Public Assessment Report - mhra.gov.uk · Ceftriaxone 500 mg powder for soln for inj, ... This is a...

Public Assessment Report

Decentralised Procedure

Ceftriaxone 500 mg powder for solution for injection

Ceftriaxone 1 g powder for solution for injection/infusion


Procedure No: UK/H/6066/001-003/DC

UK Licence No: PL 41947/0018-0020

ELC GROUP s.r.o.

Ceftriaxone 500 mg powder for soln for inj, Ceftriaxone 1 g and 2 g powder for soln for

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LAY SUMMARY

Ceftriaxone 500 mg powder for solution for injection



The products may be collectively called ‘Ceftriaxone’ or ‘Ceftriaxone 500 mg, 1 g and 2 g’ in this lay

summary.

This is a summary of the Public Assessment Report (PAR) for Ceftriaxone 500 mg powder for solution

for injection (PL 41947/0018; UK/H/6066/001/DC), Ceftriaxone 1 g powder for solution for

injection/infusion (PL 41947/0019; UK/H/6066/002/DC) and Ceftriaxone 2 g powder for solution for

injection/infusion (PL 41947/0020; UK/H/6066/003/DC). It explains how the applications for

Ceftriaxone 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 Ceftriaxone.

For practical information about using Ceftriaxone, patients should read the package leaflet or contact

their doctor or pharmacist.

What is Ceftriaxone and what is it used for?

Ceftriaxone 500 mg powder for solution for injection and Ceftriaxone 1 g and 2 g powder for solution

for injection/infusion are ‘generic’ medicines. This means that these medicines are similar to ‘reference

medicines’ already authorised in the UK called Rocephin 500mg Powder for solution for injection

(Roche Products Limited, UK) and Rocephin 1g and 2g Powder for solution for injection or infusion

(Roche Limited, UK). Rocephin 500mg Powder for solution for injection and Rocephin 1g and 2g

Powder for solution for injection or infusion may be collectively referred to as ‘Rocephin’ or ‘Rocephin

500mg, 1g and 2g’ in this lay summary.

Ceftriaxone is an antibiotic given to adults and children (including newborn babies). Ceftriaxone is used

to treat infections of

• the brain (meningitis);

• the lungs;

• the middle ear;

• the abdomen and abdominal wall (peritonitis);

• the urinary tract and kidneys;

• bones and joints;

• the skin or soft tissues;

• the blood;

• the heart.

It can be given:

• to treat specific sexually transmitted infections (gonorrhoea and syphilis);

• to treat patients with low white blood cell counts (neutropenia) who have fever due to bacterial

infection;

• to treat infections of the chest in adults with chronic bronchitis;

• to treat Lyme disease (caused by tick bites) in adults and children including newborn babies from

15 days of age;

• to prevent infections during surgery.


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How does Ceftriaxone work?

Ceftriaxone 500 mg, 1 g and 2 g contain ceftriaxone as the active substance. Ceftriaxone works by

killing bacteria that cause infections. It belongs to a group of medicines called cephalosporins.

How is Ceftriaxone used?

Ceftriaxone 500 mg is available as a powder for solution for injection. Ceftriaxone 1g and 2g are each

available as a powder for solution for injection or infusion These medicines are administered by a health

profession (doctor or nurse) as a drip (intravenous infusion) or as an injection directly into a vein or into

a muscle. Ceftriaxone is made up by the doctor, pharmacist or nurse and will not be mixed with or given

to the patient at the same time as calcium-containing injections.

The recommended dose

The prescribing doctor will decide the correct dose of Ceftriaxone for the patient. The dose will depend

on the severity and type of infection; whether the patient is on any other antibiotics; the patient’s weight

and age; how well the patient’s kidneys and liver are working. The number of days or weeks that

Ceftriaxone is given depends on the type of infection that the patient has.

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

route of administration and the duration of treatment.

Ceftriaxone can only be obtained on prescription.

What benefits of Ceftriaxone have been shown in studies?

No additional clinical studies were needed as Ceftriaxone 500 mg, 1 g and 2 g are generic medicines that

after reconstitution are aqueous solutions that are given by injection or infusion and contain the same

active substance as the respective reference medicines, Rocephin 500mg, 1g and 2g (Roche Products

Limited, UK).

What are the possible side effects of Ceftriaxone?

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

Since Ceftriaxone 500 mg, 1 g and 2 g are generic medicines and are bioequivalent to the respective

reference medicines, the benefits and possible side effects are taken as being the same as the reference

medicines.

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

For the full list of restrictions, see the package leaflet for Ceftriaxone.

Why is Ceftriaxone approved?

It was concluded that, in accordance with EU requirements, Ceftriaxone 500 mg, 1 g and 2 g have been

shown to have comparable quality and are considered to be bioequivalent to Rocephin 500mg, 1g and 2g

(Roche Products Limited, UK). Therefore, the view was that, as for Rocephin 500mg, 1g and 2g (Roche

Products Limited, UK), the benefits outweigh the identified risks.

