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Public Assessment Report
UKPAR
Captopril 25mg/5ml Sugar Free Oral Solution
Captopril 5mg/5ml Sugar Free Oral Solution
(Captopril)
UK Licence No: PL 39307/0075-0076
Syri Limited, trading as Thames Laboratories
Captopril 25mg/5ml and 5mg/5ml Sugar Free Oral Solution
PL 39307/0075-0076
2
LAY SUMMARY
Captopril 25mg/5ml Sugar Free Oral Solution
Captopril 5mg/5ml Sugar Free Oral Solution
(Captopril)
This is a summary of the Public Assessment Report (PAR) for Captopril 25mg/5ml Sugar Free Oral
Solution (PL 39307/0075) and Captopril 5mg/5ml Sugar Free Oral Solution (PL 39307/0076). For ease
of reading, the products may be collectively referred to as ‘Captopril’ or ‘Captopril 25mg/5ml and
5mg/5ml Oral Solution’ in this lay summary. The summary explains how the applications for Captopril
were assessed and their authorisation recommended, as well as the condition for use.
For practical information about using Captopril, patients should read the package leaflets or contact their
doctor or pharmacist.
What is Captopril and what is it used for?
Captopril 25mg/5ml Sugar Free Oral Solution is a ‘generic’ medicine. This means that Captopril
25mg/5ml Sugar Free Oral Solution is similar to a reference medicine already authorised in the UK
called Capoten 25 mg Tablets (PL 00034/0193; E. R. Squibb & Sons Limited, UK).
Captopril 5mg/5ml Sugar Free Oral Solution is a ‘hybrid medicine’ as this medicine is similar to the
‘reference medicine’ Captopril 25 mg Tablets (PL 00034/0193; E. R. Squibb & Sons Limited, UK); it
contains the same active substance as the reference medicine, however it is a 5mg/5ml oral solution
while the reference medicine is a 25 mg strength tablet.
Captopril is used to treat high blood pressure and certain heart conditions. If high blood pressure is left
uncontrolled it can increase the risk of heart disease or stroke. Captopril works by lowering the blood
pressure which reduces this risk.
Captopril can also help people whose heart no longer pumps blood as well as it once did. This condition
is known as heart failure.
Captopril may also be used to treat patients who recently suffered a heart attack. A heart attack happens
once one of the major blood vessels supplying blood to the heart muscle becomes blocked. This means
that the heart does not receive the oxygen it needs and the heart muscle becomes damaged.
In addition, Captopril can be used for the treatment of kidney disease in patients with diabetes.
How does Captopril work?
Captopril 25mg/5ml and 5mg/5ml Oral Solution contain the active substance, captopril, which belongs
to the group of medicines called Angiotensin Converting Enzyme (ACE) Inhibitors. ACE inhibitors
work by helping to widen the blood vessels, which then make it easier for the heart to pump blood
through them.
How is Captopril used?
Captopril 25mg/5ml and 5mg/5ml Oral Solution are each available as an oral solution (25 mg/5mg and
5mg/5ml strengths) and are taken by mouth (swallowed).
Captopril 25mg/5ml and 5mg/5ml Sugar Free Oral Solution
PL 39307/0075-0076
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Note:
Captopril 25mg/5ml Oral Solution allows the dose to be taken in a smaller volume of solution. If the
patient feels that he/she would benefit from using the higher strength product he/she should speak with
their doctor.
Captopril 5mg/5ml Oral Solution allows small doses to be measured more accurately. If the patient feels
that he/she would benefit from using the lower strength product, he/she should speak to his/her doctor.
The patient should always take this medicine exactly as advised by his/her doctor or pharmacist. The
patient should check with his/her doctor or pharmacist if not sure.
The patient should take Captopril at about the same time each morning. It can be taken before, during or
after meals. Even if you the patient feels well, he/she should continue to take Captopril until the doctor
tells the patient otherwise.
Route and method of administration
The doctor, pharmacist or nurse will show the patient how to administer this medicine by dosing cup,
syringe or by gastric feeding tube. The box containing Captopril will also contain either a 5 ml dosing
syringe, a syringe adaptor and a 30 ml dosing cup (25mg/5ml strength product only) or a 1 ml dosing
syringe, a 5ml dosing syringe and a syringe adaptor (5mg/5ml strength product only).
