Cozaar 12.5mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Losartan potassium
Available from:
CST Pharma Ltd
ATC code:
C09CA01
INN (International Name):
Losartan potassium
Dosage:
12.5mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: ; GTIN: 5055946803821

Patient Information Leaflet

Cozaar® 12.5mg film-coated tablets

(Losartan potassium)

Read all of this leaflet carefully before you start taking

this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor,

pharmacist, or nurse.

This medicine has been prescribed for you only. Do not

pass it on to others. It may harm them, even if their

signs of illness are the same as yours.

If you get any side effects, talk to your doctor,

pharmacist, or nurse. This includes any possible side

effects not listed in this leaflet. See section 4.

Your medicine is also available in the following strengths

25mg, 50mg and 100mg Tablets.

What is in this leaflet

1. What Cozaar is and what it is used for

2. What you need to know before you take Cozaar

3. How to take Cozaar

4. Possible side effects

5. How to store Cozaar

6. Contents of the pack and other information

1. What Cozaar is and what it is used for

Losartan (Cozaar) belongs to a group of medicines known

as angiotensin-II receptor antagonists. Angiotensin-II is a

substance produced in the body which binds to receptors in

blood vessels, causing them to tighten. This results in an

increase in blood pressure. Losartan prevents the binding

of angiotensin-II to these receptors, causing the blood

vessels to relax which in turn lowers the blood pressure.

Losartan slows the decrease of kidney function in patients

with high blood pressure and type 2 diabetes.

Cozaar is used

to treat patients with high blood pressure (hypertension)

in adults and in children and adolescents 6-18 years of

age.

to protect the kidney in hypertensive type 2 diabetic

patients with laboratory evidence of impaired renal

function and proteinuria ≥ 0.5 g per day (a condition in

which urine contains an abnormal amount of protein).

to treat patients with chronic heart failure when therapy

with specific medicines called

angiotensin-converting-enzyme inhibitors (ACE

inhibitors, medicine used to lower high blood pressure)

is not considered suitable by your doctor. If your heart

failure has been stabilised with an ACE inhibitor you

should not be switched to losartan.

in patients with high blood pressure and a thickening of

the left ventricle, Cozaar has been shown to decrease

the risk of stroke (“LIFE indication”).

2. What you need to know before you take Cozaar

Do not take Cozaar:

if you are allergic to losartan or to any of the other

ingredients of this medicine (listed in section 6),

if you are more than 3 months pregnant (It is also better

to avoid Cozaar in early pregnancy

see Pregnancy),

if your liver function is severely impaired,

if you have diabetes or impaired kidney function and

you are treated with a blood pressure lowering medicine

containing aliskiren.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before taking

Cozaar.

You must tell your doctor if you think you are (or might

become) pregnant.

Cozaar is not recommended in early pregnancy, and must

not be taken if you are more than 3 months pregnant, as it

may cause serious harm to your baby if used at that stage

(see pregnancy section).

It is important to tell your doctor before taking Cozaar:

if you have had a history of angioedema (swelling of the

face, lips, throat, and/or tongue) (see also section 4

‘Possible side effects’),

if you suffer from excessive vomiting or diarrhoea

leading to an extreme loss of fluid and/or salt in your

body,

if you receive diuretics (medicines that increase the

amount of water that you pass out through your

kidneys) or are under dietary salt restriction leading to

an extreme loss of fluid and salt in your body (see

section 3 ‘Dosage in special patient groups’),

if you are known to have narrowing or blockage of the

blood vessels leading to your kidneys or if you have

received a kidney transplant recently,

if your liver function is impaired (see sections 2 “Do not

take Cozaar” and 3 “Dosage in special patient

groups”),

if you suffer from heart failure with or without renal

impairment or concomitant severe life threatening

cardiac arrhythmias.

