Public Assessment Report - GOV.UK · LAY SUMMARY AKIS 25 mg/ml, 50 mg/ml and 75 mg/ml solution for injection ... This medicine is not suitable for children (under 18 years). Please

Public Assessment Report

Decentralised Procedure

AKIS 25 mg/ml, 50 mg/ml and 75 mg/ml solution for

injection

AKIS 25 mg/ml, 50 mg/ml and 75 mg/ml solution for

injection in prefilled syringe

(Diclofenac sodium)

Procedure No: UK/H/3585/0007-0012/DC

UK Licence No: PL 21039/0040-0045

IBSA Farmaceutici Italia S.r.l.

AKIS 25 mg/ml, 50 mg/ml and 75 mg/ml, sol for inj/sol for inj in prefilled syringe UK/H/3585/007-012/DC

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LAY SUMMARY

AKIS 25 mg/ml, 50 mg/ml and 75 mg/ml solution for injection

AKIS 25 mg/ml, 50 mg/ml and 75 mg/ml solution for injection in prefilled syringe

(Diclofenac sodium)

For ease of reading, the products may be collectively called ‘AKIS’ or ‘AKIS solution for injection and

AKIS solution for injection in pre-filled syringe’ in this lay summary.

This is a summary of the Public Assessment Report (PAR) for AKIS 25 mg/ml, 50 mg/ml and 75 mg/ml

solution for injection (PL 21039/0040-0042; UK/H/3585/007-009/DC) and AKIS 25 mg/ml, 50 mg/ml

and 75 mg/ml solution for injection in prefilled syringe (PL 21039/0043-0045;

UK/H/3585/010-012/DC). It explains how the applications for AKIS were assessed and their

authorisation recommended, as well as the conditions of use. It is not intended to provide practical

advice on how to use AKIS.

For practical information about using AKIS, patients should read the package leaflets or contact their

doctor or pharmacist.

What is AKIS and what is it used for?

AKIS solution for injection and AKIS solution for injection in pre-filled syringe are ‘hybrid generic

medicines’. This means that AKIS solution for injection and AKIS solution for injection in prefilled

syringe are similar to a ‘reference medicine’ containing the same active substance already authorised in

the UK called Voltarol Ampoules (75 mg/3 ml; Novartis Pharmaceuticals UK Limited). However,

unlike the reference product, which is available as a 75 mg/3 ml strength solution for injection in

ampoules, AKIS is available as 25 mg/ml, 50 mg/ml and 75 mg/ml strength solutions for injection in

ampoules/prefilled syringes.

AKIS, given by intramuscular or subcutaneous injection, is used to treat a number of painful conditions

including:

• flare-ups of joint or back pain

• attacks of gout

• pain caused by kidney stones

• pain caused by injuries, fractures or trauma

It is also used to prevent or treat pain following an operation.

AKIS, given by intravenous injection, is used in hospital settings to prevent or treat pain following an

operation.

How does AKIS work?

AKIS contains the active substance diclofenac sodium. AKIS belongs to a type of medicine called non-

steroidal anti-inflammatory drugs (NSAIDs). Other NSAIDs include aspirin and ibuprofen. These drugs

reduce pain and inflammation.

How is AKIS used?

The products are available in the pharmaceutical form solution for injection or solution for injection in

prefilled syringe.

The patient’s doctor will decide when and how to treat the patient with AKIS.


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A doctor, nurse or pharmacist will prepare the injection for the patient. Usually, a health professional (a

nurse or doctor) will administer AKIS. The patient will either be given an intramuscular injection (an

injection into a muscle usually into the buttocks), a subcutaneous injection (an injection into the skin

usually into the buttocks or thigh) or an intravenous injection (an injection into a vein, generally of an

arm). The patient’s health professional will not inject the patient in the same place twice.

AKIS must not be given by intravenous (i.v.) infusion.

Children: This medicine is not suitable for children (under 18 years).

Please read section 3 of the package leaflet for detailed information on dosing recommendations, the

route of administration and the duration of treatment.

AKIS can only be obtained on prescription.

What benefits of AKIS have been shown in studies?

As AKIS solution for injection and AKIS solution for injection in prefilled syringe are hybrid medicines,

studies in patients have been limited to tests to determine that these medicines are therapeutically

equivalent to the reference medicine, Voltarol Ampoules (75 mg/3 ml; Novartis Pharmaceutical UK

Limited). Two medicines are therapeutically equivalent when they produce the same measure of

therapeutic effect in the body.

What are the possible side effects of AKIS?

Like all medicines, AKIS can cause side effects, although not everybody gets them.

