Prednisolone 1mg gastro-resistant tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Prednisolone
Available from:
A A H Pharmaceuticals Ltd
ATC code:
H02AB06
INN (International Name):
Prednisolone
Dosage:
1mg
Pharmaceutical form:
Gastro-resistant tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF:

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Public Assessment Report

UK PAR

Deltacortril 1 mg Gastro-resistant Tablets

Prednisolone 1 mg Gastro-resistant Tablets

(Prednisolone)

UK Licence No: PL 16853/0137

Alliance Pharmaceuticals Limited

Deltacortril/Prednisolone 1 mg Gastro-resistant Tablets

PL 16853/0137

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LAY SUMMARY

Deltacortril 1 mg Gastro-resistant Tablets

Prednisolone 1mg Gastro-resistant Tablets

(Prednisolone)

This is a summary of the Public Assessment Report (PAR) for Deltacortril 1mg Gastro-resistant Tablets

/Prednisolone 1mg Gastro-resistant Tablets (PL 16853/0137). It explains how the application for

Deltacortril 1mg Gastro-resistant Tablets/Prednisolone 1mg Gastro-resistant Tablets was assessed and

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

advice on how to use Deltacortril 1mg Gastro-resistant Tablets/ Prednisolone 1mg Gastro-resistant

Tablets.

For practical information about using Deltacortril 1mg Gastro-resistant Tablets/ Prednisolone 1mg

Gastro-resistant Tablets, patients should read the package leaflet or contact their doctor or pharmacist.

The product may be referred to only as ‘Deltacortril 1 mg Gastro-resistant Tablets in this Report.

What are Deltacortril 1 mg Gastro-resistant Tablets and what are they used for?

Deltacortril 1 mg Gastro-resistant Tablets are used in a wide range of inflammatory and auto-immune

conditions including:

allergies, including severe allergic reactions

inflammation affecting the:

lungs, including asthma

blood vessels and heart

bowel or kidneys

muscles and joints, including rheumatoid arthritis

eye or nervous system

skin conditions

some infections

some cancers, including leukaemia, lymphoma and

myeloma

to prevent organ rejection after a transplant.

Deltacortril 1 mg Gastro-resistant Tablets are also used to:

boost steroid levels when the body is not making enough natural steroid on its own

treat high calcium levels.

How do Deltacortril 1 mg Gastro-resistant Tablets work?

Deltacortril 1 mg Gastro-resistant Tablets contain the active ingredient, prednisolone, which belongs to a

group of medicines called steroids. Their full name is corticosteroids. These corticosteroids occur

naturally in the body, and help to maintain health and well-being. Boosting the body with extra

corticosteroid (such as prednisolone) is an effective way to treat various illnesses involving

inflammation in the body. Prednisolone reduces this inflammation, which could otherwise go on making

your condition worse. To get maximum benefit from Deltacortril 1 mg Gastro-resistant Tablets, the

patient must take the tablets regularly.

How are Deltacortril 1 mg Gastro-resistant Tablets used?

Deltacortril 1 mg Gastro-resistant Tablets are taken by mouth.

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Deltacortril 1 mg Gastro-resistant Tablets should always be taken exactly as advised by the patient’s

doctor or pharmacist.

Depending on the patient’s illness, the daily dose of Deltacortril 1 mg Gastro-resistant Tablets may be

between 5 mg and 60 mg. In some cases, the patient may be instructed to take the tablets every other

day. The doctor will decide when and how to treat the patient with Deltacortril 1 mg Gastro-resistant

Tablets.

Once the patient’s condition starts to get better, the patient’s doctor may change the dosage to a lower

one. The doctor may also reduce the dosage before stopping treatment completely. This may depend on

the patient’s illness, dosage and how long the patient has been taking this medicine. In all cases the

patient should be careful to follow any changes.

Treatment of Children:

The use of steroids can slow down normal growth of children and adolescents. In order to lessen this

effect the tablets are often taken in a single dose every other day.