Special caution is necessary when you are treated with

a β

blocker concomitantly,

if you have problems with your heart valves or heart

muscle,

if you suffer from coronary heart disease (caused by a

reduced blood flow in the blood vessels of the heart) or

from cerebrovascular disease (caused by a reduced

blood circulation in the brain),

if you suffer from primary hyperaldosteronism

(a syndrome associated with increased secretion of the

hormone aldosterone by the adrenal gland, caused by

an abnormality within the gland),

if you are taking any of the following medicines used to

treat high blood pressure:

an ACE

inhibitor (for example enalapril, lisinopril,

ramipril), in particular if you have diabetes

related

kidney problems.

aliskiren

Your doctor may check your kidney function, blood

pressure, and the amount of electrolytes

(e.g. potassium) in your blood at regular intervals.

See also information under the heading “Do not take

Cozaar”.

if you are taking other medications that may increase

serum potassium (see section 2 “Other medicines and

Cozaar”).

Children and adolescents

Cozaar has been studied in children. For more information,

talk to your doctor.

Cozaar is not recommended for use in children suffering

from kidney or liver problems, as limited data are available

in these patient groups.

Cozaar is not recommended for use in children under

6 years old, as it has not been shown to work in this age

group.

Other medicines and Cozaar

Tell your doctor or pharmacist if you are taking, have

recently taken, or might take any other medicines.

Tell your doctor if you are taking potassium supplements,

potassium

containing salt substitutes, potassium

sparing

medicines such as certain diuretics (amiloride, triamteren,

spironolactone), or other medicines that may increase

serum potassium (e.g., heparin, trimethoprim

containing

medicines), as the combination with Cozaar is not

advisable.

Take particular care if you are taking the following

medicines while under treatment with Cozaar:

other blood pressure lowering medicines as they may

additionally reduce your blood pressure. Blood pressure

may also be lowered by one of the following drugs/

class of drugs: tricyclic antidepressants, antipsychotics,

baclofen, amifostine,

steroidal anti

inflammatory drugs such as

indomethacin, including Cox

inhibitors (medicines that

reduce inflammation, and can be used to help relieve

pain) as they may reduce the blood pressure lowering

effect of losartan.

Your doctor may need to change your dose and/or to take

other precautions:

If you are taking an ACE

inhibitor or aliskiren (see also

information under the headings “Do not take Cozaar” and

Warnings and precautions”).

If your kidney function is impaired, the concomitant use of

these medicines may lead to a worsening of the kidney

function.

Lithium containing medicines should not be taken in

combination with losartan without close supervision by your

doctor. Special precautionary measures (e.g. blood tests)

may be appropriate.

Cozaar with food and drink

Cozaar may be taken with or without food.

Pregnancy and breast

feeding

Pregnancy

You must tell your doctor if you think you are (or might

become) pregnant.

Your doctor will normally advise you to stop taking Cozaar

before you become pregnant or as soon as you know you

are pregnant and will advise you to take another medicine

instead of Cozaar. Cozaar is not recommended in early

pregnancy, and must not be taken when more than 3

months pregnant, as it may cause serious harm to your

baby if used after the third month of pregnancy.

Breast

feeding

Tell your doctor if you are breast

feeding or about to start

breast

feeding.

Cozaar is not recommended for mothers who are

breast

feeding, and your doctor may choose another

treatment for you if you wish to breast

feed, especially if

your baby is a new

born, or born prematurely.

Ask your doctor or pharmacist for advice before taking this

medicine.

Driving and using machines

No studies on the effects on the ability to drive and use

machines have been performed.

Cozaar is unlikely to affect your ability to drive or use

machines. However, as with many other medicines used to

treat high blood pressure, losartan may cause dizziness or

drowsiness in some people. If you experience dizziness or

drowsiness, you should consult your doctor before

attempting such activities.

Cozaar contains lactose

Cozaar contains lactose monohydrate. If you have been

told by your doctor that you have an intolerance to some

sugars, contact your doctor before taking this medicine.

