Marketing Authorisation Holder Invented name Strength Pharmaceutical Form

Transcription

1 ANNEX I LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTE OF ADMINISTRATION, MARKETING AUTHORISATION HOLDERS IN THE MEMBER STATES 1

2 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Austria Merck Sharp & Dohme GmbH Donau-City-Straße Wien Austria Austria Merck Sharp & Dohme GmbH Donau-City-Straße Wien Austria Austria Merck Sharp & Dohme GmbH Donau-City-Straße Wien Austria Belgium Merck Sharp & Dohme BV - Chaussée de Waterloo 1135 B-1180 Brussels Belgium Belgium Merck Sharp & Dohme BV - Chaussée de Waterloo 1135 B-1180 Brussels Belgium Belgium Merck Sharp & Dohme BV - Chaussée de Waterloo 1135 B-1180 Brussels Belgium Belgium Merck Sharp & Dohme BV - Chaussée de Waterloo 1135 B-1180 Brussels Belgium Cosaar 12,5 mg - Filmtabletten 12.5 mg Film-coated tablet Oral use Cosaar 50 mg - Filmtabletten 50 mg Film-coated tablet Oral use Cosaar 100 mg - Filmtabletten 100 mg Film-coated tablet Oral use COZAAR 100 mg 100 mg Film-coated tablet Oral use COZAAR 50 MG 50 mg Film-coated tablet Oral use COZAAR 12,5 mg 12.5 mg Film-coated tablet Oral use COZAAR CARDIO START 21 x 12.5 mg + 14 x 50 mg Film-coated tablet Oral use 2

3 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Belgium Belgium Belgium Belgium Bulgaria Cyprus Cyprus Therabel Pharma S.A. Rue Egide Van Ophem 108 B-1180 Brussels Belgium Therabel Pharma S.A. Rue Egide Van Ophem 108 B-1180 Brussels Belgium Therabel Pharma S.A. Rue Egide Van Ophem 108 B-1180 Brussels Belgium Therabel Pharma S.A. Rue Egide Van Ophem 108 B-1180 Brussels Belgium Merck Sharp & Dohme Bulgaria EOOD 55 Nikola Vaptzarov blvd. EXPO 2000, east wing, sections B1 & B2, 1st fl Sofia Bulgaria Merck Sharp & Dohme BV, Postbus 581, 2003 PC, Haarlem The Netherlands Merck Sharp & Dohme BV, Postbus 581, 2003 PC, Haarlem The Netherlands LOORTAN 100 mg 100 mg Film-coated tablet Oral use LOORTAN 50 mg 50 mg Film-coated tablet Oral use LOORTAN 12,5 mg 12.5 mg Film-coated tablet Oral use LOORTAN CARDIO START 21 x 12.5 mg + 14 x 50 mg Film-coated tablet Oral use Cozaar 50 mg Film-coated tablet Oral use COZAAR 50 mg Film-coated tablet Oral use COZAAR 100 mg Film-coated tablet Oral use 3

4 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Denmark Denmark Denmark Denmark Estonia Estonia Estonia Finland Merck Sharp & Dohme BV, Postbus 581, 2003 PC, Haarlem The Netherlands Merck Sharp & Dohme BV, Postbus 581, 2003 PC, Haarlem The Netherlands Merck Sharp & Dohme BV, Postbus 581, 2003 PC, Haarlem The Netherlands Merck Sharp & Dohme BV, Postbus 581, 2003 PC, Haarlem The Netherlands Merck Sharp & Dohme OÜ Peterburi tee Tallinn Estonia Merck Sharp & Dohme OÜ Peterburi tee Tallinn Estonia Merck Sharp & Dohme OÜ Peterburi tee Tallinn Estonia Merck Sharp & Dohme B.V. Waarderweg 39 P.O.Box PC HAARLEM the Netherlands Cozaar 12.5 mg Film-coated tablet Oral use Cozaar 50 mg Filmcoated tablet Oral use Cozaar 100 mg Filmcoated tablet Oral use Cozaar Startpakke 12.5 mg + 50 mg Filmcoated tablet Oral use Cozaar 100 mg Film-coated tablet Oral use Cozaar 50 mg Film-coated tablet Oral use Cozaar 12,5 mg 12.5 mg Film-coated tablet Oral use Cozaar 12.5 mg Film-coated tablet Oral use 4