Since AKIS solution for injection and AKIS solution for injection in prefilled syringe are hybrid generic

medicines and are comparable to the reference medicine, the benefits and possible side effects are taken

as being the same as the reference medicine.

For the full list of all side effects reported with AKIS, see section 4 of the package leaflet.

For the full list of restrictions, see the package leaflets for AKIS.

Why is AKIS approved?

In accordance with EU requirements, AKIS has been shown to have comparable quality and is

considered to be equivalent to Voltarol Ampoules (75 mg/3 ml; Novartis Pharmaceuticals UK Limited)

Therefore, the view was that, as for Voltarol Ampoules (75 mg/3 ml; Novartis Pharmaceuticals UK

Limited), the benefits outweigh the identified risks.

What measures are being taken to ensure the safe and effective use of AKIS?

A Risk Management Plan has been developed to ensure that AKIS is used as safely as possible. Based

on this plan, safety information has been included in the Summaries of Product Characteristics (SmPCs)

and the package leaflets for AKIS, including the appropriate precautions to be followed by healthcare

professionals and patients.

Other information about AKIS

Agreement for granting Marketing Authorisations was given on 17 September 2017 by the UK and the

following EU Member States: Czech Republic, Greece, Spain, France, Hungary, Italy, Poland and the

Slovak Republic. Marketing Authorisations for AKIS were granted in the UK to IBSA Farmaceutici

Italia S.r.l. on 13 October 2017.

The full PAR approved for AKIS follows this summary.


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For more information about treatment with AKIS, read the package leaflets, or contact your doctor or

pharmacist.

This summary was last updated in December 2017.


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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 10

V User consultation Page 17

VI Overall conclusion, benefit/risk assessment and recommendation Page 18

Annex 1- Table of content of the PAR update for MRP and DCP Page 27


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Scientific discussion

I. INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Member States considered that the

applications for AKIS 25 mg/ml, 50 mg/ml, 75 mg/ml solution for injection (PL 21039/0040-0042.

UK/H/3585/007-009/DC) and AKIS 25 mg/ml, 50 mg/ml, 75 mg/ml solution for injection in prefilled

syringe (PL 21039/0043-0045); UK/H/3585/010-012/DC) could be approved. The products may be

collectively called ‘AKIS’ in this scientific discussion, for ease of reading.

The products are Prescription Only Medicines (POM) and are indicated in the treatment of the

following:

• By intramuscular and subcutaneous injection: AKIS is effective in acute forms of pain, including

renal colic, exacerbations of osteo- and rheumatoid arthritis, acute back pain, acute gout, acute

trauma and fractures, and post-operative pain.

By intravenous bolus injection: for treatment or prevention of post-operative pain in the hospital

settings.

AKIS is indicated in adults. Use in children and adolescents is not recommended.

These products contain the active substance diclofenac sodium. Diclofenac is a phenylacetic acid

derivative and belongs to the group of non-steroidal anti-inflammatory drugs (NSAIDs) that also exhibit

analgesic and antipyretic properties. NSAIDs are inhibitors of the enzyme cyclo-oxygenase and directly

inhibit the biosynthesis of prostaglandins and thromboxanes from arachidonic acid.

The applications were submitted using the Decentralised Procedure, with the UK as Reference Member

State (RMS) and the Czech Republic, Greece, Spain, France, Hungary, Italy, Poland and the Slovak

Republic as Concerned Member States (CMS). The applications were submitted under Article 10(3) of

Directive 2001/83/EC, as amended, as hybrid applications. The applications refer to Voltarol Ampoules

(75 mg/3 ml; PL 00101/0466), for which a licence was first granted to Ciba-Geigy Plc in August 1981.

After a subsequent change of ownership procedure, approved on 11 July 1997, the current Marketing

Authorisation Holder is Novartis Pharmaceuticals UK Limited.

Akis has previously been approved in the same strengths and presentations as the current applications,

following the Decentralised procedures UK/H/3585/01-06/DC, which concluded positively on

07 November 2012. The proposed applications (UK/H/3585/007-012/DC) are line extensions of the

previously approved Akis applications (UK/H/3585/01-06/DC), to include use as an intravenous bolus

injection, in addition to the already approved intramuscular and subcutaneous indications.

There is no Paediatric Development Program in place for these products.

No new non-clinical data was required for these applications, given that the applications were based on

being hybrid applications of an originator product that has been in clinical use for over 10 years.

Nevertheless, two in vitro studies were submitted: firstly, a human plasma proteins binding study

comparing Akis to the reference product Voltarol for solution for injection and secondly, a haemolytic

study investigating the possible haemolytic effects of Akis 75mg/ml when placed in contact with human

red blood cells at different blood concentrations.