3. How to take Cozaar

Always take this medicine exactly as your doctor or

pharmacist has told you. Check with your doctor or

pharmacist if you are not sure. Your doctor will decide on

the appropriate dose of Cozaar, depending on your

condition and whether you are taking other medicines. It is

important to continue taking Cozaar for as long as your

doctor prescribes it in order to maintain smooth control of

your blood pressure.

Adult patients with High Blood Pressure

Treatment usually starts with 50 mg losartan (one tablet

Cozaar 50 mg) once a day. The maximal blood pressure

lowering effect should be reached 3-6 weeks after

beginning treatment. In some patients the dose may later

be increased to 100 mg losartan (two tablets Cozaar 50 mg

or one tablet of Cozaar 100 mg) once daily.

If you have the impression that the effect of losartan is too

strong or too weak, please talk to your doctor or

pharmacist.

Use in children and adolescents

Children below 6 years of age

Cozaar is not recommended for use in children under

6 years old, as it has not been shown to work in this age

group.

Children aged 6-18 years old

The recommended starting dose in patients who weigh

between 20 and 50 kg is 0.7 mg of losartan per kg of body

weight administered once a day (up to 25 mg of Cozaar).

The doctor may increase the dose if blood pressure is not

controlled.

Other form(s) of this medicine may be more suitable for

children; ask your doctor or pharmacist.

L-02-1232-03

Adult patients with high blood pressure and Type 2

diabetes

Treatment usually starts with 50 mg losartan (one tablet

Cozaar 50 mg) once a day. The dose may later be

increased to 100 mg losartan (two tablets Cozaar 50 mg or

one tablet of Cozaar 100 mg) once daily depending on your

blood pressure response.

Losartan may be administered with other blood pressure

lowering medicines (e.g. diuretics, calcium channel

blockers, alpha- or beta-blockers, and centrally acting

agents) as well as with insulin and other commonly used

medicines that decrease the level of glucose in the blood

(e.g. sulfonylureas, glitazones and glucosidase inhibitors).

Adult patients with Heart Failure

Treatment usually starts with 12.5 mg losartan (one tablet

Cozaar 12.5 mg) once a day. Generally, the dose should

be increased weekly step-by-step (i.e., 12.5 mg daily during

the first week, 25 mg daily during the second week, 50 mg

daily during the third week, 100 mg daily during the fourth

week, 150 mg daily during the fifth week) up to the

maintenance dose as determined by your physician.

A maximum dose of 150 mg losartan (for example, three

tablets of Cozaar 50 mg or one tablet each of Cozaar

100 mg and Cozaar 50 mg) once daily may be used.

In the treatment of heart failure, losartan is usually

combined with a diuretic (medicine that increases the

amount of water that you pass out through your kidneys)

and/or digitalis (medicine that helps to make the heart

stronger and more efficient) and/or a beta-blocker.

Dosage in special patient groups

The doctor may advise a lower dose, especially when

starting treatment in certain patients such as those treated

with diuretics in high doses, in patients with liver

impairment, or in patients over the age of 75 years. The

use of losartan is not recommended in patients with severe

hepatic impairment (see section "Do not take Cozaar").

Administration

The tablets should be swallowed whole with a glass of

water. You should try to take your daily dose at about the

same time each day. It is important that you continue to

take Cozaar until your doctor tells you otherwise.

If you take more Cozaar than you should

If you accidentally take too many tablets, contact your

doctor immediately. Symptoms of overdose are low blood

pressure, increased heartbeat, possibly decreased

heartbeat.

If you forget to take Cozaar

If you accidentally miss a daily dose, just take the next

dose as normal. Do not take a double dose to make up for

a forgotten tablet. If you have any further questions on the

use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects,

although not everybody gets them.

If you experience the following, stop taking losartan tablets

and tell your doctor immediately or go to the casualty

department of your nearest hospital:

A severe allergic reaction (rash, itching, swelling of the

face, lips, mouth or throat that may cause difficulty in

swallowing or breathing).