Treatment of the elderly:

When steroids are taken by elderly patients some of the unwanted side effects can be more serious

especially brittle bone disease, diabetes, high blood pressure, infections and thinning of the skin.

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

route of administration, and the duration of treatment.

Deltacortril 1 mg Gastro-resistant Tablets can only be obtained with a prescription.

What benefits of Deltacortril 1 mg Gastro-resistant Tablets have been shown in studies?

The Marketing Authorisation Holder (MAH; Alliance Pharmaceuticals Limited), provided its own data

on efficacy and safety studies. These studies have shown that Deltacortril 1 mg Gastro-resistant Tablets

is effective in the proposed indications.

In addition, the Marketing Authorisation Holder (Alliance Pharmaceuticals Limited) has provided data

from the published literature on prednisolone.

What are the possible side effects of Deltacortril 1 mg Gastro-resistant Tablets?

Like all medicines, Deltacortril 1 mg Gastro-resistant Tablets can cause side effects although not

everybody gets them.

For the full list of all side effects reported with Deltacortril 1 mg Gastro-resistant Tablets, see section 4

of the package leaflet.

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

Why is Deltacortril 1 mg Gastro-resistant Tablets approved?

It was concluded that, in accordance with EU requirements that, for Deltacortril 1 mg Gastro-resistant

Tablets, the benefits are greater than its risks and it was recommended that it be approved for use.

What measures are being taken to ensure the safe and effective use of Deltacortril 1 mg

Gastro-resistant Tablets?

A Risk Management Plan has been developed to ensure that Deltacortril 1 mg Gastro-resistant Tablets is

used as safely as possible. The relevant safety information has been included in the Summary of Product

Characteristics and the package leaflet for Deltacortril 1 mg Gastro-resistant Tablets, including the

appropriate precautions to be followed by healthcare professionals and patients.

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Known side effects are continuously monitored. Furthermore, new safety signals reported by

patients/healthcare professionals will be monitored / reviewed continuously.

Other information about Deltacortril 1 mg Gastro-resistant Tablets

A Marketing Authorisation was granted in the UK on 17 March 2016.

The full PAR for Deltacortril 1 mg Gastro-resistant Tablets follows this summary.

For more information about treatment with Deltacortril 1 mg Gastro-resistant 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

Introduction

Page 6

Quality aspects

Page 7

Non-clinical aspects

Page 9

Clinical aspects

Page 10

User consultation

Page 12

Overall conclusion, benefit/risk assessment and recommendation

Page 12

Steps taken after authorisation-summary

Page 20

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Scientific discussion

I

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the MHRA granted Alliance

Pharmaceuticals Limited a Marketing Authorisation for the medicinal product Deltacortril 1mg

Gastro-resistant Tablets/Prednisolone 1 mg Gastro-resistant Tablets (PL 16853/0137) on 17 March 2016.

The product is a Prescription Only Medicine (POM) indicated for the following:

Allergy and anaphylaxis:

bronchial asthma, drug hypersensitivity reactions, serum sickness,

angioneurotic oedema, anaphylaxis.

Arteritis/collagenosis:

giant cell arteritis/polymyalgia rheumatica, mixed connective tissue disease,

polyarteritis nodosa, polymyositis.

Blood disorders:

haemolytic anaemia (auto-immune), leukaemia (acute and chronic lymphocytic),

lymphoma, multiple myeloma, idiopathic thrombo-cytopenic purpura.

Cardiovascular disorders:

post-myocardial infarction syndrome, rheumatic fever with severe

carditis.

Endocrine disorders:

primary and secondary adrenal insufficiency, congenital adrenal hyperplasia.

Gastro-intestinal disorders:

Crohn’s disease, ulcerative colitis, persistent coeliac syndrome (coeliac

disease unresponsive to gluten withdrawal), auto-immune chronic active hepatitis, multisystem disease

affecting liver, biliary peritonitis.

