public assessment report ukpar - gov.uk · the package leaflet or contact their doctor or...

Public Assessment Report

UKPAR

LIOTHYRONINE SODIUM 20 MICROGRAMS TABLETS (liothyronine sodium)

UK Licence No: PL 20117/0270

Morningside Healthcare Limited

PAR Liothyronine Sodium 20 micrograms Tablets PL 20117/0270

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LAY SUMMARY Liothyronine Sodium 20 micrograms Tablets

(liothyronine sodium)

This is a summary of the Public Assessment Report (PAR) for Liothyronine Sodium 20 micrograms

Tablets (PL 20117/0270). It explains how Liothyronine Sodium 20 micrograms Tablets were assessed

and their authorisation recommended as well as their conditions of use. It is not intended to provide

practical advice on how to use Liothyronine Sodium 20 micrograms Tablets.

For practical information about using Liothyronine Sodium 20 micrograms Tablets, patients should read

the package leaflet or contact their doctor or pharmacist.

This medicinal product will be referred to as Liothyronine Sodium Tablets for the remainder of this

summary, for ease of reading.

What are Liothyronine Sodium Tablets and what are they used for?

Liothyronine Sodium Tablets are a ‘generic medicine’. This means that Liothyronine Sodium Tablets

are similar to a ‘reference medicine’ already authorised in the European Union (EU) called Liothyronine

Sodium BP 20 micrograms Tablets (also known as Tertroxin 20 microgram Tablets).

Liothyronine Sodium Tablets are used to treat some of the more severe conditions in which the thyroid

does not produce enough thyroxine. They are also used to balance the effect of medicines used to treat

an overactive thyroid.

How do Liothyronine Sodium Tablets work?

Liothyronine Sodium Tablets contain the active ingredient liothyronine sodium, which is a form of

thyroxine which is quick acting and long lasting. Thyroxine is a hormone produced by the thyroid gland

in the neck which controls many body functions.

How are Liothyronine Sodium Tablets taken?

This medicine is only available on prescription.

Liothyronine Sodium Tablets are taken by mouth. For a dose of 20 micrograms, the tablet should be

swallowed whole tablet with a glass of water.

For doses lower than 20 micrograms, the tablet should be crushed and allowed to dissolve in 20 ml of

water for 5 minutes, in the small measuring cup provided. The patient should stir the solution gently for

a few seconds and then, using the syringe provided, draw the amount of liquid corresponding to the dose

recommended (5 ml for a 5 microgram dose; 10 ml for a 10 microgram dose). The patient can squirt the

liquid directly into their mouth from the syringe by gently pressing the plunger.

The recommended dose in adults will depend upon the condition, ranging from 10 micrograms to 60

micrograms daily in divided doses.

For children below 12 years of age, the dose may be started at 5 micrograms a day.

For adolescents (children 12 -17 years of age), the dose is initially 10 - 20 micrograms daily; increased

to 60 micrograms daily in 2-3 divided doses.

For the elderly, the dose may be started at 5 micrograms a day.

A doctor will monitor the patient’s thyroid function regularly to make sure that they are given the right

dose for their condition.


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What benefits of Liothyronine Sodium Tablets have been shown in studies?

As Liothyronine Sodium Tablets are a generic medicine, studies in people have been limited to tests to

determine that it is bioequivalent to the reference medicine, Liothyronine Sodium BP 20 micrograms

Tablets (also known as Tertroxin 20 microgram Tablets). Two medicines are bioequivalent when they

produce the same levels of the active substance in the body.

What are the possible side effects of Liothyronine Sodium Tablets?

As Liothyronine Sodium Tablets are a generic medicine, their possible side effects are taken as being the

same as those of the reference medicine, Liothyronine Sodium BP 20 micrograms Tablets (also known

as Tertroxin 20 microgram Tablets).

For the full list of all side effects reported with Liothyronine Sodium Tablets, see section 4 of the

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

Why were Liothyronine Sodium Tablets approved?