This is a serious but rare side effect, which affects more

than 1 out of 10,000 patients but fewer than 1 out of 1,000

patients. You may need urgent medical attention or

hospitalisation.

The following side effects have been reported with Cozaar:

Common (may affect up to 1 in 10 people):

dizziness,

low blood pressure (especially after excessive loss of

water from the body within blood vessels e.g. in patients

with severe heart failure or under treatment with high

dose diuretics),

dose-related orthostatic effects such as lowering of

blood pressure appearing when rising from a lying or

sitting position,

debility,

fatigue,

too little sugar in the blood (hypoglycaemia),

too much potassium in the blood (hyperkalaemia),

changes in kidney function including kidney failure,

reduced number of red blood cells (anaemia),

increase in blood urea, serum creatinine and serum

potassium in patients with heart failure.

Uncommon (may affect up to 1 in 100 people):

somnolence,

headache,

sleep disorders,

feeling of increased heart rate (palpitations),

severe chest pain (angina pectoris),

shortness of breath (dyspnoea),

abdominal pain,

obstipation,

diarrhoea,

nausea,

vomiting,

hives (urticaria),

itching (pruritus),

rash,

localised swelling (oedema),

cough.

Rare (may affect up to 1 in 1,000 people):

hypersensitivity,

angioedema,

inflammation of blood vessels (vasculitis including

Henoch-Schönlein purpura),

numbness or tingling sensation (paraesthesia),

fainting (syncope),

very rapid and irregular heartbeat (atrial fibrillation),

brain attack (stroke),

inflammation of the liver (hepatitis),

elevated blood alanine aminotransferase (ALT) levels,

usually resolved upon discontinuation of treatment.

Not known (frequency cannot be estimated from the

available data):

reduced number of thrombocytes,

migraine,

liver function abnormalities,

muscle and joint pain,

flu-like symptoms,

back pain and urinary tract infection,

increased sensitivity to the sun (photosensitivity),

unexplained muscle pain with dark (tea-coloured) urine

(rhabdomyolysis),

impotence,

inflammation of the pancreas (pancreatitis),

low levels of sodium in the blood (hyponatraemia),

depression,

generally feeling unwell (malaise),

ringing, buzzing, roaring, or clicking in the ears

(tinnitus),

disturbed taste (dysgeusia).

Side effects in children are similar to those seen in adults.

Reporting of side effects

If you get any side effects, talk to your doctor or

pharmacist. This includes any possible side effects not

listed on this leaflet. You can also report side effects

directly via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard or search for MHRA Yellow

Card in the Google Play or Apple App Store. By reporting

side effects, you can help provide more information on the

safety of this medicine.

5. How to store Cozaar

Keep out of the sight and reach of children.

Do not use Cozaar after the expiry date which is stated on

the carton label. The expiry date refers to the last day of

that month.

Store in the original package in order to protect from light

and moisture. Do not open the blister pack until you are

ready to take the medicine.

If the tablets show any signs of deterioration or

discolouration, consult your pharmacist for advice.

If damaged please tell your doctor or pharmacist.

Medicines should not be disposed of via wastewater or

household waste. Ask your pharmacist how to dispose of

medicines no longer required. These measures will help to

protect the environment.

6. Contents of the pack and other information

Cozaar 12.5mg tablets are blue, oval shaped film-coated

tablets marked 11 on one side and plain on the other.

Each tablet contains 12.5mg of the active ingredient

losartan potassium.

Also contains microcrystalline cellulose (E460), lactose

monohydrate, pregelatinized maize starch, magnesium

stearate (E572), hyprolose (E463), hypromellose (E464).

Each Cozaar 12.5mg tablet contains

1.06mg (0.027 mEq) of potassium, carnauba wax (E903),

titanium dioxide (E171) and indigo carmine (E132)

aluminium lake.

Cozaar Tablets are available in blister packs of 28 tablets.