To further support the applications, the applicant submitted a four-part pharmacokinetic study of a single

bolus intravenous dose of Akis. Scientific advice has been provided by the MHRA concerning the

design of the pharmacokinetic study. The applicant has stated that the pharmacokinetic study was

conducted in compliance with Good Clinical Practice (GCP) requirements.


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The applicant also provided comparative published pharmacokinetic data from the literature for Dyloject

75 mg/2 ml solution for injection, another diclofenac product that was previously approved for intravenous

bolus administration.

The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in

place at all sites responsible for the manufacture, assembly and batch release of these products.

For manufacturing sites within the Community, the RMS has accepted copies of current manufacturing

authorisations issued by inspection services of the competent authorities as certification that acceptable

standards of GMP are in place at those sites.

The RMS and CMS considered that the applications could be approved at the end of procedure

(Day 210) on 17 September 2017. After a subsequent national phase, Marketing Authorisations were

granted in the UK to IBSA Farmaceutici Italia S.r.l on 13 October 2017.

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.

The products are clear to slightly amber coloured transparent solutions for injection in glass

ampoules/glass prefilled syringes.

Each ampoule/prefilled syringe contains 25 mg, 50mg or 75 mg, respectively of the active substance

diclofenac sodium.

The products also contain pharmaceutical excipients, namely hydroxypropylbetadex, polysorbate 20 and

water for injections.

AKIS 25 mg/ml, 50 mg/ml and 75 mg/ml solution for injection are packaged in Type I glass ampoules.

AKIS 25 mg/ml, 50 mg/ml and 75 mg/ml solution for injection in prefilled syringe are packaged in

transparent type I glass prefilled syringes, each with an isoprene-bromobutyl blend tip cap, chlorobutyl

rubber plunger and polystyrene plunger rod. AKIS 25 mg/ml, 50 mg/ml and 75 mg/ml solution for

injection in prefilled syringe are also packed with:

• 1 needle for subcutaneous injection (27 gauge) grey

• 1 needle for intramuscular and intravenous injection (21 gauge) green

All the products are packaged in pack sizes of either 1, 3 or 5 ampoules or prefilled syringes. Not all

pack sizes may be marketed.

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 parenteral products.

II.2 DRUG SUBSTANCE

Diclofenac sodium

INN: Diclofenac sodium

Chemical name: Sodium 2-[(2,6-diclorophenyl)amino] phenyl acetate


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Molecular formula: C14H10Cl2NNaO2

Structure:

Mr: 318.1

Appearance: White to slightly yellowish crystalline powder.

Solubility: Sparingly soluble in water, freely soluble in methanol, soluble in alcohol

and slightly soluble in acetone.

All aspects of the manufacture and control of the active substance diclofenac sodium, except for stability

data to support a suitable retest period when stored in the proposed packaging, are covered by a

European Directorate for the Quality of Medicines (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 formulate globally acceptable and stable products

that were available in volumes of 1ml in a water-based solution. Suitable pharmaceutical development

data have been provided for these applications.

Manufacturing Process

A satisfactory batch formula has been provided for the manufacture of each strength of the product,

along with an appropriate account of the manufacturing process. The manufacturing process has been

validated with full production-scale batches that have shown satisfactory results.

Control of Finished Product

The finished product specifications are acceptable. Test methods have been described that have been

validated adequately. Batch data complying 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 “Store below 25°C. Do not refrigerate or freeze. Store in the original

packaging in order to protect from light.” has been accepted.

Additionally, after use the instructions are, “The medicinal products must be used immediately after

opening. Any remaining solution must be discarded.”

Bioequivalence/Bioavailability

Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the

pharmacokinetic study. The pharmacokinetic study is discussed in Section IV.2, Clinical Aspects,

Pharmacokinetics.

II.4 Discussion on chemical, pharmaceutical and biological aspects


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It is recommended that Marketing Authorisations are granted for AKIS from a quality point of view.

III NON-CLINICAL ASPECTS

III.1 Introduction

The pharmacodynamic, pharmacokinetic and toxicological properties of diclofenac sodium are

well-known. The applicant cross-refers to the non-clinical studies presented in the original submission

for the reference products Voltarol (diclofenac sodium) and Dyloject, a marketed diclofenac-

hydroxypropylbetadex (HPβCD) solution for injection.

No additional animal studies were deemed necessary. Nevertheless, two specific issues were addressed

by in vitro studies:

• the binding of diclofenac to human plasma proteins when released by Akis or Voltaren solution

for injection (reference product)

• any potential haemolytic effect of Akis 75 mg/ml when placed in contact with human red blood

cells at different blood concentrations.

A summary of the in vitro studies is provided in Section III.2, Pharmacology below.

