butylamine is an ACE inhibitor and is used in the treatment of hypertension (2-8 mg),
the treatment of symptomatic heart failure (2-4 mg), and the reduction of risk of cardiac events in
patients with stable coronary artery disease with a history of myocardial infarction and/or
revascularisation (2-8 mg). It is a well-known active substance with established efficacy and
tolerability.
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The clinical pharmacology and efficacy and safety of perindopril (tert-butylamine and arginine salts)
have already been extensively studied and characterized during the development of the several
available products.
Pharmacodynamic
Four studies (2 single-dose and 2 repeated-dose) were performed in healthy volunteers and 28 studies
were carried out in hypertensive patients (repeated-doses and 24-hour antihypertensive activity
studies) and in patients with symptomatic heart failure.
These studies allowed the following conclusion:
- Perindopril reduces peripheral vascular resistance, leading to blood pressure reduction.
- The antihypertensive activity is maximal between 4 and 6 hours after a single dose and is sustained
for at least 24 hours: trough effects are about 87-100 % of peak effects.
- The decrease in blood pressure occurs rapidly. Discontinuation of treatment does not lead to a
rebound effect.
Perindopril reduces left ventricular hypertrophy.
- In man, perindopril has been confirmed to demonstrate vasodilatory properties. It improves large
artery elasticity and decreases the media: lumen ratio of small arteries.
- Studies in patients with heart failure have demonstrated a decreased left and right ventricular filling
pressure, reduced total peripheral vascular resistance, an increased cardiac output and improved
cardiac index.
- In comparative studies, the first administration of 2 mg of perindopril to patients with mild to
moderate heart failure was not associated with any significant reduction of blood pressure as
compared to placebo.
Clinical efficacy
The clinical efficacy of perindopril tert-butylamine (2 and 4 mg) has been demonstrated in the 3
claimed indications: treatment of hypertension, symptomatic heart failure and reduction of risk of
cardiac events in patients with stable coronary artery disease with a history of myocardial infarction
and/or revascularisation.
Overall, 28 studies were carried out in these indications.
1/. Five comparative versus reference phase III studies to evaluate the efficacy and safety of
perindopril in the treatment of hypertension. A total of 391 patients were treated for up to 3 months
with perindopril whilst 397 received a reference antihypertensive drug:
- 231 a beta-blocker, atenolol,
- 83 a diuretic association, HCTZ + amiloride,
- 83 an ACE inhibitor, captopril.
There were three combination studies with HCTZ and one with a calcium channel blocker,
nifedipine.
The acceptability of perindopril in the long-term treatment of patients with mild to severe essential
hypertension was assessed in a large European, multicentre trial including 856 patients.
Several studies were performed in high-risk populations of patients (elderly, hypertensive patients
with moderate renal impairment, hypertensive patients with diabetes and patients with hepatic
impairment).
Patients of both genders, different stage of hypertension and concomitant illnesses (diabetes
melitus, renal impairment, hepatic impairment) have been included in these studies.
These studies showed the efficacy of perindopril in the treatment of hypertension (mild to
moderate). A reduction in systolic and diastolic blood pressures in both supine and standing
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positions is observed. The dose should be adjusted according to the patient profile and blood
pressure response. In elderly patients treatment should be initiated at a dose of 2 mg which may be
progressively increased.
2/. Four studies demonstrated the efficacy of perindopril in the treatment of mild to moderate heart
failure and the safety of the product in this patient population. These studies involved 528 patients
treated for up to 30 months with perindopril and 170 patients receiving placebo for up to 6 months.
These studies showed the efficacy of perindopril in the treatment of symptomatic heart failure.
Perindopril reduced cardiac work. Studies in patients with heart failure have demonstrated that
perindopril decreased left and right ventricular filling pressures, reduced total peripheral vascular
resistance and increased cardiac output and improved cardiac index.
However, perindopril should be introduced under close medical supervision with a recommended
starting dose of 2 mg. The dose of perindopril should be adjusted according to the patient profile
and blood pressure response.
Blood pressure, renal function and serum potassium should be monitored closely, both before and
during treatment with perindopril.
Treatment should be initiated under careful supervision in severe heart failure and in other patients
considered to be at high risk (patients with impaired renal function and a tendency to have
electrolyte disturbances, patients receiving simultaneous treatment with diuretics and/or treatment
with vasodilating agents).
3/. The EUROPA trial provided evidence of the benefit of the long acting ACE inhibitor perindopril
added to standard therapy, in reducing the risk of cardiac events in all patients with documented
stable coronary artery disease without evidence of heart failure, irrespective of age or
cardiovascular risk profile.
Results showed that treatment with perindopril once daily resulted in a significant absolute
reduction in the composite primary endpoint of non-fatal MI, cardiovascular death and cardiac
arrest with successful ressuscitation. This benefit was also statistically significant for the non-fatal
MI subcomponent and a favourable trend was observed for the two other components.
Clinical safety
The safety profile of perindopril has been widely established and is well documented.
General clinical acceptability was evaluated by recording spontaneous complaints of patients and
answers to direct questioning asked periodically. Information was therefore collected on all clinical
studies involving administration of perindopril to humans in clinical pharmacology and clinical trials
up to the end of 1994.