Manufactured by: Merck Sharp & Dohme BV, Waarderweg

39, 2031 BN Haarlem, The Netherlands or Merck Sharp &

Dohme Ltd., Shotton Lane, Cramlington, Northumberland,

NE23 3JU, United Kingdom. Procured from within the EU.

Product Licence holder: Quadrant Pharmaceuticals Ltd,

Lynstock House, Lynstock Way, Lostock, Bolton BL6 4SA.

Repackaged by Maxearn Limited. Unit 29, Oakhill Trading

Estate, Devonshire Road, Worsley, Manchester, M28 3PT.

Cozaar 12.5mg film-coated Tablets PL 20774/1232

Cozaar is a registered trademark of Merck Sharp & Dohme

Corp.

Date of preparation 4

October 2019

Blind or partially sighted?

Is this leaflet hard to see or read?

Contact Quadrant

Pharmaceuticals Ltd,

Tel: 01204 471 269

L-02-1232-03

POM

UKPAR Cozaar-Comp 100mg/12.5mg film-coated tablets

PL 00025/0473

1

COZAAR-COMP 100MG/12.5MG FILM-COATED TABLETS

(LOSARTAN POTASSIUM / HYDROCHLOROTHIAZIDE)

PL 00025/0473

UKPAR

TABLE OF CONTENTS

Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 19

Summary of Product Characteristics

Page 20

Product Information Leaflet

Page 30

Labelling

Page 34

UKPAR Cozaar-Comp 100mg/12.5mg film-coated tablets

PL 00025/0473

2

COZAAR-COMP 100MG/12.5MG FILM-COATED TABLETS

(LOSARTAN POTASSIUM / HYDROCHLOROTHIAZIDE)

PL 00025/0473

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Merck

Sharp & Dohme Limited a Marketing Authorisation (licence) for the medicinal

product Cozaar-Comp 100mg/12.5mg film-coated tablets (PL 00025/0473) on 17

October 2007. This is a prescription-only medicine (POM) used for the treatment of

high blood pressure and stroke.

Cozaar-Comp 100mg/12.5mg film-coated tablets contain two active ingredients,

losartan potassium and hydrochlorothiazide. Losartan belongs to a group of medicines

known as angiotensin-II receptor antagonists. Angiotensin II is a chemical occurring

in the body, which tightens your blood vessels making it harder for the blood to pass

through them and causing your blood pressure to increase. Losartan blocks this effect

of angiotensin II, causing the blood vessels to relax. Hydrochlorothiazide works by

making your kidneys pass more water and salt. The combined effect of losartan and

hydrochlorothiazide lowers high blood pressure.

No new or unexpected safety concerns arose from this application and it was therefore

judged that the benefits of taking Cozaar-Comp 100mg/12.5mg film-coated tablets

outweigh the risks, hence a Marketing Authorisation has been granted.

UKPAR Cozaar-Comp 100mg/12.5mg film-coated tablets

PL 00025/0473

3

COZAAR-COMP 100MG/12.5MG FILM-COATED TABLETS

(LOSARTAN POTASSIUM / HYDROCHLOROTHIAZIDE)

PL 00025/0473

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 9

Clinical assessment

Page 10

Overall conclusion and risk benefit assessment

Page 18

UKPAR Cozaar-Comp 100mg/12.5mg film-coated tablets

PL 00025/0473

4

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the UK granted Merck

Sharp & Dohme Limited a Marketing Authorisation for the medicinal product Cozaar-

Comp 100mg/12.5mg film-coated tablets (PL 00025/0473) on 17

October 2007. This

is a prescription-only medicine (POM) used for the treatment of high blood pressure

and stroke.

Cozaar-Comp 100mg/12.5mg film-coated tablets contain two active ingredients,

losartan potassium and hydrochlorothiazide. Losartan belongs to a group of medicines

known as angiotensin-II receptor antagonists and is approved as a single agent and in

combination with hydrochlorothiazide for treatment of hypertension.