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

The pharmacological profile of diclofenac is well known. No new data is required for applications of

this type. However, the applicant submitted the below studies to support the applications.

Binding to human plasma proteins

This in vitro study assessed the protein binding of diclofenac in human plasma when released by Akis in

comparison with that for diclofenac originating from Voltaren solution for injection. The applicant

submitted the study based on the rationale that HPβCD (hydroxypropylbetadex) may modify the

systemic disposition of the NSAID as there was a theoretical chance that HPβCD could interfere with

the binding of diclofenac sodium to plasma proteins. However, there is no evidence in the literature to

suggest that HPβCD can displace diclofenac sodium from its binding to plasma proteins and, therefore,

the study was performed with a confirmatory intent that HPβCD does not interfere with the PK of

diclofenac sodium.

The evaluation of plasma protein binding of diclofenac was assessed in vitro in a pool of plasma

samples obtained from three donors at the target plasma concentration of 15 μg/ml. The percentage of

diclofenac protein binding determined in human plasma after incubation of the Akis formulation was

99.82% (range: 99.81%-99.83%). This value is equivalent to the binding obtained after incubation of the

reference formulation Voltaren.

Haemolytic study

Although there is no evidence in literature of a possible haemolytic effect of HPβCD, this study was

aimed at gathering information on the possible haemolytic effects of Akis 75 mg/ml when placed in

contact with human red blood cells at different blood concentrations.

The test concentrations of Akis were chosen considering a minimum blood flow of 40 ml/minute,

equivalent to 0.67 ml/second, of the cephalic or basilic veins as injection site in vivo. Akis, at the highest

final blood concentration tested (37.5 mg/ml), induced a 52.7% of haemolysis. While at the final blood

concentrations of 18.75 mg/ml, 7.5 mg/ml, 3.75 mg/ml and 1.50 mg/ml, Akis did not induce any

haemolytic effect on human blood erythrocytes, as compared to negative control samples. Haemolytic


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effects were only observed at the highest concentration of 37.5 mg/mL, i.e. a two-fold concentration to

the one expected following intravenous bolus injection of Akis 75 mg/ml at the quickest (5 second)

injection rate.

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 of already authorised products, it is not expected that environmental

exposure of diclofenac will increase following approval of the Marketing Authorisations for the

proposed products. An environmental risk assessment is therefore not deemed necessary.

III.6 Discussion of the non-clinical aspects

The pharmacodynamic, pharmacokinetic and toxicological properties of diclofenac sodium administered

via the proposed routes are well known. Akis is already been approved for intramuscular and

subcutaneous administration, and Dyloject (diclofenac sodium) is approved for intravenous bolus

administration; therefore, no additional non-clinical data were considered necessary for these

applications.

Nevertheless, the applicant submitted two in vitro studies. The first study investigated the binding of

human of diclofenac compared to the reference product Voltarol for solution for injection. The second

study investigated potential haemolytic effects of Akis 75mg/ml when in contact with human red blood

cells at different blood concentrations. The studies raised no safety concerns. Therefore, it was

concluded that the safety profile of Akis remains unchanged after intravenous administration and no

further non-clinical studies are required.

In conclusion, there are no objections to the approval of AKIS, from a non-clinical point of view.

IV. CLINICAL ASPECTS

IV.1 Introduction

The clinical pharmacology of diclofenac 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.

To support the applications, the applicant submitted a four-part pharmacokinetic study designed to

compare the pharmacokinetics of a single bolus intravenous injection of Akis 75mg/ml versus the

reference products Voltaren, diclofenac sodium 75 mg/3ml solution for intramuscular injection in

ampoules (Novartis Farma S.p.A, Italy) and Voltarol, diclofenac sodium 75 mg/3 ml solution for

injection in ampoules (Novartis Pharmaceuticals UK Limited, UK) in male and female healthy

volunteers. The reference products may be referred to as Voltaren 75 mg/3 ml and Voltarol 75 mg/3 ml

in the remainder of this discussion.

Considering the different administration routes of the test and reference products, the rate of absorption

(that is, peak plasma concentrations, Cmax) was expected to differ between Akis (administered as an

intravenous (i.v.) bolus) and the reference products (administered intramuscularly or by slow

intravenous infusion). Therefore, the applicant provided further comparison of the pharmacokinetic (PK)

profile of Akis administered as an i.v. bolus with published PK data for Dyloject 75 mg/ 2 ml Solution


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for Injection (UK Public Assessment Report (UKPAR): Dyloject 75 mg/ 2ml Solution for Injection,

PL 25053/0001). Dyloject 75 mg/2 ml Solution for Injection is not currently available on the market. For

ease of reading Dyloject 75 mg/2 ml Solution for Injection will be referred to as Dyloject in the

remainder of this scientific discussion.