Hypercalcaemia:

sarcoidosis, vitamin D excess.

Infections (with appropriate chemotherapy):

helminthic infestations, Herxheimer reaction,

infectious mononucleosis, miliary tuberculosis, mumps orchitis (adult), tuberculous meningitis,

rickettsial disease.

Muscular disorders:

polymyositis, dermatomyositis.

Neurological disorders:

infantile spasms, Shy-Drager syndrome, sub-acute demyelinating

polyneuropathy.

Ocular disease:

scleritis, posterior uveitis, retinal vasculitis, pseudo-tumours of the orbit, giant cell

arteritis, malignant ophthalmic Graves disease.

Renal disorders:

lupus nephritis, acute interstitial nephritis, minimal change glomerulonephritis.

Respiratory disease:

allergic pneumonitis, asthma, occupational asthma, pulmonary aspergillosis,

pulmonary fibrosis, pulmonary alveolitis, aspiration of foreign body, aspiration of stomach contents,

pulmonary sarcoid, drug induced lung disease, adult respiratory distress syndrome, spasmodic croup.

Rheumatic disorders:

rheumatoid arthritis, polymyalgia rheumatica, juvenile chronic arthritis,

systemic lupus erythematosus, dermatomyositis, mixed connective tissue disease.

Skin disorders:

pemphigus vulgaris, bullous pemphigoid, systemic lupus erythematosus, pyoderma

gangrenosum.

Miscellaneous:

sarcoidosis, hyperpyrexia, Behçets disease, immuno-suppression in organ

transplantation.

This national abridged application was submitted under Article 8(3) of Directive 2001/83/EC, as

amended, as a known active substance. The application is a line extension representing a new strength to

an existing Product Licence and refers to Deltacortril/Prednisolone 2.5 mg and 5 mg Gastro-resistant

Tablets (PL 16853/0092- 0093; Alliance Pharmaceuticals Limited), which were first authorised in the

UK on 27 April 1987 and 23 December 1976, respectively. The proposed indications for Deltacortril

1mg Gastro-resistant Tablets are the same as that for the existing products Deltacortril/Prednisolone 2.5

mg and 5 mg Gastro-resistant Tablets (PL 16853/0092- 0093; Alliance Pharmaceuticals Limited).

Deltacortril 1 mg Gastro-resistant Tablets contain the active substance, prednisolone, which is a

synthetic glucocorticoid that is used clinically for its anti-inflammatory and immune-suppressive

properties. It has low mineralocorticoid activity making the drug of choice for all conditions in which

routine systemic corticosteroid therapy is indicated.

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Prednisolone is the active metabolite of prednisone, with a predominant glucocorticoid and low

mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and

auto-immune conditions.

No new non-clinical studies were conducted, which is acceptable given that the product is a

line-extension of an approved product containing a well-known active substance.

Non new clinical studies were submitted or required for this application. A biowaiver was sought and

was accepted on clinical and quality grounds.

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 taking Deltacortril 1 mg Gastro-

resistant Tablets outweigh the risks.

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.

Deltacortril 1 mg Gastro-resistant Tablets are yellow, round biconvex gastro-resistant tablets.

Each gastro-resistant tablet contains 1 mg prednisolone, as the active substance. The product also

contain pharmaceutical excipients in the tablet core and coating , namely calcium carbonate, lactose

monohydrate, magnesium stearate, maize starch, polyvinyl alcohol, titanium dioxide (E171), talc,

lecithin (soya), simethicone emulsion, xanthan gum (E415), polyvinyl acetate phthalate, macrogol 4000,

sodium hydrogen carbonate, triethyl citrate, purified stearic acid, sodium alginate (E401), colloidal

anhydrous silica, methylcellulose (E461), sodium carboxymethylcellulose, yellow iron oxide (E172),

white beeswax (E901), carnauba wax (E903), polysorbate 20 (E432) and sorbic acid (E200).

