Public Assessment Report - GOV.UK · Rubio, S.A., Spain).Therefore, the MHRA decided that, as for Hydrapres 25 mg and 50 mg Tablets (Laboratorios Rubio, S.A., Spain), the benefits

Public Assessment Report

UK PAR

Hydralazine 25 mg Tablets Hydralazine 50 mg Tablets

(hydralazine)

UK Licence No: PL 20117/0258-0259

Morningside Healthcare Limited

Hydralazine 25 mg and 50 mg Tablets PL 20117/0258-0259

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LAY SUMMARY


(Hydralazine)

This is a summary of the Public Assessment Report (PAR) for Hydralazine 25 mg and 50 mg Tablets (PL 20117/0258-0259). It explains how the applications for Hydralazine 25 mg and 50 mg Tablets were assessed and their authorisations recommended, as well as the conditions of use. It is not intended to provide practical advice on how to use Hydralazine 25 mg and 50 mg Tablets. For practical information about using Hydralazine 25 mg and 50 mg Tablets, patients should read the package leaflet or contact their doctor or pharmacist. Collectively, the products may be referred to as ‘Hydralazine Tablets’in this report. What are Hydralazine Tablets and what are they used for? Hydralazine 25 mg and 50 mg Tablets are ‘generic’ medicines’. This means that Hydralazine 25 mg and 50 mg Tablets are similar to ‘reference medicines’ already authorised in the EU called Hydrapres 25 mg and 50 mg Tablets (Laboratorios Rubio, S.A., Spain), first licensed in Spain on 01 August1983. Hydralazine Tablets are used to reduce high blood pressure. How do Hydralazine Tablets work? Hydralazine Tablets contain the active ingredient, hydralazine hydrochloride. Hydralazine hydrochloride belongs to group of medicines called antihypertensives. These medicines relax the muscles of artery walls and cause blood vessels to expand and help to reduce high blood pressure. How are Hydralazine Tablets used? Hydralazine Tablets are taken by mouth. The tablets should always be taken exactly as advised by the patient’s doctor or pharmacist. The patient should check with his/her doctor or pharmacist if he/she is not sure. The usual doses are: Adults (including the elderly): Hypertension – Initially, 25 mg twice a day or 50 mg once a day. The patient’s doctor may gradually increase this, up to a maximum of 200 mg a day. The patient’s doctor will decide on the best dose. Heart failure - Treatment should be started in hospital and dosages can vary. The maintenance dose is 50 mg – 75 mg four times a day. Use in children: Hydralazine Tablets is for adults only, it is not for use in children. Please read section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration, the duration of treatment and the need for any specific monitoring of certain parameters or for diagnostic tests. Hydralazine Tablets can only be obtained with a prescription.


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What benefits of Hydralazine Tablets have been shown in studies? As Hydralazine Tablets are generic medicines, studies in patients have been limited to tests to determine that they are bioequivalent to their respective reference medicines, Hydrapres 25 mg and 50 mg Tablets (Laboratorios Rubio, S.A., Spain). Two medicines are bioequivalent when they produce the same levels of the active substance in the body. What are possible side effects of Hydralazine Tablets? Because HydralazineTablets are generic medicines that are considered bioequivalent to the reference medicines, Hydrapres 25 mg and 50 mg Tablets (Laboratorios Rubio, S.A., Spain), the benefits and possible side effects are taken as being the same as the respective reference medicines. For the full list of all side effects reported with Hydralazine Tablets, see section 4 of the package leaflet. For the full list of restrictions, see the package leaflet. Why are Hydralazine Tablets approved? It was concluded that, in accordance with EU requirements, Hydralazine Tablets have been shown to have comparable quality and to be bioequivalent to Hydrapres 25 mg and 50 mg Tablets (Laboratorios Rubio, S.A., Spain).Therefore, the MHRA decided that, as for Hydrapres 25 mg and 50 mg Tablets (Laboratorios Rubio, S.A., Spain), the benefits outweigh the identified risks and recommended that Hydralazine Tablets can be approved for use. What measures are being taken to ensure the safe and effective use of Hydralazine Tablets? A Risk Management Plan has been developed to ensure that Hydralazine Tablets are used as safely as possible. Based on this plan, safety information has been included in the Summaries of Product Characteristics and the package leaflet for Hydralazine Tablets, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously. Other information about Hydralazine Tablets Marketing Authorisations were granted for Hydralazine Tablets to Morningside Healthcare Limited on 06 April 2016. The full PAR for Hydralazine Tablets follows this summary. For more information about treatment with Hydralazine Tablets read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in May 2016.