Please read section 3 of the package leaflets for detailed information on dosing recommendations, the
route of administration and the duration of treatment.
Captopril can only be obtained on prescription.
What benefits of Captopril have been shown in studies?
As Captopril 25mg/5ml and 5mg/5ml Oral Solution are generic/hybrid medicines, studies have been
limited to tests to determine that these medicines are bioequivalent/therapeutically equivalent to the
reference medicine Capoten 25mg Tablets (25 mg x1 tablet; E.R. Squibb & Sons Limited, UK). Two
medicines are bioequivalent/therapeutically equivalent when they produce the same levels of the active
substance in the body.
What are the possible side effects of Captopril?
Like all medicines, Captopril 25mg/5ml and 5mg/5ml Oral Solution can cause side effects, although not
everybody gets them.
Since Captopril 25mg/5ml and 5mg/5ml Oral Solution are generic/hybrid medicines and comparable to
the reference medicine Capoten 25 mg Tablets (E. R. Squibb & Sons Limited, UK) the possible side
effects are taken as being the same as those of the reference medicine.
For the full list of all side effects reported with Captopril, see section 4 of the package leaflets.
For the full list of restrictions, see the package leaflets for Captopril.
Why is Captopril approved?
It was concluded that, in accordance with EU requirements, Captopril 25mg/5ml and 5mg/5ml Oral
Solution have been shown to have comparable quality and are considered to be
bioequivalent/therapeutically equivalent to Capoten 25mg Tablets (E. R. Squibb & Sons Limited, UK).
Therefore, the view was that, as for Capoten 25mg Tablets (E. R. Squibb & Sons Limited, UK), the
benefits outweigh the identified risks.
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What measures are being taken to ensure the safe and effective use of Captopril?
A Risk Management Plan has been developed to ensure that Captopril is used as safely as possible.
Based on this plan, safety information has been included in the Summaries of Product Characteristics
and the package leaflets for Captopril, including the appropriate precautions to be followed by
healthcare professionals and patients.
Other information about Captopril
Marketing Authorisations for Captopril 25mg/5ml Sugar Free Oral Solution (PL 39307/0075) and
Captopril 5mg/5ml Sugar Free Oral Solution (PL 39307/0076) were granted in the UK to Syri Limited,
trading as Thame Laboratories on 08 November 2017.
The full Public Assessment Report approved for Captopril follows this summary.
For more information about treatment with Captopril, read the package leaflets, or contact your doctor or
pharmacist.
This summary was last updated in January 2018.
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SCIENTIFIC DISCUSSION
TABLE OF CONTENTS
I Introduction Page 6
II Quality aspects Page 7
III Non-clinical aspects Page 9
IV Clinical aspects Page 9
V User consultation Page 11
VI Overall conclusion, benefit/risk assessment and recommendation Page 11
Annex 1- Table of content of the PAR update for MRP and DCP Page 14
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Scientific discussion
I. INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products
Regulatory Agency (MHRA) granted Syri Limited (trading as Thame Laboratories) Marketing
Authorisations for the medicinal products Captopril 25mg/5ml Sugar Free Oral Solution
(PL 39307/0075) and Captopril 5mg/5ml Sugar Free Oral Solution (PL 39307/0076) on 08 November
2017. For ease of reading, the products may be referred to collectively as ‘Captopril’ or ‘Captopril
25 mg/5ml and 5mg/5ml Oral Solution ‘in this scientific discussion.
The products are Prescription Only Medicines (POM) and are indicated in the following:
• Hypertension: Captopril is indicated for the treatment of essential hypertension.
• Heart failure: Captopril is indicated for the treatment of chronic heart failure.
• Myocardial infarction:
➢ Short-term (4 weeks) treatment: Captopril is indicated in any clinically stable patient within the
first 24 hours of an infraction.
➢ Long-term prevention of symptomatic heart failure: Captopril is indicated in clinically stable
patients with asymptomatic left ventricular dysfunction.
• Type I Diabetic nephropathy: Captopril is indicated for the treatment of macroproteinuric diabetic
nephropathy in patients with type I diabetes.