Hydrochlorothiazide is a thiazide diuretic used for many years in treatment of

hypertension.

This is a national, abridged, application, submitted as a line extension for a fixed dose

combination product containing 100mg losartan potassium and 12.5mg

hydrochlorothiazide made under article 8.3(i)(a) of directive 2001/83/EC (as

amended). The application cross-refers to “Cozaar Comp” (50mg losartan

potassium/12.5mg hydrochlorothiazide; PL 00025/0338) which is also held by the

proposed MA holder. In addition to “Cozaar Comp” Merck, Sharp and Dohme Ltd.

also hold a Marketing Authorisation for “Fortzaar” (PL 00025/0374) which contains

100mg losartan/25mg hydrochlorothiazide.

The application was referred to the Commission for Human Medicines (CHM) in

March 2006 for consideration whether the safety, quality and efficacy of the product

was demonstrated. At that time, the Commission advised that a marketing

authorisation should not be approved.

The applicants’ response and further data were considered at the CHM meeting in

June 2007. Following consideration of the additional data, the Commission advised

the approval of the marketing authorisation.

UKPAR Cozaar-Comp 100mg/12.5mg film-coated tablets

PL 00025/0473

5

PHARMACEUTICAL ASSESSMENT

ACTIVE SUBSTANCE

Losartan potassium

Nomenclature:

INN:

Losartan potassium

Chemical name:

2-Butyl-4-chloro-1-[[2’-(1H-tetrazol-5-yl)[1,1’-biphenyl]-4-

yl]methyl]-1H-imidazole-5-methanol, monopotassium salt

Structure:

Molecular formula:

ClKN

Molecular weight:

461.0

CAS No:

124750-99-8

Physical form:

White to off-white free flowing crystalline powder

Solubility:

Freely soluble in water

Synthesis of the drug substance from the designated starting material has been

adequately described and appropriate in-process controls and intermediate

specifications are applied. Satisfactory specifications are in place for all starting

materials and reagents and these are supported by relevant certificates of analysis.

An appropriate active substance specification has been provided based on USP and Ph

Eur. monographs.

Analytical methods have been appropriately validated and are satisfactory for

ensuring compliance with the relevant specifications.

Active losartan potassium is stored in appropriate packaging under ambient conditions

of temperature and humidity. It is packed in double polyethylene bags. Specifications

and certificates of analysis have been provided. The polyethylene bags in direct

contact with the drug substance satisfy Directive 2002/72/EC (as amended), and are

suitable for contact with foodstuffs.

Batch analysis data are provided and comply with the proposed specification.

Satisfactory certificates of analysis have been provided for standards used by the

active substance manufacturer during validation studies.

Appropriate stability data have been generated for drug substance stored in the same

immediate packaging as the commercial packaging. This data demonstrate the

stability of the drug substance and supports a retest period of 4 years when stored in

the proposed packaging.

UKPAR Cozaar-Comp 100mg/12.5mg film-coated tablets

PL 00025/0473

6

ACTIVE SUBSTANCE

Hydrochlorothiazide

Nomenclature:

INN:

Hydrochlorothiazide

Chemical name:

6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-

sulfonamide-1,1-dioxide

Structure:

Molecular formula:

Molecular weight:

297.7

CAS No:

58-93-5

Physical form:

White to off-white odourless crystalline powder

Solubility:

Very slightly soluble in water, soluble in aqueous solutions of

inorganic bases, e.g. sodium hydroxide / ammonium hydroxide,

and in organic bases like n-butylamine

Synthesis of the drug substance from the designated starting material has been

adequately described and appropriate in-process controls and intermediate

specifications are applied. Satisfactory specifications are in place for all starting

materials and reagents and these are supported by relevant certificates of analysis.

An appropriate active substance specification has been provided based on USP and

European Pharmacopeia requirements.

Analytical methods have been appropriately validated and are satisfactory for

ensuring compliance with the relevant specifications.

