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Public Assessment Report
Scientific discussion
Quinapril Polpharma 5mg/10mg/20mg/40mg
film-coated tablets Quinapril hydrochloride
CZ/H/147/01-04/DC
Applicant: Pharmaceutical Works POLPHARMA SA
This module reflects the scientific discussion for the approval of Quinapril Polpharma
5mg/10mg/20mg/40mg film-coated tablets. The procedure was finalised at 16-01-2008.
INTRODUCTION
This generic application for marketing authorisation concerns Quinapril Polpharma,
Pharmaceutical Works POLPHARMA SA , film-coated tablets, in the strengths
5mg/10mg/20mg/40mg. These four strengths of Q-pril are approved in a Decentralized
Procedure on 16th January 2008. The Concerned Member State were LT, LV, HU, PL.
The originator product is Acuprel from Laboratorios Pfizer, S.A., registered in the EU for
more than 10 years. In the Czech Republic it has been authorised since 3rd February 1993
(product name Accupro ).
Quinapril is a specific, long-acting angiotensin-converting enzyme (ACE) inhibitor which
suppresses the renin-angiotensin-aldosterone system and thereby the conversion of the
inactive angiotensin I to angiotensin II which is a potent vasoconstrictor.
The tablets are claimed to be essentially similar to the originator product - Acuprel from
Laboratorios Pfizer, S.A., registered in the EU for more than 10 years. In the Czech Republic
it has been authorised since 3rd February 1993 (product name Accupro ).
The main indications are hypertension and congestive heart failure, the bases of which are
well known.
The reference products used in the bioequivalence study was ACUPREL ® 5 mg/10mg tablets
(Pfizer, Spain). No new pre-clinical and clinical studies, besides the bioequivalence studies,
were conducted. This is acceptable for this abridged application.
QUALITY ASPECTS
Introduction
Quinapril Polpharma 5mg, 10 mg, 20 mg and 40 mg is presented in the form of film-coated
tablets containing 5 mg, 10 mg, 20 mg or 40 mg of the active substance quinapril (as qunapril
hydrochloride). The excipients are magnesium carbonate, heavy, low-substituted
hydroxypropyl cellulose, crospovidone, magnesium stearate, eudragit E12,5%, titanium
dioxide, talc, macrogol, red iron oxide and yellow iron oxide.
The film-coated tablets are packed in blisters made of PA-ALU-PVC foil/ALU foil. The
materials comply with the Ph.Eur. and with EU directives.
Blisters are placed, together with a package leaflet, into a paper folding box.
Active Substance
The active substance is only described in the US Pharmacopoiea. It is a white to off-white
powder, very soluble in water, ethanol, methylene chloride and isopropyl alcohol. It is
practically insoluble in diethyl ether, ethyl acetate, toluene and tetrahydrofurane. No
polymorphism is known. It was supported by X-ray diffraction. Quinapril hydrochloride has
three asymmetric centres. The isomeric purity is controlled by its optical rotation.
The scientific information has been submitted in form of an Active Substance Master File.
The Letter of Access from the manufacturer of the active substance was provided. The
manufacture has been described in detail.
An appropriate specification for quinapril hydrochloride based on USP monograph has been
proposed. Additional tests on residual solvents have been provided. Certificates of analysis
have been provided for three production scale batches. Results comply with the proposed
specification and confirm the consistency of the process.
The substance is packed in PE bags placed in HDPE drums. Both the inner bags and drums
are adequately sealed. Plastic bags meet the requirements of EU Directive.
Appropriate stability studies according to ICH guidelines have been carried out. The product
was subjected to forced degradation. Based on the stability results the re-test period of 4 years
when stored at 5±3°C is justified when substance is kept in the proposed packaging.
Medicinal Product
Quinapril Polpharma exists as film-coated tablets. The qualitative and quantitative
composition of all strengths is detailed for the core and the film-coating. All excipients are
common pharmaceutical grade products covered by Ph.Eur. monograph except Eudragit
E12.5% , yellow iron oxide and red iron oxide which are controlled using an in-house
specification. Satisfactory Certificates of Analysis of all excipients have been provided.
No material of animal origin is used in composition.
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Pharmaceutical Development
The development of medicinal product has been sufficiently described; the essential similarity
with brand leader product Acuprel has been documented.
Manufacturing of the product
The manufacturing process can be considered as standard. The manufacture and in-process
controls are fully described in the dossier. All physical and chemical properties which are
critical for quality of the product were monitored. Results of process validation on pilot scale
batches have been submitted. It may be concluded that the manufacturing process has been
shown to be reliable and capable of consistently producing a product that complies with preestablished quality and specifications.
Product specification
Satisfactory control tests are applied at the time of release and during shelf-life. Release and
shelf life limits for the assay of quinapril are in line with batch and stability data. Limits for
related substances are in line with ICH guidelines and stability data. Analytical methods have
been satisfactorily described and validated in accordance with regulatory requirements.