The application for Captopril 25mg/5ml Sugar Free Oral Solution was submitted under Article 10(1) of
Directive 2001/83/EC, as amended, claiming to be a generic medicinal product of the reference
medicinal product Capoten 25mg Tablets (PL 00034/0193; E. R. Squibb & Sons Limited), which was
first authorised in the UK on 27 March 1981.The application for Captopril 5mg/5ml Sugar Free Oral
Solution was submitted under Article 10(3) of Directive 2001/83/EC, as amended, as a hybrid
application, cross-referring to Capoten 25mg Tablets (PL 00034/0193; E. R. Squibb & Sons Limited).
The active substance, captopril, is a highly specific, competitive inhibitor of angiotensin-I converting
enzyme (ACE inhibitors).
No new non-clinical studies were performed, which is acceptable given that the applications were based
on being generic/hybrid applications of a reference medicinal product that has been in clinical use for
over 10 years.
One bioequivalence study was submitted to support these applications, comparing the applicant’s test
product Captopril 25 mg/5 ml oral solution (5ml; 25 mg) with the reference product Capoten 25mg
tablets (E.R Squibb & Sons Limited, UK) in healthy subjects under fasting conditions. A biowaiver was
requested for the 5mg/5ml strength, on the basis of linear kinetics and the pharmaceutical criteria in the
bioequivalence guideline.
The applicant has stated that the bioequivalence study was conducted in compliance with International
Conference on Harmonisation (ICH) Good Clinical Practice (GCP). The applicant has stated that the
bioequivalence study was conducted in compliance with Good Clinical Practice (GCP) requirements.
The MHRA has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in
place for this product type at all sites responsible for the manufacturing and assembly of these products.
Evidence of compliance with GMP has been provided for the named manufacturing and assembly sites.
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No new or unexpected safety concerns arose during review of information provided by the Marketing
Authorisation Holder and it was, therefore, judged that the benefits of Captopril outweigh the risks and
Marketing Authorisations were granted.
II. QUALITY ASPECTS
II.1 Introduction
The submitted documentation concerning the proposed product is of sufficient quality and meets the
current EU regulatory requirements.
The quality overall summary has been written by an appropriately qualified person and is a suitable
summary of the pharmaceutical aspects of the dossier.
The products are each a clear, colourless oral solution.
Each 5 ml of Captopril 25 mg/5 ml Sugar Free Oral Solution contains 25 mg captopril, as the active
substance; each 1 ml of oral solution contains 5 mg captopril as the active substance.
Each 5 ml of Captopril 5 mg/5 ml Sugar Free Oral Solution contains 5 mg of captopril, as the active
substance; each 1 ml of oral solution contains 1 mg captopril as the active substance.
The products also contain pharmaceutical excipients, namely sodium benzoate (E211), citric acid
monohydrate (E330), sodium citrate (E331), disodium edetate and purified water. Appropriate
justification for the inclusion of each excipient has been provided.
The products are supplied in Ph. Eur Type III amber glass 100 ml amber glass bottles, each with a
tamper evident, child resistant white plastic cap consisting of a polypropylene inner, outer and expanded
polyethylene (EPE) liner fitted with a child resistant and tamper evident cap.
The 25mg/5ml strength product is also packaged with a 5 ml oral syringe with 0.2 ml graduation mark
and a syringe adaptor and 30 ml measuring cup with 5 ml graduation marks and having additional
graduation of 2.5 ml and 7.5 ml.
The 5mg/5ml strength product is also packaged with a 1 ml oral syringe with 0.01 ml graduation mark
and 5 ml oral syringe with 0.2 ml graduation mark and a syringe adaptor.
Satisfactory specifications and Certificates of Analysis for the primary packaging material have been
provided. All primary packaging is controlled to European Pharmacopoeia standards that comply with
guidance concerning materials in contact with foodstuff.
II.2 DRUG SUBSTANCE
Captopril
INN: Captopril
Chemical name (2S)-1-[(2S)-2-Methyl-3-sulfanylpropanoyl] pyrrolidine-2-carboxylic
acid.
Molecular formula: C9H15NO3S
Structure:
Mr: 217.3
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Appearance: White or almost white crystalline powder
Solubility: Soluble in water, freely soluble in methanol and in methylene chloride.
Captopril dissolves in dilute solutions of alkali hydroxides
Captopril is the subject of a European Pharmacopoeia monograph.
All aspects of the manufacture and control of the active substance, captopril, are covered by a European
Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability.