Active hydrochlorothiazide is stored in appropriate packaging for long-term storage. It

is packed in double polyethylene liners. Specifications and certificates of analysis

have been provided. The polyethylene bags in direct contact with the drug substance

satisfy Directive 2002/72/EC (as amended), and are suitable for contact with

foodstuffs.

Batch analysis data are provided and comply with the proposed specification.

Satisfactory certificates of analysis have been provided for standards used by the

active substance manufacturer during validation studies.

Appropriate stability data have been generated for active substance stored in similar

immediate packaging to the commercial packaging. This data demonstrate the

stability of the drug substance and supports a retest period of 5 years when stored in

the proposed packaging.

UKPAR Cozaar-Comp 100mg/12.5mg film-coated tablets

PL 00025/0473

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DRUG PRODUCT

Other ingredients

Other ingredients consist of pharmaceutical excipients, namely

hydroxypropylcellulose (E463), hypromellose (E464), lactose monohydrate,

magnesium stearate (E572), microcrystalline cellulose (E460), pregelatinised maize

starch, titanium dioxide (E171), and carnauba wax. Appropriate justification for the

inclusion of each excipient has been provided.

The excipients used comply with their respective European Pharmacopoeia

monographs. Satisfactory certificates of analysis have been provided for all

excipients.

Magnesium stearate is of vegetable origin. The applicant has confirmed that lactose is

derived from healthy animals and is collected under the same conditions as milk for

human consumption. The lactose is not prepared using other ruminant materials.

There were no novel excipients used and no overages.

Pharmaceutical development

Details of the pharmaceutical development of the drug product have been supplied

and are satisfactory.

Manufacture

A description and flow-chart of the manufacturing method has been provided.

In-process controls have been provided and are appropriate considering the nature of

the product and the method of manufacture. Process validation has been carried out on

validation batches. The results are satisfactory.

Finished product specification

The finished product specification is satisfactory. Acceptance limits have been

justified with respect to conventional pharmaceutical requirements and, where

appropriate, safety. Test methods have been described and have been adequately

validated, as appropriate. Batch data have been provided and comply with the release

specification. Certificates of analysis have been provided for any standards used.

Container Closure System

The tablets are packed in white, opaque PVC (polyvinylchloride) / PE (polyethylene)

/PVDC (polyvinylidene chloride) blisters with aluminium foil lidding. The calendar

blister strips are packaged with the PIL into cardboard boxes. The product is packaged

in a pack size of 28 tablets. In-house specifications, and certificates of analysis, for all

packaging types and components used have been provided. These are satisfactory.

All primary product packaging complies with EU legislation, Directive 2002/72/EC

(as amended), and is suitable for contact with food.

Stability

Finished product stability studies have been conducted in accordance with current

guidelines and results were within the proposed specification limits. Based on the

results, a shelf-life of 36 months has been set, which is satisfactory. Storage

conditions are “Do not store above 30°C”, “Store in the original packaging”.

UKPAR Cozaar-Comp 100mg/12.5mg film-coated tablets

PL 00025/0473

8

Efficacy Studies

The applicant provided results from a bioequivalence study where the proposed

combination product was compared against co-administration of corresponding

monotherapies. In the course of assessment, the applicant provided a further efficacy

study (P264) using a formulation representative of that intended for marketing. The

formulation intended for marketing is justified considering the evidence of efficacy

provided and supporting quality data.

Clinical efficacy study P264:

Composition - The composition of each of the formulations used in the study has been

provided. The composition of Losartan Potassium Tablets 100 mg is identical to that

of the UK market product (Cozaar 100mg film-coated tablets), except that carnauba

wax is omitted. The composition of Losartan Potassium-Hctz Tablets 100-12.5 mg is

identical to that of the proposed market product.

Manufacturing sites - The proposed market product is manufactured by the same

manufacturers as the Losartan Potassium-Hctz Tablets 100-12.5 mg used in the

efficacy study.