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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

I Introduction Page 5 II Quality aspects Page 6 III Non-clinical aspects Page 8 IV Clinical aspects Page 8 V User consultation Page 10 VI Overall conclusion, benefit/risk assessment and recommendation Page 10 Steps taken after Authorisation – Summary Page 14


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Scientific discussion I INTRODUCTION The Medicines and Healthcare products Regulatory Agency (MHRA) granted Morningside Healthcare Marketing Authorisations for the medicinal products Hydralazine 25 mg and 50 mg Tablets (PL 20117/0258-0259) on 06 April 2016. These are Prescription Only Medicines (POM) indicated in the treatment of moderate to severe hypertension as an adjunct to other anti-hypertensive agents. Due to the complementary mechanism of action the combination of hydralazine with β-blockers and diuretics may enable antihypertensive efficacy at lower dose levels and counteract accompanying hydralazine effects such as reflex tachycardia and oedema. Hydralazine Tablets are also indicated as supplementary medication for use in combination with long-acting nitrates in moderate to severe chronic congestive cardiac failure in patients in whom optimal doses of conventional therapy have proved insufficient. The applications for Hydralazine 25 mg and 50 mg Tablets were submitted in accordance to Article 10(1) of Directive 2001/83/EC, as amended, as generic applications and cross-refer to the reference products Hydrapres 25 mg and 50 mg Tablets(Laboratorios Rubio, S.A., Spain), which were first licensed in Spain on 01 August 1983. The active ingredient, hydralazine hydrochloride, is an anti-hypertensive whose exact mode of action has not been determined. It is a vasodilator, acting directly and preferentially on the smooth muscle of pre-capillary arterioles in the coronary, cerebral, and renal circulations, with a lesser effect in skin and muscle. Capacitance vessels (veins and coronary arteries) are not appreciably affected. Diastolic pressure is affected more than systolic and this, in combination with the preferential arteriolar effect, directly increases cardiac output, heart rate, stroke volume. Postural hypotension is minimized. The systemic hypotension resulting from arteriolar vasodilation is a powerful stimulant of the sympathetic nervous system via the baroreceptor reflex, causing increased heart rate and myocardial contractility, increased plasma renin activity, and fluid retention. Some stimulation of norepinephrine release from sympathetic nerve terminals and direct positive chronotropic and inotropic effects augmenting myocardial contractility is thought to contribute. One postulated mechanism of action suggests chelation of certain trace metals involved in smooth muscle contraction with differing regional effects. It has been found that there is no consistent change in heart rate or blood pressure when hydralazine is used in the treatment of congestive heart failure, even though total dose requirements tend to be higher. A bioequivalence study was submitted to support the applications comparing the applicant’s test product Hydralazine Tablets 50 mg (Morningside Healthcare Limited) with the reference product Hydrapres Tablets 50 mg (Laboratorios Rubio, S.A., Spain), under fasting conditions. The applicant has stated that the bioequivalence study was conducted in accordance with Good Clinical Practice (GCP). With the exception of the bioequivalence study, no new non-clinical or clinical data were submitted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been in clinical use for over 10 years. 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 Hydralazine Tablets outweigh the risks and Marketing Authorisations were granted.


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II QUALITY ASPECTS II.1 Introduction The submitted documentation concerning the proposed products 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. Hydralazine 25 mg tablets are yellow to light yellow, round, flat tablets with ‘C’ and ‘1’ debossed on either side of a break-line on one side and plain on the other side with diameter of 6.5 mm. Hydralazine 50 mg tablets are yellow to light yellow, round, flat tablet with ‘C’ and ‘2’ debossed on either side of break-line on one side and plain on the other side with diameter of 8.0 mm. Each Hydralazine 25 mg and 50 mg tablet contains 25 mg and 50 mg, respectively, of the active substance, hydralazine hydrochloride. The products also contain the pharmaceutical excipients microcrystalline cellulose, dicalcium phosphate anhydrous, polyvinyl pyrrolidone, sodium starch glycolate, stearic acid, colloidal anhydrous silica and quinoline yellow aluminium lake. Appropriate justification for the inclusion of each excipient has been provided. The finished products are supplied in 250 mm aluminium/aluminium cold form film with 25 micron aluminium lidding foil blisters, in pack sizes of 7, 10, 14, 20, 28, 30, 56, 60, 84, 90, 100 and 112 tablets. Satisfactory specifications and Certificates of Analysis for the primary packaging materials have been provided. All primary packaging complies with current European regulations concerning materials in contact with foodstuff. II.2 DRUG SUBSTANCE Hydralazine hydrochloride INN: Hydralazine hydrochloride Chemical Name: Phthalazine, 1-hydrazino-, monohydrochloride; Molecular formula:

C8H8N4·HCl Mr: 196.64 Structure:

Appearance: White to almost white, crystalline powder Solubility: Soluble in water, slightly soluble in ethanol and very slightly soluble in

methylene chloride. Polymorphism Does not exhibit polymorphism Stereochemistry/potential Hydralazine hydrochloride exhibits optical isomerism as the molecule

isomerism contains one chiral carbon. However the hydralazine hydrochloride manufactured is a racemic mixture hence molecule does not rotate plan polarized light and does not exhibit optical rotation.