Appropriate stability data have been generated supporting a suitable retest period when stored in the
proposed packaging.
II.3 MEDICINAL PRODUCT
Pharmaceutical Development
The objective of the development programme was to produce safe, efficacious, stable oral solutions that
were interchangeable with the reference product Capoten 25mg Tablets (E.R. Squibb & Sons Limited).
Suitable pharmaceutical development data have been provided for these applications.
All the excipients comply with their respective European Pharmacopoeia monographs. Certificates of
Analysis have been provided for all excipients, showing compliance with their respective specifications..
None of the excipients contain materials of animal or human origin and no genetically modified
organisms (GMO) have been used in the preparation of these excipients.
Manufacturing Process
Satisfactory batch formulae have been provided for the manufacture of the products, along with an
appropriate account of the manufacturing process. The manufacturing process has been validated with
pilot-scale batches that have shown satisfactory results. The Marketing Authorisation Holder has
committed to performing process validation studies on future full production-scale batches.
Control of Finished Product
The finished product specifications are acceptable. Test methods have been described that have been
validated adequately. Batch data have been provided that comply with the release specifications
Certificates of Analysis have been provided for all working standards used.
Stability of the Product
Finished product stability studies were performed in accordance with current guidelines on batches of
finished product in the packaging proposed for marketing. Based on the results, a shelf-life of 24 months
for the unopened products has been accepted. The products should be discarded 21 days after first
opening. The special precautions for storage for the products is ‘Do not store above 30°C.’
Suitable post approval stability commitments have been provided to continue stability testing on batches
of finished product.
Bioequivalence/Bioavailability
Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the
bioequivalence study. The bioequivalence study is discussed in Section IV, Clinical Aspects.
Discussion on chemical, pharmaceutical and biological aspects
It is recommended that Marketing Authorisations are granted, from a quality point of view.
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III NON-CLINICAL ASPECTS
III.1 Introduction
As the pharmacodynamic, pharmacokinetic and toxicological properties of captopril are well-known, no
new non-clinical data have been submitted and none are required.
The applicant’s non-clinical overview has been written by an appropriately qualified person and is
satisfactory, providing an appropriate review of the relevant non-clinical pharmacology,
pharmacokinetics and toxicology.
III.2 Pharmacology
No new data have been submitted and none are required for applications of this type. Refer to Section
III.1 Introduction, above.
III.3 Pharmacokinetics
No new data have been submitted and none are required for applications of this type. Refer to Section
III.1 Introduction, above.
III.4 Toxicology
No new data have been submitted and none are required for applications of this type. Refer to Section
III.1 Introduction, above.
III.5 Ecotoxicity/Environmental Risk Assessment (ERA)
Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As
the applications are for substitution for an already authorised product, it is not expected that
environmental exposure will increase following approval of the Marketing Authorisations for the
proposed products.
III.6 Discussion of the non-clinical aspects
No new non-clinical studies were conducted, which is acceptable given that the applications were
generic/hybrid applications of a medicinal reference product that has been licensed for over 10 years.
It is recommended that Marketing Authorisations are granted, from a non-clinical point of view.
.IV. CLINICAL ASPECTS
IV.1 Introduction
The clinical pharmacology of captopril is well-known. The clinical overview has been written by an
appropriately qualified person and is a suitable summary of the clinical aspects of the dossier.
With the exception of data from the bioequivalence study detailed below, no new pharmacokinetic data
are provided or required for these applications
IV.2 Pharmacokinetics
The clinical pharmacokinetic properties of captopril are well known and are adequately described in the
applicant’s clinical overview.
In support of the applications, the applicant submitted the following bioequivalence study:
A randomised, open-label, single-dose, two-sequence, two-treatment, two- period way, crossover,
bioequivalence study comparing the test products Captopril 25 mg/5 ml oral solution (x 5 ml)
versus the reference product Capoten 25mg tablets (x1 tablet; E.R. Squibb & Sons Limited, UK)
in healthy adult male and female subjects, under fasting conditions.