Satisfactory batch analysis data have been provided for three pilot batches of 5, 10 and 20 mg
strengths and two commercial batches of 40 mg strength.
Stability of the product
Stability trials were performed on the drug product according to the stability protocols and
ICH guidelines. Based on the data, shelf-life 2 years when stored up to 25 0C (5mg and 10mg
strengths) and shelf-life 3 years when stored up to 30°C (20 mg and 40 mg strengths) in the
original package (blister) to protect the product from moisture has been approved as it is
claimed in the SPC.
Discussion on chemical and pharmaceutical aspects
Information on development, manufacture and control of the drug substance and drug product
has been presented in a satisfactory manner. The results of tests carried out indicate
satisfactory consistency and uniformity of important product quality characteristics, and these
in turn lead to the conclusion that the product should have a satisfactory and uniform
performance in the clinic.
CLINICAL ASPECTS
With the Czech Republic as the Reference Member State in this Decentralized Procedure,
Pharmaceutical Works POLPHARMA SA, 19 Pelplińska Street, 83-200 Starogard Gdański,
Poland, is applying for the Marketing Authorisations for Q-pril 5mg/10mg/20mg/40mg filmcoated tablets in an abridged application, according to Article 10(1) so called “generic
application”, also in the following Concerned Member States (CMS): LT, LV, HU, PL.
Quinapril is a specific, long-acting angiotensin-converting enzyme (ACE) inhibitor which
suppresses the renin-angiotensin-aldosterone system and thereby the conversion of the
inactive angiotensin I to angiotensin II which is a potent vasoconstrictor. At recommended
doses, the effect of quinapril in hypertensive patients and in patients with chronic heart failure
is maintained for up to 24 hours. It is indicated for the treatment of all grades of essential
hypertension. Quinapril is effective as monotherapy or concomitantly with diuretics in
patients with hypertension. It may be used for the treatment of congestive heart failure when
given concomitantly with a diuretic and/or cardiac glycoside. Treatment of congestive heart
failure with quinapril should always be initiated under close medical supervision. The
recommended initial dosage is 10 mg once daily in uncomplicated hypertension. Depending
up on clinical response, patient's dosage may be titrated (by doubling the dose allowing
adequate time for dosage adjustment) to a maintenance dosage of 20 to 40 mg/day given as a
single dose or divided into 2 doses. Long-term control is maintained in most patients with a
single daily dosage regimen. Patients have been treated with dosages up to 80 mg/day. Take
either with or without food. The dose should always be taken at about the same time of day to
help increase compliance. In order to determine if excess hypotension will occur, an initial
dosage of 2.5 mg of quinapril is recommended in patients who are being treated with a
diuretic. After this the dosage of quinapril should be titrated (as described above) to the
optimal response. In the treatment of congestive heart failure a single 2.5 mg initial dosage is
recommended. After this, patients should be titrated to an effective dose (up to 40 mg/day)
given in 1 or 2 doses with concomitant diuretic and/or cardiac glycoside therapy. Patients are
usually maintained effectively on doses of 10-20 mg/day given with concomitant therapy
The adverse effects are similar to those described for all group of ACE inhibitors, including
the hazard of use during pregnancy.
The ATC code is C09A A06.
To support the application, the applicant has submitted reports of two bioequivalence studies
with the 5 and 40 mg dosage strengths and claims biowaiver for 10 and 20 dosage strengths
(an open label, single dose, randomised, two-period, two treatment, cross-over, study
designed to evaluate the comparative bioavailability of two formulations of quinapril 40mg
and 5mg tablets under fasting conditions). The applicant claims biowaiver based on the
fulfilment of the criteria for such waiver as per section 5.4 of the NfG on Bioavailability &
Bioequivalence . Standard statistical principles were proposed in the protocol. Analysis of
variance (ANOVA) was applied to log transformed AUC0-t, AUC0-inf and Cmax for quinapril
and quinaprilat. The least square means, the differences between treatments least Sq means
and corresponding standard error were estimated for log transformed parameters. The
residual area of AUCo-∞ is below 20% in each individual subject for both test and reference
products. No pre-dose levels of quinapril/quinaprilat were observed before period 2 drug
administration indicating that wash-out period is adequate. No subject reached Cmax at the
first sample time indicating that the sampling scheme was adequate. The 90% confidence
intervals for all three primary parameters AUCo-t, AUCo-∞ and Cmax are within the
acceptance range of 80-125%. The prespecified widening of limits for Cmax is therefore not
considered relevant.
Bioequivalence according to current EU guidelines on bioavailability/bioequivalence is
shown in both studies. Both bioequivalence studies presented have been performed in
accordance with GCP. Tolerability of the test product is acceptable and not significantly
different from reference product.
The application contains an adequate review of published clinical data and the bioequivalence
has been shown. The quality of the drug product is considered to be acceptable too. Approval
is recommended from the both points of view.