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

A Risk Management Plan has been developed to ensure that Ceftriaxone 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 leaflet for Ceftriaxone, including the appropriate precautions to be followed

by healthcare professionals and patients.


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Other information about Ceftriaxone

Agreement for granting Marketing Authorisations was given on 23 August 2017 by the UK and the

following EU Member States: France and Germany. Marketing Authorisations were granted in the UK

to ELC GROUP s.r.o. on 21 September 2017.

The full PAR approved for Ceftriaxone follows this summary.

For more information about treatment with Ceftriaxone, read the package leaflet, or contact your doctor

or pharmacist.

This summary was last updated in November 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 11

VI Overall conclusion, benefit/risk assessment and recommendation Page 12

Annex 1- Table of content of the PAR update for MRP and DCP Page 22


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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 Ceftriaxone 500 mg powder for solution for injection (PL 41947/0018;

UK/H/6066/001/DC), Ceftriaxone 1 g powder for solution for injection/infusion (PL 41947/0019;

UK/H/6066/002/DC) and Ceftriaxone 2 g powder for solution for injection/infusion (PL 41947/0020;

UK/H/6066/003/DC) could be approved. The products may be called ‘Ceftriaxone’ or ‘Ceftriaxone

500 mg, 1 g and 2 g’ in this scientific discussion.

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

infections in adults and children including term neonates (from birth):

- bacterial meningitis

- community acquired pneumonia

- hospital acquired pneumonia

- acute otitis media

- intra-abdominal infections

- complicated urinary tract infections (including pyelonephritis)

- infections of bones and joints

- complicated skin and soft tissue infections

- gonorrhoea

- syphilis

- bacterial endocarditis

Ceftriaxone may be used:

- for treatment of acute exacerbations of chronic obstructive pulmonary disease in adults

- for treatment of disseminated Lyme borreliosis (early (stage II) and late (stage III)) in adults and

children including neonates from 15 days of age

- for pre-operative prophylaxis of surgical site infections

- in the management of neutropenic patients with fever that is suspected to be due to a bacterial

infection

- in the treatment of patients with bacteraemia that occurs in association with, or is suspected to be

associated with, any of the infections listed above.

Ceftriaxone should be co-administered with other antibacterial agents whenever the possible range of

causative bacteria would not fall within its spectrum.

Consideration should be given to official guidelines on the appropriate use of antibacterial agents.

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

State (RMS) and France (procedure UK/H/6066/001/DC only) and Germany as Concerned Member

States (CMS).

The applications were submitted under Article 10(1) of Directive 2001/83/EC, as amended, claiming to

be generic medicinal products of Rocephin 500mg, 1g and 2g Powder for solution for injection

(PL 00031/0170 -0172; Roche Products Limited, UK), which were granted in the UK on 02 September

1988.

The active ingredient, ceftriaxone, is classified as a synthetic third-generation, parenteral

aminothiazole-oxime-cephalosporin (cefotaxime – group) antibacterial agent (ATC code: J01DD04)

with a long half life and a broadened spectrum of antibacterial activity. It has bactericidal activity

resulting from the inhibition of bacterial cell wall synthesis ultimately leading to cell death.


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No new non-clinical studies were performed, 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 clinical data have been submitted and none are required for applications of this type. A

bioequivalence study was not necessary to support these applications for parenteral products and the

applicant submitted none. According to CPMP guidelines, bioequivalence studies are not generally

required for parenteral aqueous solutions (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**, Guideline on the

Investigation of Bioequivalence).

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 manufacturer

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 23 August 2017. After a subsequent national phase, Marketing Authorisations were

granted in the UK to ELC Group s.r.o. on 21 September 2017.

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 either a white to pale yellow powder for solution for injection (500 mg strength) or a

white to pale yellow powder for solution for injection/infusion (1g and 2 g strengths).

Each vial of the 500 mg strength product contains 596.4 mg of ceftriaxone sodium, equivalent to 500 mg

of ceftriaxone.

Each vial of the 1 g strength product contains 1.196 g of ceftriaxone sodium, equivalent to 1g of

ceftriaxone.

Each vial of the 2 g strength product contains 2.386 g of ceftriaxone sodium, equivalent to 2g of

ceftriaxone.

The products contain no excipients.

The 500 mg strength product is packed in 17 mL vials (colourless type III glass), each with a stopper

(chlorobutyl) and flip-off cap (aluminium), in boxes of 1, 5 and 10 vials.

The 1 g strength product is packed in 15/17 mL vials (colourless type III glass), each with a stopper

(chlorobutyl) and cap (aluminium), in boxes of 1, 5 and 10 vials.

The 2 g strength product is packed in 50 mL vials (colourless type II glass), each with a stopper

(chlorobutyl) and flip-off cap (aluminium), in boxes of 1, 5 and 10 vials.


