Public Assessment Report UKPAR Captopril 25mg/5ml Sugar ... · Public Assessment Report UKPAR Captopril 25mg/5ml Sugar Free Oral Solution Captopril 5mg/5ml Sugar Free Oral Solution

Public Assessment Report

UKPAR

Captopril 25mg/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

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LAY SUMMARY



(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).


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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



III.4 Toxicology



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:


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Captopril 5mg/5ml Sugar Free Oral Solution:


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(Captopril)

PL 39307/0075-0076

STEPS TAKEN AFTER AUTHORISATION - SUMMARY

Date submitted Application

type

Scope Outcome

Documents

Public Assessment Report UKPAR Captopril 25mg/5ml Sugar ... · Public Assessment Report UKPAR Captopril 25mg/5ml Sugar Free Oral Solution Captopril 5mg/5ml Sugar Free Oral Solution