The pharmacokinetic study and the comparative PK data generated for Akis and Dyloject are discussed

in detail in Section IV.2, Pharmacokinetics below.

With the exception of data from the pharmacokinetic study, no new pharmacokinetic data is provided or

required for these applications.

In the previous Decentralised Procedure applications for Akis (PL 21039/0018-0021 and

PL 21039/0023-0024; UK/H/3585/001-006/DC), clinical studies relevant to the approved intramuscular

and subcutaneous indications were submitted and reviewed. The studies included two bioavailability

studies (CRO-PK-08-812; and CRO-PK-04-118), two efficacy studies (Dental Pain Study

09PUK/DCSC04; and Dental Pain Study 09PUK/DCSC05); and one tolerability study with efficacy

data (Study 08I-DCSC04). These studies are not discussed again in this report. For further details

regarding these please refer to the link below.

http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con239402.pdf

IV.2 Pharmacokinetics

The pharmacokinetic properties of diclofenac are well known and are adequately described in the

applicant’s clinical overview.

The Marketing Authorisation Holder submitted the following pharmacokinetic study to support the

applications.

Study CRO-PK-04-290

This Phase I pharmacokinetic study was designed to compare the bioavailability in terms of extent of

exposure (AUC) of the test product Akis 75 mg/ml administered as a single intravenous bolus versus the

reference products Voltaren 75 mg/3ml (Novartis Farma S.p.A., Italy) administered by intramuscular

injection and Voltarol 75 mg/3ml (Novartis Pharmaceuticals UK Limited, UK) administered by

intramuscular (i.m.) injection and intravenous (i.v.) infusion over 30 minutes in male and female healthy

volunteers.

The study was conducted as a single centre, open-labelled, single dose, four-part pharmacokinetic study.

The four parts of the study were:

• Part 0: Three-cohort, dose-escalation study

• Part 1: Randomised, 4-way cross-over, pilot pharmacokinetic study for selecting the rate of

administration

• Part 2: Randomised, 3-way cross-over, comparative bioavailability study

• Part 3: One-arm, descriptive pharmacokinetic study

Parts 0, 1 and 2 of the study were conducted as planned. Part 3 of the study was not performed as

according to the protocol, PK data obtained for Akis in Parts 1 and 2 of the study were considered

sufficient to satisfy the study requirements.

The study objectives were:

• Part 0 (dose-escalation):

(i) to evaluate the safety and tolerability of a single dose of Akis 25 mg/ml (T1), 50 mg/ml

(T2) and 75 mg/ml (T3) administered as a single 5 second (5 sec) i.v. bolus;

(ii) to confirm the safety and tolerability of T3 before performing the subsequent study parts.

http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con239402.pdf


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• Part 1 (rate of administration):

(i) to preliminarily evaluate the pharmacokinetic (PK) profile after single i.v. bolus injection

of Akis 75 mg/ml at three different injection rates [5 sec (T3), 15 sec (T4), 30 sec (T5)] and

to select the injection rate for study Parts 2 and 3 (if applicable);

(ii) to evaluate the pharmacokinetic profile of Voltaren administered by i.m. injection (R).

• Part 2 (comparative bioavailability):

(i) to evaluate the bioavailability in terms of extent of exposure (AUC) of T3 as a single i.v.

bolus (injection rate selected in Part 1) in comparison to Voltarol 75 mg/3 ml administered

by i.m. injection (R2) and Voltarol75 mg/3 ml administered by i.v. infusion over 30 min

(R3);

(ii) to describe the PK profile of T3; to evaluate the need for study Part 3 and, if applicable, to

calculate the sample size for study Part 3.

• Part 3 (if applicable):

(i) to further describe the PK profile of T3 (injection rate selected in Part 1).

• Parts 0, 1, 2 and 3 (Part 3 if applicable):

(i) to evaluate the safety and tolerability of the Test (T1, T2, T3, T4 and T5) and Reference (R,

R2 and R3) treatments.

• Parts 1, 2 and 3 (Part 3 if applicable):

(i) to evaluate the peak plasma concentration (Cmax) of T3 to allow comparison to literature

data (UKPAR Dyloject, PL 25053/0001)

Study end-points

Part 0 (dose-escalation):

➢to collect safety and tolerability data of T1, T2 and T3

➢to confirm the safety and tolerability of T3.

Part 1 (rate of administration):

➢to evaluate the PK profile of Akis 75 mg/ml i.v. bolus at 3 injection rates and determine the

injection rate to be used in study Part 2 and 3 (Part 3, if applicable) based on PK results and adverse

events (AEs) occurrence;

➢to evaluate the PK profile of Voltaren 75 mg/3 ml.