It was concluded that, in accordance with EU requirements, Liothyronine Sodium Tablets have been

shown to have comparable quality and to be bioequivalent to Liothyronine Sodium BP 20 micrograms

Tablets. Therefore, the MHRA decided that, as for Liothyronine Sodium BP 20 micrograms Tablets

(also known as Tertroxin 20 microgram Tablets), the benefits outweigh the identified risks and

recommended that Liothyronine Sodium Tablets could be approved for use.

What measures are being taken to ensure the safe and effective use of Liothyronine Sodium

Tablets?

A risk management plan (RMP) has been developed to ensure that Liothyronine Sodium Tablets are

used as safely as possible. Based on this plan, safety information has been included in the Summary of

Product Characteristics (SmPC) and the package leaflet for this product 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 and reviewed continuously.

Other information about Liothyronine Sodium Tablets

A Marketing Authorisation was granted in the UK on 15 June 2017.

The full PAR for Liothyronine Sodium Tablets follows this summary. For more information about

treatment with Liothyronine Sodium Tablets, read the package leaflet, or contact your doctor or

pharmacist.

This summary was last updated in June 2017.


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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

I Introduction Page 5

II Quality aspects Page 6

III Non-clinical aspects Page 9

IV Clinical aspects Page 9

V User consultation Page 14

VI Overall conclusion, benefit-risk assessment and

recommendation

Page 14

Annex 1 Table of content of the PAR update

Page 15


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I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products

Regulatory Agency (MHRA) granted Morningside Healthcare Limited a Marketing Authorisation for

the medicinal product Liothyronine Sodium 20 micrograms Tablets (PL 20117/0270) on 15 June 2017.

This product is a prescription only medicine (legal classification POM).

This application was submitted according to Article 10(1) of Directive 2001/83/EC, as amended,

claiming to be a generic medicinal product of the reference product Liothyronine Sodium BP 20

micrograms Tablets (PL 10972/0033; also known as Tertroxin 20 microgram Tablets), which was

granted a licence to Mercury Pharma Group Limited, on 23 August 1993.

Liothyronine Sodium Tablets are indicated in adults and children for the treatment of coma of

myxedema, the management of severe chronic thyroid deficiency and hypothyroid states occurring in

the treatment of thyrotoxicosis.

Liothyronine sodium can be used also as an adjunct to carbimazole to prevent subclinical

hypothyroidism developing during carbimazole treatment of thyrotoxicosis.

Liothyronine sodium may be preferred for treating severe and acute hypothyroid states because of its

rapid and more potent effect, but thyroxine sodium is normally the drug of choice for routine

replacement therapy.

This product contains the active substance liothyronine sodium, which is a naturally occurring thyroid

hormone. The biological action of liothyronine sodium is quantitatively similar to that of Levothyroxine

sodium, but the effects develop in a few hours and disappear within 24 to 48 hours of stopping

treatment.

With the exception of the bioequivalence study, no new clinical or non-clinical studies were conducted,

which is acceptable given that the application was based on being a generic medicinal product of an

originator product that has been licensed for over 10 years.

A bioequivalence study was performed, which compared the pharmacokinetics of the test product

Liothyronine Sodium 20 micrograms Tablets to those of the reference product Liothyronine Sodium BP

20 micrograms Tablets (Tertroxin 20 microgram Tablets). The bioequivalence study was carried out in

accordance with Good Clinical Practice (GCP).

The MHRA has been assured that acceptable standards of Good Manufacturing Practice are in place for

this product type at all sites responsible for the manufacture, assembly and batch release of this product.

A summary of the pharmacovigilance system and a detailed Risk Management Plan (RMP) have been

provided with this application and these are satisfactory.

During assessment of these applications, advice was sought from the Expert Advisory Groups on the

adequacy of the pharmaceutical development and clinical equivalency. The application was presented to

the Expert Advisory Groups, including the Commission on Human Medicines (CHM). The advisory

groups considered the evidence and the arguments presented by the applicant, and advised the MHRA.

Further data were subsequently submitted by the applicant. These data were reviewed by the Expert

Advisory Groups and the CHM in January 2017. Upon provision of satisfactory responses to the

outstanding points following these meetings, the application was considered to have satisfied the

necessary requirements and therefore could be approved.