Appropriate justification for the inclusion of each excipient has been provided.

The finished product is supplied in:

White high-density polyethylene (HPDE) bottles, each with a white polypropylene

child-resistant, tamper-evident screw cap, in a pack size of 100 tablets.

Aluminium/aluminium blisters packaged in cardboard cartons, in a pack size of 30 tablets.

Not all pack sizes may be marketed.

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

Prednisolone

INN:

Prednisolone

Chemical name:

11β,17α,21-trihydroxypregna-1,4-diene-3,20-dione

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Structure:

Molecular formula:

Molecular weight:

360.4

Appearance:

White or almost white crystalline, hygroscopic powder

Solubility

Very slightly soluble in water, soluble in ethanol (96 per cent) and in methanol,

sparingly soluble in acetone and slightly soluble in methylene chloride

Polymorphism

Prednisolone exhibits polymorphism.

Prednisolone is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance, prednisolone, are covered 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, stable,

gastro-resistant tablet containing 1 mg of prednisolone. The formulation development was based on the

formulations for the existing products Deltacortril/Prednisolone 2.5 mg and 5 mg Gastro-resistant

Tablets (PL 16853/0092-0093; Alliance Pharmaceuticals Limited). Suitable pharmaceutical

development data have been provided for this application.

Comparative

in-vitro

dissolution profiles have been provided for this product and the reference product,

Deltacortril 2.5 mg gastro-resistant tablets (Alliance Pharmaceuticals Limited). The dissolution profiles

were satisfactory.

With the exception of lecithin (soya), simethicone emulsion, polyvinyl acetate phthalate and yellow iron

oxide (E172), all the excipients comply with their respective European Pharmacopoeia monographs.

Lecithin (soya), simethicone emulsion polyvinyl acetate phthalate and yellow iron oxide (E172) are

controlled to their United States-National Formulary specifications. In addition, yellow iron oxide

(E172) is compliant with current EU Directive concerning the use of colouring agents. Satisfactory

Certificates of Analysis have been provided for all excipients.

With the exception of lactose monohydrate, none of the excipients contain materials of animal or human

origin. The supplier of lactose monohydrate has confirmed that the milk used in the production of

lactose monohydrate is sourced from healthy animals under the same conditions as that intended for

human consumption. In addition, the supplier has confirmed that no ruminant material other than calf

rennet is used during the production of lactose monohydrate.

No genetically modified organisms (GMO) have been used in the preparation of these excipients.

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Manufacturing Process

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

appropriate description of the manufacturing process. The manufacturing process has been validated

with production scale batches and has shown satisfactory results.

Control of Finished Product

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

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

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

Stability of the Product

Finished product stability studies were performed in accordance with current guidelines on batches of

finished product in the packaging proposed for marketing. Based on the results, a shelf-life of 24

months, with the special storage conditions ‘Do not store above 25°C. Store in the original container to

protect from moisture.’ has been accepted.

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

of finished product.

Bioequivalence/Bioavailability

The justification for a biowaiver was considered acceptable, and as a result bioequivalence studies were

not required.

II.4

Discussion on chemical, pharmaceutical and biological aspects

It is recommended that a Marketing Authorisation is granted for the application for Deltacortril 1 mg

Gastro-resistant Tablets, from a quality point of view.

III

NON-CLINICAL ASPECTS

III.1

Introduction

The pharmacodynamic, pharmacokinetic and toxicological properties of prednisolone 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 relevant non-clinical pharmacology, pharmacokinetics and toxicology.

III.2

Pharmacology

No new data have been submitted and none are required for an application of this type. Refer to Section

III.1, Introduction, above.

III.3

Pharmacokinetics

No new data have been submitted and none are required for an application of this type. Refer to Section

III.1, Introduction, above.

III.4

Toxicology

No new data have been submitted and none are required for an application of this type. Refer to Section

III.1, Introduction, above.