Part 2 (comparative bioavailability):

Primary end-point: to compare the bioavailability in terms of diclofenamic acid extent of exposure

[AUC0-t and AUC0-∞ (if feasible)] of Akis 75mg/ml administered as a single i.v. bolus injection at the

rate selected in Part 1 [i.e. 5 sec (T3)] and of Voltarol 75 mg/3 ml administered by i.m. injection

(R2) and by i.v. infusion over 30 min (R3),

Secondary end-points:

➢ to describe the PK profile of T3, R2 and R3;

➢ to confirm the need for study Part 3 and, if applicable, to calculate the sample size for study Part

Part 3 (descriptive pharmacokinetics):

➢ to further evaluate the PK profile of Akis 75mg/ml administered as a single i.v. bolus at the

injection rate selected in Part 1 [i.e. 5 sec (T3)], if applicable.

Parts 1, 2 and 3 (Part 3 if applicable):

➢ to descriptively evaluate diclofenamic acid peak plasma concentration (Cmax) after Akis 75mg/ml

i.v. bolus administration at the injection rate selected in Part 1 [i.e. 5 sec (T3)], in comparison to

literature data (UKPAR Dyloject, PL 25053/0001);

➢ safety and tolerability data collection.


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Results

Study Part 0

Subjects were treated according to a dose-escalation design: an equal number of subjects received either

Akis 25 mg/ml (T1), Akis 50 mg/ml (T2) or Akis 75 mg/ml (T3) as a single 5-sec i.v. bolus. The second

and third cohorts were treated only after full safety assessment of the previous cohort. The number of

subjects per cohort was deemed sufficient for the evaluation of the safety and tolerability profile of T1,

T2 and T3. Safety of T3 was confirmed and selected for the subsequent study parts. as this is the i.v

infusion dose administered in common clinical practice.

Study Part 1 - Pharmacokinetic data

All subjects randomised in study Part 1 were included in the PK analysis.

Descriptive statistics of plasma levels of diclofenac at each time-point up to 8 h post-dose for Akis

75mg/mL administered as i.v. bolus at the injection rate of 5 sec (T3), 15 sec (T4) and 30 sec (T5) and

of Voltaren 75 mg/3ml administered by i.m. injection (R) were reported. To support the claim that the

chosen first point of blood collection following administration was adequate to capture Cmax, the

applicant has provided a worse case analysis for Cmax: the applicant presented the PK parameter, C0,

which may be considered a more accurate estimator of the actual peak concentration after i.v. bolus.

This parameter represents the extrapolated concentration at the administration time (t=0). The

justification provided for the use of the parameter C0 is accepted.

Descriptive statistics of diclofenac PK parameters after T3, T4, T5 and R treatments are summarised in

the Table 1 below.

Table 1: Plasma diclofenac PK parameters after single dose administration of T3, T4, T5 and R.

The PK parameters of Akis 75 mg/ml administered as i.v. bolus at the three injection rates (5, 15 and 30

sec) were very similar, with superimposable curves for the three treatments (T3, T4 and T5), The results

indicated that the injection rate did not have any effect on the diclofenac maximum observed plasma

concentration (Cmax) and extent of exposure (AUC). On the basis of these results the fastest (5 second)

injection rate was chosen for further evaluation in the subsequent parts of the study.

The PK profiles for Akis administered as i.v. bolus at the 3 injection rates (T3, T4 and T5) differed from

that for Voltaren 75 mg/ 3ml administered by i.m. injection (R). This was expected, considering the

different methods of administration.

Cmax for the test treatments (T3, T4 and T5) was higher and occurred at a median time of 0.05 hour


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versus 0.33 hour for i.m. Voltaren 75 mg/ 3ml (R). Based on the AUC0-t ratios, diclofenac bioavailability

was approximately 25% higher for T3 than R. The point estimate (PE), calculated as the T3/R ratio of

the geometric means of AUC0-t and AUC0-∞ confirmed a higher diclofenac bioavailability for T3. As a

consequence, the 90% confidence interval of the test/reference ratio for AUC values lie outside the

acceptable upper limit of 125.00%.

Study Part 2 - Pharmacokinetic data

All subjects randomised in study Part 2 were included in the PK analysis.

Descriptive statistics of plasma levels of diclofenac was determined at each time-point up to 8 h

post-dose for Akis 75mg/ml administered as i.v. bolus at the injection rate of 5 sec (T3) and of Voltarol

75 mg/3ml administered by i.m. injection (R2) and i.v. infusion (R3).

The AUC0-t/AUC0-∞ ratio was > 80% in all subjects indicating that the sampling schedule was sufficient

to characterise the concentration curve.