Finished product specifications - Specifications are generally identical for the

Losartan potassium tablets-Hctz 100-12.5 mg and Losartan potassium tablets 100mg

used in the efficacy study, and for the products intended to market.

Dissolution profiles - The dissolution profile of Losartan Potassium tablets-Hctz 100-

12.5 mg used in the efficacy study versus the product intended for marketing is

comparable.

Expert report

A detailed quality overall summary has been provided, which has been prepared by an

appropriately qualified expert.

Conclusion

The grounds for this application are considered adequate. It is recommended that a

Marketing Authorisation is granted for this application.

UKPAR Cozaar-Comp 100mg/12.5mg film-coated tablets

PL 00025/0473

9

PRECLINICAL ASSESSMENT

This is a national, abridged, application, submitted as a line extension for a fixed dose

combination product containing 100mg losartan potassium and 12.5mg

hydrochlorothiazide made under article 8.3(i)(a) of directive 2001/83/EC (as amended).

No new preclinical data have been supplied with this application and none are

required for an application of this type. A preclinical expert report has been written by

a suitably qualified person and is satisfactory.

UKPAR Cozaar-Comp 100mg/12.5mg film-coated tablets

PL 00025/0473

10

CLINICAL ASSESSMENT

INTRODUCTION

This is a national, abridged, application, submitted as a line extension (new

combination of strengths of known active ingredients) for Cozaar compound. Two

other strengths for the same combination of actives (losartan and

hydrochlorothiazide), 50/12.5 and 100/25 mg have already been approved since 1996.

The applicant (MSD) claims this strength (100/12.5) on the basis of clinical use,

posology approved based on LIFE study data and the currently approved SmPCs.

As the applicant claims the legal basis of the application to be a line extension, most

data submitted in the dossier were bibliographic, except for the clinical efficacy

studies.

CLINICAL BACKGROUND

The applicant argues that addition of low dose diuretic (hydrochlorothiazide) to a

renin-angiotensin blocker such as losartan provides additional antihypertensive

efficacy over that provided by monotherapy with either agent. The availability of the

intermediate strength of 100/12.5 mg combination (to those already approved (50/12.5

and 100/25mg) achieves or offers greater flexibility for titration to physicians who

prefer to use the lower dose of hydrochlorothiazide (12.5mg). The applicant also

argues that there is wealth of evidence supporting the use of 100/12.5 mg combination

and that this new combination will permit a step wise titration from 100mg losartan in

those who show inadequate response.

INDICATIONS

For the treatment of hypertension in patients whose blood pressure is not adequately

controlled on hydrochlorothiazide or losartan monotherapy.

In hypertensive patients with left ventricular hypertrophy a reduced risk of stroke was

demonstrated with losartan administered usually in combination with

Hctz

. The data

do not support the use of losartan for this indication in black patients (LIFE study).

Assessor’s Comment: These indications are identical to the currently authorised

strengths and are acceptable.

The first is a non-responder indication and would need data in those not

responding to monotherapy with losartan 100mg or hydrochlorothiazide 12.5mg as

per the CHMP guidance note hypertension (CHMP/EWP/238/95 Rev.2) “two add on

studies one in non-responders to X and one with non-responders to Y should be

carried out”.

In this context, the 100+25mg combination has already been authorised and

therefore it seems established that addition of 100mg losartan to those not responding

to 25mg of hydrochlorothiazide is beneficial. It would not be unreasonable to infer

that addition of 100mg to those not responding to 12.5mg would also derive a

clinically meaningful benefit. The question is whether addition of 12.5mg

hydrochlorothiazide to those non-responding to 100mg losartan monotherapy

produces a clinically meaningful benefit.

The second indication is supported by the LIFE study. The approved SmPCs

(50/12.5 & 100/25 strengths) suggest a place for the 100/12.5mg strength that was

accepted at the time of authorisation of these, based on data from the LIFE study.

This fact permits a conclusion that data were supportive of the use of 100/12.5mg in

this indication and therefore no new studies are required.

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