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II QUALITY ASPECTS

II.1 Introduction

Liothyronine Sodium 20 micrograms Tablets are white to off-white, circular, biconvex, uncoated tablets

that are plain on one side and embossed with ‘T3’ on the other side, with a 5.5 mm diameter. Each tablet

contains 20 micrograms of liothyronine sodium.

Other ingredients consist of the pharmaceutical excipients, namely lactose monohydrate, partially

pregelatinized maize starch, spray dried acacia, sodium chloride and magnesium stearate.

The finished product is packaged in aluminium foil blisters in a pack size of 7, 10, 14, 20, 28, 30, 56, 60,

84, 90 and 112 tablets. Not all pack sizes may be marketed.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging

components. All primary packaging complies with the current European regulations concerning

materials in contact with food.

II.2 Drug substance rINN: Liothyronine Sodium

Chemical name: 1. sodium (2S)-2-amino-3-[4-(4-hydroxy-3-iodophenoxy)-3,5-

2. diiodophenyl]propanoate

3. Triiodothyronine, sodium

Structural formula:

Molecular formula: C15H11I3NNaO4

Appearance: White or slightly coloured hygroscopic powder

Solubility: Practically insoluble in water, slightly soluble in alcohol. It dissolves in dilute

solutions of alkali hydroxides

Molecular weight: 673

All aspects of the manufacture of the active substance from its starting materials are controlled by a

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

II.3 Medicinal Product

Pharmaceutical Development

The objective of the development programme was to formulate a safe, efficacious and stable product

that could be considered a generic medicinal product of the reference product Liothyronine Sodium BP

20 micrograms Tablets (also known as Tertroxin 20 microgram Tablets).

A satisfactory account of the pharmaceutical development has been provided.

Comparative dissolution data have been presented for the test and reference products.

All of the excipients comply with their respective European Pharmacopoeia monographs.


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With the exception of lactose monohydrate, none of the excipients are sourced from animal or human

origin. The milk used in the production of lactose monohydrate is sourced from healthy animals under

the same conditions as for human consumption. No genetically modified organisms (GMO) have been

used in the preparation of this product.

Manufacturing Process

A satisfactory batch formula has been provided for the manufacture of the product, along with an

appropriate description of the manufacturing process. Suitable in-process controls are in place to ensure

the quality of the finished product. The manufacturing process has been validated using three

commercial-scale batches and has shown satisfactory results.

Finished Product Specification

The finished product specification proposed is acceptable. Test methods have been described that have

been adequately validated. Batch data have been provided which comply with the release specification.

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

Stability of the product

Stability studies were performed, in accordance with current guidelines, on batches of finished product

in the packaging proposed for marketing.

The results from these studies support a shelf-life of 2 years with the special storage conditions of “Do

not store above 30°C. Store in the original package to protect from light”.

II.4 Discussion on chemical, pharmaceutical and biological aspects

It is recommended that a Marketing Authorisation is granted for Liothyronine Sodium 20 micrograms

Tablets.

II.5 Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and

Labels

The SmPC, PIL and labels are satisfactory and, where appropriate, in line with current guidance.

In accordance with Directive 2010/84/EU, the current version of the SmPC and PIL are available on the

MHRA website.

The approved labels for Liothyronine Sodium 20 micrograms Tablets are shown below:


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III NON-CLINICAL ASPECTS

III.1 Introduction

The pharmacodynamic, pharmacokinetic and toxicological properties of the active substance

liothyronine sodium are well known. No new non-clinical data have been submitted for this application

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 product’s pharmacology and toxicology.

III.2 Pharmacology

No new pharmacology data are required for this application and none have been submitted.

III.3 Pharmacokinetics No new pharmacokinetic data are required for this application and none have been submitted.

III.4 Toxicology

No new toxicology data are required for this application and none have been submitted.

III.5 Ecotoxicity/Environmental risk Assessment (ERA)

As this product is intended for generic substitution of products that are already marketed, no increase in

environmental exposure to liothyronine sodium is anticipated. Thus the absence of an ERA is accepted.