Descriptive statistics of diclofenac PK parameters after T3, R2 and R3 treatments are summarised in

Table 2 below.

Table 2: Plasma diclofenac PK parameters after single dose administration of T3, R2 and R3

T3 versus R3 comparison

Consistent with the different administration rate of a rapid i.v. bolus (5 sec) versus a 30-minute i.v.

infusion, Cmax was on average approx. 2.7-fold higher and occurred earlier (i.e. 0.05 hour vs. 0.50 hour)

for T3 as compared to R3. The mean half-life was very similar with mean values of 1.47±0.32 and

1.37±0.34 h for T3 and R3, respectively.

Diclofenac relative bioavailability (Frel) calculated as AUC0-t T3/R3 ratio was 113.22±11.08% (mean ±

SD).

Overall, exposure to diclofenac for T3 and R3 was equivalent, with T3/R3 ratios of geometric means

(PE%) for AUC0-t and AUC0-∞ of 112.69% and 112.65%, respectively. The 90% confidence intervals

were well within the acceptance limits of 80.00% to 125.00%, demonstrating comparable bioavailability

of the two treatments in terms of AUC values.

Results of the statistical analysis for AUC values for the T3 vs. R3 comparison are summarised in

Table 3 below.


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Table 3: T3 and R3 diclofenac plasma PK parameters – Statistical analysis

Geometric mean Ratio: Test/Reference (%)

Parameter Test Reference Point estimate

(PE)

90% CI

T3 vs R3

AUC0-t (hr*ng/mL) 5050.81 4482.10 112.69 108.32 - 117.24

AUC0-∞ (hr*ng/mL) 5090.36 4518.72 112.65 108.21 - 117.27

T3: Akis, diclofenac sodium 75 mg/mL solution - injection rate 5 sec

R3: Voltarol, diclofenac sodium 75 mg/3 mL solution, i.v. infusion

T3 versus R2 comparison

As expected, considering the different administration routes, the PK profiles of Akis 75 mg/ml i.v. bolus

injection (T3) and Voltarol 75 mg/3ml administered by i.m. injection (R2) were very different.

Diclofenac relative bioavailability (Frel), calculated as AUC0-t T3/R2 ratio was 125.87±8.87% (mean ±

SD). Similarly, T3/R2 ratio of geometric means (PE%) was 120.76% for AUC0-0-∞ and 125.58% for

AUC0-t.

Diclofenac exposure for the two treatments was equivalent in terms of AUC0-∞ with the 90% confidence

intervals within the acceptance limits of 80.00% – 125.00%. However, the 90% confidence interval

upper interval for AUC0-t for diclofenac was outside the acceptable limit of 125.00%.

The results of the statistical analysis for AUC values for the T3 vs. R2 comparison are summarised in

Table 4 below.


Geometric mean Ratio: Test/Reference (%)

Parameter Test Reference Point estimate 90% CI

T3 vs R2

AUC0-t

(hr*ng/mL)

5050.81 4021.99 125.58 122.14 - 129.12

AUC0-∞

(hr*ng/mL)

5090.36 4215.16 120.76 117.87 - 123.73

T3: Akis, diclofenac sodium 75 mg/mL - injection rate 5 sec

R2: Voltarol diclofenac sodium 75 mg/3 mL solution, i.m. injection

Overall conclusion of Study CRO-PK-04-290

For the two comparisons (T3 vs R2 and T3 vs R3) a sequence effect was observed for both AUC0-t and

AUC0-∞. Bioequivalence is robust against the true sequence effect because the sequence effect is a

component of inter-subject variability and does not affect the calculation of confidence intervals. The

presence of unequal carry-over can be a relevant bias since it suggests that the washout period was

inadequate. However, this is not of concern here as the pre-dose levels at the start of each period were

either zero (R2 vs T3 comparison) or less than 5% of Cmax (R3 vs T3 comparisons).

It is not unusual to obtain a significant p value for the treatment effect while establishing

bioequivalence, as is the case here, and vice-versa. The differences are of no concerns provided they are

within the acceptance range for bioequivalence.

Therefore, the proposed intravenous bolus administration of Akis is considered equivalent to the

intravenous infusion of the reference product Voltarol in terms of AUC, but not in terms of Cmax, as Cmax

was on average approximately 2.7-fold higher and occurred earlier (i.e. 0.05 hour vs. 0.50 hour) for Akis

75 mg/ml (T3) as compared to Voltarol 75/ml (R3). To address this issue, the applicant has provided a


16

comparison between the data generated in this study and published pharmacokinetics data for Dyloject.

another diclofenac product that was previously approved for intravenous bolus administration.