Hydralazine hydrochloride is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance, hydralazine hydrochloride, are covered by European Directorate for the Quality of Medicine and Healthcare (EDQM) Certificate of Suitability.


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II.3 MEDICINAL PRODUCT Pharmaceutical Development The objective of the development programme was to formulate safe, efficacious, stable hard capsules, which were bioequivalent to Hydrapres Tablets 25 mg and 50 mg (Rubio Pharma, Spain). Suitable pharmaceutical development data have been provided for these applications. Comparative in-vitro dissolution profiles have been provided for these products and the respective reference products. The dissolution profiles were satisfactory. With the exception of quinoline yellow aluminium lake, all excipients comply with their respective European Pharmacopoeia monographs. Satisfactory Certificates of Analysis have been provided for all excipients. None of the excipients contain materials of animal or human origin. 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 all strengths of the product, along with an appropriate description of the manufacturing process. The manufacturing process has been validated with pilot scale batches and has shown satisfactory results. The Marketing Authorisation Holder has committed to performing process validation studies on future full-scale production batches. Control of Finished Product The finished product specifications are acceptable. Test methods have been described and have been validated adequately. Batch data that comply with the release specifications have been provided. 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 2 years, with the special storage conditions ‘Do not store above 25oC.’, has been accepted. 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 studies. II.4 Discussion on chemical, pharmaceutical and biological aspects It is recommended that Marketing Authorisations are granted for these applications for Hydralazine 25 mg and 50 mg Tablets. II.5 Summaries of Product Characteristics (SmPCs), Patient Information Leaflet (PIL) and Labels The SmPCs, PIL and labelling are satisfactory and, where appropriate, in line with current guidance.


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III NON-CLINICAL ASPECTS III.1 Introduction The pharmacodynamic, pharmacokinetic and toxicological properties of hydralazine hydrochloride are well known. No new non-clinical data have been submitted for these applications and none are required.

The applicant has provided an overview based on published literature. The 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 The non-clinical pharmacology of hydralazine hydrochloride is well known and adequately described in the applicant’s non-clinical overview. III.3 Pharmacokinetics The pharmacokinetic properties of hydralazine hydrochloride are well known and adequately described in the applicant’s non-clinical overview. III.4 Toxicology The toxicological properties of hydralazine hydrochloride are well known and adequately described in the applicant’s non-clinical overview. III.5 Ecotoxicity/Environmental Risk Assessment (ERA) Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As these products are intended for generic substitution with products that are already marketed, no increase in environmental exposure to hydralazine hydrochloride is anticipated. Thus, the justification for non-submission of an Environmental Risk Assessment is accepted. III.6 Discussion of the non-clinical aspects It is recommended that Marketing Authorisations are granted for Hydralazine Tablets, from a non-clinical point of view. IV. CLINICAL ASPECTS IV.1 Introduction The clinical pharmacology of hydralazine hydrochloride is well-known. In accordance with the regulatory requirements CPMP/EWP/QWP/1401/98 Rev 1/Corr**, Guideline on the Investigation of Bioequivalence, the Marketing Authorisation Holder submitted bioequivalence study to support these generic applications. With the exception of data from the bioequivalence study, no new pharmacodynamic or pharmacokinetic data are provided or required for these applications. IV.2 Pharmacokinetics The clinical pharmacokinetic properties of hydralazine hydrochloride are well-known. In support of the applications, a bioequivalence study was submitted. Details of the study are provided below. A randomised, open-label, two-treatment, two-period, two-sequence, single-dose, two- way, crossover bioequivalence study comparing the pharmacokinetics of the applicant’s test product Hydralazine Tablets 50 mg (Morningside Healthcare Limited) and the reference product Hydrapres


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Tablets 50 mg (Laboratorios Rubio, S.A., Spain) in healthy, adult, human subjects under fasting conditions. The subjects were administered one dose (1 tablet; 50 mg) either the test or the reference product with 240 ml of water, after at least a 10-hour overnight fast. Blood samples were collected before and up to and including 24 hours after each administration. The washout period between the treatment phases was a minimum of 7 days. The pharmacokinetic results are presented below: Table:1 Geometric Means, Ratio of Means, and 90% Confidence Intervals for Hydralazine Parameter Geometric