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Subjects were administered a single oral dose (25 mg) of either (5 ml of the test product or 1 tablet of
the reference product) treatment with 240±2 ml of water after a 10-hour overnight fast. Blood sampling
was performed pre-dose and up to 24 hours post dose in each treatment period. A washout period of
12 days was kept between each consecutive dosing period. The pharmacokinetic results are presented
below:
Table of Geometric Means and 90% Confidence Interval for Captopril
Bioequivalence Discussion and Conclusion
The Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**)
defines the confidence limits for ratio of geometric means for acceptance of bioequivalence as 80.00%
to 125.00% for Cmax and AUC values. Thus, the results support the claim that 5 ml (25 mg captopril) of
the applicant’s 25 mg/5 ml strength test product is bioequivalent to 1 x 25 mg tablet (25 mg of captopril)
of the reference product Capoten 25 mg tablets (E.R Squibb & Sons Limited, UK), under fasting
conditions.
The justification for biowaiver for the 5 mg/5 ml strength product can be accepted as the applicant’s
25 mg/5 ml and 5 mg/5 ml strength oral solutions meet the biowaiver criteria specified in the Guideline
on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**).
IV.3 Pharmacodynamics
The clinical pharmacodynamic properties of captopril are well-known. No new pharmacodynamic data
were submitted and none are required for applications or this type.
IV.4 Clinical Efficacy
The clinical efficacy of captopril is well-known.
With the exception of the bioequivalence study, no new clinical data were submitted and none are
required for applications of this type.
Bioequivalence between 5 ml of applicant’s 25 mg/5 ml strength oral solution and 1 x 25 mg tablet of
the reference product, Capoten 25 mg tablets (E R Squibb & Sons Limited, UK), has been demonstrated
under fasting conditions.
The results with the applicant’s 25 mg/5 ml strength product can be extrapolated to the 5 mg/5 ml
strength product, according to conditions in the Guideline on the Investigation of Bioequivalence
CPMP/EWP/QWP/1401/98 Rev. 1/Corr**, section 4.1.6.
IV.5 Clinical Safety
The safety profile of captopril is well known. With the exception of data generated from the
bioequivalence study detailed above, no new safety data are provided or required for these applications.
No new or unexpected safety issues arose during the bioequivalence study.
IV.6 Risk Management Plan
The MAH has submitted a Risk Management Plan, in accordance with the requirements of Directive
2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to
identify, characterise, prevent or minimise risks relating to Captopril Oral Solution.
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A summary of safety concerns is listed in the table below:
Routine pharmacovigilance and risk minimisation measures are proposed. This is acceptable.
IV.7 Discussion of the clinical aspects
It is recommended that Marketing Authorisations are granted, from a clinical point of view.
V. USER CONSULTATION
A package leaflet for Captopril 25mg/5ml Sugar Free Oral Solution (PL 39307/0075) has been evaluated
via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of
Directive 2001/83/EC. The language used for the purpose of user testing the pack leaflet was English.
The results show that the package leaflet meets the criteria for readability as set out in the Guideline on
the readability of the label and package leaflet of medicinal products for human use.
A user consultation with target patient groups on the package leaflet (PL) for Captopril 5mg/5ml Sugar
Free Oral Solution has been performed on the basis of a bridging report making reference to the package
leaflet for Captopril 25mg/5ml Sugar Free Oral Solution. The bridging report submitted by the applicant
has been found acceptable.
VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
The quality of the products is acceptable, and no new non-clinical safety concerns have been identified.
Extensive clinical experience with captopril in the proposed indications is considered to have
demonstrated the therapeutic value of the compound. The proposed products are considered
bioequivalent/therapeutically equivalent to the reference product.
The overall benefit/risk balance is, therefore, considered to be positive.
The grant of Marketing Authorisations is recommended.
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In accordance with Directive 2010/84/EU, the current version of the SmPCs and package leaflet is
available on the MHRA website. The current labelling is presented below:
Captopril 25mg/5ml Sugar Free Oral Solution:
Captopril 25mg/5ml and 5mg/5ml Sugar Free Oral Solution
PL 39307/0075-0076
13
Captopril 5mg/5ml Sugar Free Oral Solution:
Captopril 25mg/5ml and 5mg/5ml Sugar Free Oral Solution
PL 39307/0075-0076
14
Captopril 25mg/5ml Sugar Free Oral Solution
Captopril 5mg/5ml Sugar Free Oral Solution
(Captopril)
PL 39307/0075-0076
STEPS TAKEN AFTER AUTHORISATION - SUMMARY
Date submitted Application
type
Scope Outcome
Recommended