Part 1 + Part 2 Cmax data – PK analysis and comparison with literature data

The mean AUC0-t and AUC0-∞ values (5252.03±1193.01 and 5287.66±1196.85 ng/mL*h) obtained in the

present pharmacokinetic study (Part 1+ 2 data) were higher than those (4363±1600 and 4420±1636)

reported in the literature for Dyloject. Hence a direct and reliable comparison of AUC between Akis

administered by intravenous bolus and that reported in the literature for Dyloject is not considered

possible.

The mean Cmax values obtained for T3 for in the present study (Parts 1 and 2 data together) and that

reported for Dyloject administered as an i.v bolus over 15 seconds (UKPAR PL 25053/0001) are

summarised in the following table:


An exploratory analysis suggested that the data reported for Dyloject in the literature could have been

underestimated as a consequence of applying a different PK calculation method to that use for the

calculation of the data for Akis.

On the basis of the presented data, similarity between the bolus injection of Akis and Dyloject for the

PK parameter Cmax has not been clearly demonstrated. This could be due to the difference in study

methodology. However, the worst-case scenario presented by the applicant regarding the highest

possible value of Cmax, provides some reassurance that there is not likely to be a significant difference

between Cmax values for Akis and Dyloject after intravenous. administration of these products.

IV.3 Pharmacodynamics

The clinical pharmacodynamic properties of diclofenac sodium are well-known. No new

pharmacodynamic data were submitted and none are required for applications of this type.

IV.4 Clinical Efficacy

The clinical efficacy of diclofenac sodium is well-known. No new efficacy data are presented or are

required for applications of this type.

IV.5 Clinical Safety

The safety profile of diclofenac sodium is well known.

No new or unexpected safety concerns arose from the pharmacokinetic study.

The applicant argues that the impact on the systemic safety of the apparently higher (~10%) diclofenac

exposure following Akis as compared to Dyloject i.v. bolus can be regarded as negligible, based on the

conditions and restrictions for the use of the Akis compared to the reference comparators. The applicant

has committed to conduct a post-approval safety study to collect relevant safety data following use of

Akis i.v. bolus injection in the approved conditions of use.

IV.6 Risk Management Plan

The applicant 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 Akis.


17

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

Table: Summary of safety concerns

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 previously has been evaluated for Akis (PL 0018-0023; UK/H/3585/001-006/DC) 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.

As the changes added to the previously user tested package leaflet only include information regarding

the intravenous use of AKIS (PL 0040-0045; UK/H/3585/012-0012/DC), further user testing has not

been performed. This is accepted.


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IV. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

The quality of the products is acceptable.

The current line extension applications propose to include the i.v. route of administration for AKIS, with

indications proposed in the treatment and prevention of post-operative pain. The applications are

supported by data generated in a bioequivalence study which compares the PK profile of Akis following

a single i.v. bolus injection with the PK profile of the reference product Voltarol administered as an i.v.

infusion. As expected the highest concentration of diclofenac noted in the study is higher with Akis than

for the reference product.

Based on a worst case scenario analysis, the applicant has provided suitable argument to justify that the

highest possible Cmax is in line with the projected C0 calculated in the submitted study, which is similar

to that expected with Dyloject.

An exploratory analysis suggested that the data reported for Dyloject in the literature could have been

underestimated as a consequence of applying a different PK calculation method to that use for the

calculation of the data for Akis.

Based on the proposed short duration of use and the hospital setting in which the product is likely to be

used, justification of a low risk of systemic toxicity of the product, in spite of the higher Cmax value with

Akis in comparison to the reference product Voltarol used is accepted.

On the basis of the data and justifications provided, the benefit risk balance is considered positive for

AKIS in the proposed indications.

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 leaflets is

available on the MHRA website.

The current labelling text is presented below. The Marketing Authorisation Holder has committed to

submit the labelling for review to the regulatory authorities before marketing any pack size.


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AKIS 25 mg/ml, 50 mg/ml and 75 mg/ml solution for injection:


21


22


23


24

Akis 25 mg/ml, 50 mg/ml and 75 mg/ml solution for injection in prefilled syringe


25


26

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ANNEX 1-Table of content of the PAR update for MRP and DCP

Steps taken after the initial procedure with an influence on the Public Assessment Report

Scope Procedure

number

Product

information

affected

Date of

start of the

procedure

Date of end

of

procedure

Approval/

non

approval

Assessment

report

attached

Y/N

(version)

Documents

Public Assessment Report - GOV.UK · LAY SUMMARY AKIS 25 mg/ml, 50 mg/ml and 75 mg/ml solution for injection ... This medicine is not suitable for children (under 18 years). Please