LSM (Reference)

Geometric LSM (Test)

Ratio (T/R)*100

90%CI (%)

Intra CV (%)

Power

Ln Cmax

(ng/mL) 69.286 69.801 100.74 82.33-123.27 38.77 57.25

lnAUC0-t

(ng/mL X hr)) 105.165 104.843 99.69 93.18-106.66 12.58 99.96

lnAUC0-∞

(ng/mL X hr) 110.505 110.427 99.93 93.84-106.42 11.71 99.98

Cmax maximum plasma concentration AUC0-t area under the plasma concentration-time curve from time zero to t hours AUC0-∞ area under the plasma concentration-time curve from time zero to infinity CV% Coefficient of variation Ratios and 90% CI calculated from ln-transformed data The 90% confidence intervals of the test/reference ratio for Cmax and AUC values lie within the acceptable limits of 80.00% to 125.00%, in line with the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**). Thus, the data support the claim that the applicant’s test product Hydralazine Tablets 50 mg (Morningside Healthcare Limited) is bioequivalent to the reference product Hydrapres Tablets 50 mg (Laboratorios Rubio, S.A., Spain) under fasting conditions. As the 25 mg and 50 mg strength tablets of the test product meet the criteria for a biowaiver specified in the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**), the results and conclusions from the bioequivalence study with the 50 mg tablet strength can be extrapolated to the 25 mg strength tablet. IV.3 Pharmacodynamics The clinical pharmacodynamic properties of hydralazine hydrochloride are well-known. No new pharmacodynamics data were submitted and none are required for applications of this type. IV.4 Clinical Efficacy The clinical efficacy of hydralazine hydrochloride is well-known. No new efficacy data were presented for applications of this type. IV.5 Clinical Safety With the exception of the safety data generated during the bioequivalence study no new safety data were submitted and none are required for applications of this type. The safety profile of hydralazine hydrochloride is well-known. No new or unexpected safety issues were raised during the bioequivalence studies. 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 Hydralazine Tablets.


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A summary of safety concerns is listed in the table below:

Routine pharmacovigilance and routine risk minimisation activities are acceptable to monitor the safety concerns described in the Risk Management Plan. IV.7 Discussion of the clinical aspects It is recommended that Marketing Authorisations are granted for Hydralazine Tablets. V. USER CONSULTATION A package leaflet 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.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION QUALITY The important quality characteristics of Hydralazine Tablets are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance.


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NON-CLINICAL No new non-clinical data were submitted and none are required for applications of this type. As the pharmacokinetics, pharmacodynamics and toxicology of hydralazine hydrochloride are well-known, no additional data were required. EFFICACY With the exception of the bioequivalence study, no new data were submitted and none are required for applications of this type. The 90% confidence intervals of the test/reference ratio for Cmax and AUC values lie within the acceptable limits of 80.00% to 125.00%, in line with the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**). Thus, the data support the claim that the applicant’s test product Hydralazine Tablets 50 mg (Morningside Healthcare Limited) is bioequivalent to of the reference product Hydrapres Tablets 50 mg (Laboratorios Rubio, S.A., Spain), under fasting conditions. As the 25 mg and 50 mg strength tablets of the test product meet the criteria for a biowaiver specified in the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**), the results and conclusions from the bioequivalence study with the 50 mg tablet strength can be extrapolated to the 25 mg strength tablet. SAFETY The safety profile of hydralazine hydrochloride is well-known. No new or unexpected safety issues or concerns arose from these applications. PRODUCT LITERATURE The SmPCs, PIL and labelling text are satisfactory and in line with current guidance. In accordance with Directive 2010/84/EU, the current version of the SmPCs and PIL are available on the MHRA website. The current labelling is presented below: Hydralazine 25 mg Tablets:


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Hydralazine 50 mg Tablets:


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BENEFIT/RISK ASSESSMENT The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with hydralazine hydrochloride is considered to have demonstrated the therapeutic value of the compound. The benefit/risk assessment is therefore considered to be positive. RECOMMENDATION The grant of Marketing Authorisations is recommended.


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(Hydralazine hydrochloride)

PL 20117/0258-0259

STEPS TAKEN AFTER AUTHORISATION-SUMMARY

Date submitted Application

type Scope Outcome

Documents

Public Assessment Report - GOV.UK · Rubio, S.A., Spain).Therefore, the MHRA decided that, as for Hydrapres 25 mg and 50 mg Tablets (Laboratorios Rubio, S.A., Spain), the benefits