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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

Ceftriaxone sodium

INN: Ceftriaxone sodium

Chemical name: Disodium -(6R,7R) -7 -[[(2Z)-(2-aminothiazol-4-yl) (methoxy-imino)

acetyl] amino]-3-[[(2-methyl- 6- oxido- 5- oxo-2,5 - dihydro-1,2,4 -

triazin-3-yl) sulphanyl] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-

ene-2-carboxylate 3.5 hydrate

Molecular formula: C18H16N8Na2O7S3, 3.5H2O (ceftriaxone disodium salt, hemiheptahydrate)

Structure:

Mr: 662

Appearance: Almost white or yellowish crystalline powder, slightly hygroscopic.

Solubility: Freely soluble in water (40 g soluble in 100 ml at 25°C), sparingly soluble

in methanol, very slightly soluble in ethanol.

Polymorphism Not considered relevant for injectable dosage forms.

Ceftriaxone sodium is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance, ceftriaxone sodium, are covered by

European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificates of Suitability.

II.3 MEDICINAL PRODUCT

Pharmaceutical Development

The objective of the development programme was to produce safe, efficacious, stable powders for

solution for injection or for injection/infusion that were equivalent to the reference products Rocephin

500mg, 1g and 2g Powder for solution for injection (Roche Products Limited, UK). Suitable

pharmaceutical development data have been provided for these applications.

Comparative impurity profiles have been provided for these products and the reference products

Rocephin 500mg, 1g and 2g Powder for solution for injection (Roche Products Limited, UK). The

impurity profiles were satisfactory.

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 specification have been provided.

Certificates of Analysis have been provided for all working standards used.


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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 3 years,

with the special storage conditions “Store below 30°C. Keep the vials in the original packaging in order

to protect from light.” has been accepted.

After reconstitution, from a microbiological point of view, the products should be used immediately.

Suitable post approval stability commitments have been provided to continue stability testing on batches

of finished product.

Bioequivalence/Bioavailability

II.4 A bioequivalence study was not necessary to support these applications for parenteral products,

since Ceftriaxone 500 mg, 1 g and 2 g, after reconstitution, are aqueous parenteral solutions containing

the same active substance in the same concentration as the respective reference products Rocephin

500mg, 1g and 2g (Roche Products Limited, UK).

II.5 Discussion on chemical, pharmaceutical and biological aspects

It is recommended that Marketing Authorisations are granted for Ceftriaxone, from a quality point of

view.

III NON-CLINICAL ASPECTS

III.1 Introduction

As the pharmacodynamic, pharmacokinetic and toxicological properties of ceftriaxone 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 generic versions of already authorised products, it is not expected that

environmental exposure of ceftriaxone will increase following approval of the Marketing Authorisations

for the proposed products.


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III.6 Discussion of the non-clinical aspects

No new non-clinical studies were conducted, which is acceptable given that the applications were based

on being generic medicinal products of reference products that have 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 ceftriaxone is well-known. No new clinical pharmacology data have been

submitted and none are required for applications of this type. A bioequivalence study was not necessary

to support these applications for parenteral products and the applicant submitted none. According to

CPMP guidelines, bioequivalence studies are not generally required for parenteral aqueous solutions

(CPMP/EWP/QWP/1401/98 Rev. 1/Corr**, Guideline on the Investigation of Bioequivalence).

All the relevant clinical information provided is literature based. The clinical overview has been written

by an appropriately qualified person and is a suitable summary of the clinical aspects of the dossier.

IV.2 Pharmacokinetics

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

applicant’s clinical overview. No new pharmacokinetic data were submitted and none are required for

applications of this type.

IV.3 Pharmacodynamics

The clinical pharmacodynamic properties of ceftriaxone 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 ceftriaxone 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 ceftriaxone is well known. No new safety data have been submitted with these

applications and none are required. No new or unexpected safety concerns arose from these applications.

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 Ceftriaxone.

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


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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 has been evaluated for Ceftriaxone Panpharma 500 mg Powder for Solution for

Injection (Parent PIL). 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 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) has been performed on the

basis of a bridging report making reference to the package leaflet for Ceftriaxone Panpharma 500 mg

Powder for Solution for Injection (Parent PIL). The bridging report submitted by the applicant has been

found acceptable.


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IV. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

The quality of the product is acceptable, and no new non-clinical safety concerns have been identified.

Extensive clinical experience with ceftriaxone in the proposed indications is considered to have

demonstrated the therapeutic value of the compound. The proposed products are considered

bioequivalent to the respective reference products.

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 leaflets is

available on the MHRA website. The current labelling is presented below:

Ceftriaxone 500 mg:

Ceftriaxone 500 mg powder for soln for inj, Ceftriaxone 1 g and 2 g powder for soln for inj/inf UK/H/6066/001-003/DC

14


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Ceftriaxone 1 mg:


17

Ceftriaxone 500 mg powder for soln for inj, Ceftriaxone 1 g and 2 g powder for soln for inj/inf

18

Ceftriaxone 500 mg powder for soln for inj, Ceftriaxone 1 g and 2 g powder for soln for inj/inf

19

Ceftriaxone 2 mg:


20


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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)

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