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III.5

Ecotoxicity/Environmental Risk Assessment (ERA)

In accordance with the

Guideline on the Environmental Risk Assessment of Medicinal Products for

Human use [EMEA/CHMP/SWP/4447/00 corr 2*]

, the Marketing Authorisation Holder submitted a

Phase I Environmental Risk Assessment. The Predicted Environmental Concentration (PEC) in surface

water was calculated as below the PEC action limit of 0.01 microgram/L. This result indicates that the

therapeutic use of Deltacortril 1 mg Gastro-resistant Tablets is unlikely to pose a risk to the environment

following prescribed usage.

III.6

Discussion of the non-clinical aspects

It is recommended that a Marketing Authorisation is granted for Deltacortril 1 mg Gastro-resistant

Tablets, from a non-clinical point of view.

IV.

CLINICAL ASPECTS

IV.1

Introduction.

The clinical pharmacology of prednisolone is well-known. No new clinical pharmacology data are

provided and none are required for this application.

A biowaiver has been applied for on quality and clinical grounds. This is acceptable.

IV.2

Pharmacokinetics

The pharmacokinetic profile of prednisolone is well known No new clinical pharmacokinetic data have

been submitted and none are required for an application of this type.

IV.3

Pharmacodynamics

The clinical pharmacodynamics properties of prednisolone are well-known. No new pharmacodynamic

data were submitted and none are required for an application of this type.

IV.4

Clinical Efficacy

The clinical efficacy of prednisolone is well-known. No new efficacy data are presented or are required

for this type of application.

IV.5

Clinical Safety

The safety profile of prednisolone is well-known and has been adequately summarised by the Applicant

in the clinical overview. No new safety data have been submitted with this application and none are

required. No new or unexpected safety concerns arose from this application.

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 Deltacortril 1 mg Gastro-resistant Tablets.

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

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Routine pharmacovigilance is proposed for all safety concerns.

No additional risk minimisation activities were required beyond those included in the product

information.

IV.7

Discussion of the clinical aspects

It is recommended that a Marketing Authorisation is granted for Deltacortril 1 mg Gastro-resistant

Tablets, from a clinical point of view.

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V.

USER CONSULTATION

A user consultation with target patient groups on the package information leaflet (PIL) has been

performed on the basis of a bridging report making reference to the PIL for Deltacortril 2.5 mg and 5 mg

Gastro-resistant Tablets (PL 16853/0092-0093). The bridging report submitted by the applicant has been

found acceptable.

VI.

OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

QUALITY

The important quality characteristics of Deltacortril 1 mg Gastro-resistant 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.

NON-CLINICAL

No new non-clinical data were submitted and none are required for an application of this type. As the

pharmacokinetics, pharmacodynamics and toxicology of prednisolone are well-known, no additional

data were required.

EFFICACY

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

biowaiver has been granted on quality and clinical grounds.

SAFETY

No new safety data have been submitted with this application and none are required. No new or

unexpected safety concerns arose from this application.

PRODUCT LITERATURE

The SmPCs, PILs and labelling are satisfactory and, where appropriate, in line with current guidance.

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

the MHRA website. The current labelling is presented below:

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Deltacortril 1 mg Gastro-resistant Tablets:

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Deltacortril/Prednisolone 1 mg Gastro-resistant Tablets

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Deltacortril/Prednisolone 1 mg Gastro-resistant Tablets

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Prednisolone 1 mg Gastro-resistant Tablets:

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Deltacortril/Prednisolone 1 mg Gastro-resistant Tablets

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BENEFIT/RISK ASSESSMENT

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

identified. Extensive clinical experience with prednisolone 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 a Marketing Authorisation is recommended.

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Deltacortril 1 mg Gastro-resistant Tablets/

Prednisolone 1 mg Gastro-resistant Tablets

(Prednisolone)

UK Licence No: PL 16853/0137

STEPS TAKEN AFTER AUTHORISATION-SUMMARY

Date submitted

Application

type

Scope

Outcome

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