The most common adverse events are the followings: headache, dizziness, vertigo, paresthaesia, vision
disturbance, tinnitus, hypotension, cough, dyspnoea, nausea, vomiting, abdominal pain, dysgeusia,
dyspepsia, diarrhoea, constipation, rash, pruritus, muscle cramps, asthenia.
In EUROPA study only deaths, hospitalisations and serious adverse drug reactions were to be
reported. Hypotension and syncope were the most frequent serious adverse events.
Section 4.8 of the SPC has been updated recently and extensively describes the undesirable effects in
the three different indications.
Overall, the following wording was added in section 4.8 of the SPC as a conclusion of the safety
profile of perindopril in the Europa study:
“During the randomised period of the EUROPA study, only serious adverse events were collected.
Few patients experienced serious adverse events: 16 (0.3%) of the 6122 perindopril patients and 12
(0.2%) of the 6107 placebo patients. In perindopril-treated patients, hypotension was observed in 6
patients, angioedema in 3 patients and sudden cardiac arrest in 1 patient. More patients withdrew for
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cough, hypotension or other intolerance on perindopril than on placebo, 6.0% (n=366) versus 2.1%
(n=129) respectively.”
4.2 Discussion on the clinical aspects
No new clinical studies were conducted, which is acceptable for this kind of application. Coversyl
2mg and 4 mg were approved in France, with more than 10 years of experience. The safety profile can
be considered as well-established and no product-specific pharmacovigilance issues were identified
which are not adequately covered by the current SPC.
Additional risk minimisation activities have not been identified for the reference medicinal product.
A detailed Risk management Plan is not necessary for this product.
4.3 Pharmacokinetics
The clinical pharmacokinetic of perindopril (tert-butylamine and arginine salts) has already been
extensively studied and characterized during the development of the several drug products.
Summary of the several pharmacokinetics studies were part of this application: perindopril
pharmacokinetics and simultaneous modelling of perindopril and perindoprilat, population
pharmacokinetics combined-analysis of perindoprilat, pharmacokinetic study for perindopril tertbutylamine salt and its active metabolite, pharmacokinetic drug interactions. Numerous studies in
healthy volunteers, in hypertensive patients, in patients with symptomatic heart failure and in specific
populations were performed.
These studies allowed the following conclusions:
- Perindopril pharmacokinetics has been shown linear and proportional to the dose over the
therapeutic range.
- After oral administration, absorption of perindopril is rapid and the peak concentration complete
within 1 hour..
- Twenty seven percent of the administered perindopril dose reaches the bloodstream as the active
metabolite perindoprilat. The plasma half-life of perindopril is equal to 1 hour. The peak plasma
concentration of perindoprilat is achieved within 3 to 4 hours.
- As ingestion of food decreases conversion to perindoprilat, hence bioavailability, perindopril
should be administered orally in a single daily dose in the morning before a meal.
- Perindoprilat is eliminated in the urine and the half-life of the unbound fraction is approximately 17
hours.
- After repeated administration, no accumulation of perindopril is observed.
In general, PK studies showed that the pharmacokinetics of the perindopril was comparable in
healthy volunteers and specific populations such as:
The pharmacokinetics of the prodrug was not influenced by the degree of renal impairment.
However, the pharmacokinetics of the active metabolite was widely influenced by the status of
renal function. Elimination of perindoprilat is decreased in the elderly, and also in patients with
heart or renal failure. Dosage adjustment in renal insufficiency is required depending on the degree
of impairment as measured by the creatinine clearance.
Section 5.2 adequately reflects the PK profile of perindopril and its active metabolite.
5.
OVERALL DISCUSSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
The Marketing Authorisation Holder applied for the registration of a duplicate of Coversyl 2 and 4
mg in accordance with the article 10c “informed consent application” of Directive 2001/83/EC.
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Perindopril is a well-known active substance with established efficacy and tolerability.
Perindopril tert-butylamine is an ACE inhibitor and is used in the treatment of hypertension (2-8
mg dose), in the treatment of symptomatic heart failure (2- 4 mg dose) and the reduction of risk of
cardiac events in patients with stable coronary artery disease with a history of myocardial
infarction and/or revascularisation (2-8 mg dose).
A comprehensive description of indications and doses is given in the SPC.
The chemical-pharmaceutical quality of DOMANION 2 mg and 4 mg is demonstrated.
Satisfactory chemical-pharmaceutical documentation has been provided, assuring consistent and
sufficient quality of the product.
All preclinical data and clinical data concerning the perindopril tert-butylamine salt were part of
the Innovator file. The studies of this application were given for information only. No new
preclinical or clinical studies were conducted.
The clinical pharmacology, efficacy and safety of perindopril (tert-butylamine and arginine salts)
have already been extensively studied and characterized during the development of the several
drug products.
Agreement between Member States was reached during procedure. No potential serious risk to
public health was raised during the procedure.
The SPC, Package Leaflet (PL) and packaging are in the agreed template.
The following post-approval commitment was made during the procedure:
The applicant committed to submit a type II variation to include a specific wording in the relevant
sections of the SPC in order to take into account the recommendation of the Pharmacovigilance
Working Party (PhVWP) on ACE inhibitors and lactation “ACE Inhibitors and Angiotensin II
Receptor
Antagonists
(AIIRAs)
and
Use
during
Breastfeeding”(EMEA/CHMP/PHVWP/21285/2008).
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