III.6 Discussion of the non-clinical aspects


Tablets.

IV. CLINICAL ASPECTS

IV.1 Introduction

With the exception of the bioequivalence study detailed below, no new clinical studies have been

performed and none are required for this type of application. The applicant’s clinical overview has been

written by an appropriately qualified person and is considered acceptable.

IV.2 Pharmacokinetics

In support of this application, the applicant submitted the following bioequivalence study:

Study 1:

A randomised, open-label, 2-way cross-over bioequivalence study comparing the

pharmacokinetics of the test product, Liothyronine Sodium 20 micrograms Tablets, to those of the

reference product, Liothyronine Sodium BP 20 micrograms Tablets (also known as Tertroxin 20

microgram Tablets; Mercury Pharma Group Limited), following a 100 microgram dose

(administered as 5 x 20 microgram tablets) in healthy subjects, under fasting conditions.

Volunteers were given each treatment after a 10 hour fast. Blood samples were collected for the

measurement of pharmacokinetic parameters pre-dose and up to 72 hours post dose. Each treatment was

separated by an adequate washout period.

A summary of the main pharmacokinetic results is presented below:


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Summary of pharmacokinetic parameters for baseline corrected liothyronine for test and

reference treatment

Mean ± SD (CV%)

Parameter Test Reference

Cmax

(pg/mL) 7993.17 ± 1213.50 (15.18) 8444.31 ± 1400.54 (16.59)

AUC(0-t) (pg.h/mL) 76250.35 ± 13859.80 (18.18) 80190.30 ± 15898.36 (19.83)

AUC(0-∞) (pg.h/mL) 78357.77 ± 13574.44 (17.32) 83000.73 ± 15860.22 (19.11)

Tmax

(h) Median (range) 2.00 (1.25 - 3.00) 2.25 (1.50 - 3.00)

p-values for AUC0-t, AUC0-inf, and Cmax for baseline corrected liothyronine

Results for log-transformed test/reference ratios with 90% Confidence Intervals:

Parameter Log-transformed T/R ratio1

90% Confidence Interval

Cmax

(pg/mL) 94.84% 91.34 - 98.47%

AUC(0-t) (pg.h/mL) 95.23% 92.56 – 97.98%

AUC(0-∞) (pg.h/mL) 94.57% 91.75 – 97.47%

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Calculated using the geometric least squares means

Compared with the reference product, the 90 % confidence intervals for the test product are within the

bioequivalence acceptance limits of 80.00-125.00 % for Cmax and AUC. Liothyronine Sodium 20

micrograms Tablets can, therefore, be considered bioequivalent to Liothyronine Sodium BP 20

micrograms Tablets (also known as Tertroxin 20 microgram Tablets).

IV.3 Pharmacodynamics

No new pharmacodynamic data were submitted and none are required for applications of this type.

IV.4 Clinical efficacy

No new data on efficacy have been submitted and none are required for applications of this type.

IV.5 Clinical Safety

No new data on safety have been submitted and none are required for applications of this type.

IV.6 Risk Management Plan (RMP) and Pharmacovigilance System

The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides

adequate evidence that the applicant has the services of a qualified person responsible for

pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected

of occurring either in the Community or in a third country.

The MAH has submitted a RMP, 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 Liothyronine Sodium 20 micrograms Tablets.

A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, is

listed below:


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IV.7 Discussion of the clinical aspects


Tablets.

V. USER CONSULTATION The package leaflet has been evaluated in accordance with the requirements of Articles 59(3) and 61(1)

of Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and

organised, easy to understand and written in a comprehensive manner. The test shows that patients/users

are able to act upon the information that it contains.

VI OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT AND

RECOMMENDATION

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

identified. The data supplied support the claim that the applicant’s product and the reference product are

interchangeable. Extensive clinical experience with liothyronine sodium is considered to have

demonstrated the therapeutic value of the compound. The benefit-risk assessment is therefore considered

to be positive.


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Annex 1 Table of content of the PAR update

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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