5 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Finland Finland Finland France France Germany Germany Merck Sharp & Dohme B.V. Waarderweg 39 P.O.Box PC HAARLEM the Netherlands Merck Sharp & Dohme B.V. Waarderweg 39 P.O.Box PC HAARLEM the Netherlands Merck Sharp & Dohme B.V. Waarderweg 39 P.O.Box PC HAARLEM the Netherlands Merck Sharp Dohme Chibret 3 av. Hoche Paris Cedex 08 France Merck Sharp Dohme Chibret 3 av. Hoche Paris Cedex 08 France MSD Chibropharm GmbH Postfach 1202 D Haar Germany MSD Chibropharm GmbH Postfach 1202 D Haar Germany Cozaar 12.5 mg + 50 mg Film-coated tablet Oral use Cozaar 50 mg Film-coated tablet Oral use Cozaar 100 mg Film-coated tablet Oral use Cozaar 100 mg film-coated tablets Cozaar 50 mg scored coated tablets CARDOPAL START 12,5 mg Filmtabletten LORZAAR 100 mg Filmtabletten 100 mg Film-coated tablet Oral use 50 mg Scored coated tablet Oral use 12.5 mg Film-coated tablet Oral use 100 mg Film-coated tablet Oral use 5

6 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Germany Germany Germany Germany Germany Germany Germany Greece Greece Greece MSD Chibropharm GmbH Postfach 1202 D Haar Germany MSD Chibropharm GmbH Postfach 1202 D Haar Germany MSD Chibropharm GmbH Postfach 1202 D Haar Germany MSD Chibropharm GmbH Postfach 1202 D Haar Germany MSD Chibropharm GmbH Postfach 1202 D Haar Germany MSD Chibropharm GmbH Postfach 1202 D Haar Germany VARIPHARM ARZNEIMITTEL GmbH Lindenplatz , Haar, Germany VIANEX A.E. Tatoiou Street, Nea Erythraia Greece VIANEX A.E. Tatoiou Street, Nea Erythraia Greece VIANEX A.E. Tatoiou Street, Nea Erythraia Greece LORZAAR 50 mg Filmtabletten 50 mg Film-coated tablet Oral use LORZAAR PROTECT 100 mg Filmtabletten LORZAAR PROTECT 50 mg Filmtabletten LORZAAR START 12,5 mg Filmtabletten 100 mg Film-coated tablet Oral use 50 mg Film-coated tablet Oral use 12.5 mg Film-coated tablet Oral use PINZAAR 100 mg Filmtabletten 100 mg Film-coated tablet Oral use PINZAAR 50 mg Filmtabletten 50 mg Film-coated tablet Oral use LORZAAR VARIPHARMSTART 12,5 mg Filmtabletten 12.5 mg Film-coated tablet Oral use COZAAR 12.5 mg Film-coated tablet Oral use COZAAR 50 mg Film-coated tablet Oral use COZAAR 100 mg Film-coated tablet Oral use 6

7 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Hungary Hungary Hungary Iceland Iceland Iceland Ireland Merck Sharp & Dohme Hungary Ltd 50, Alkotas str. H-1123 Budapest Hungary Merck Sharp & Dohme Hungary Ltd 50, Alkotas str. H-1123 Budapest Hungary Merck Sharp & Dohme Hungary Ltd 50, Alkotas str. H-1123 Budapest Hungary Merck Sharp & Dohme PO Box PC Haarlem The Netherlands Merck Sharp & Dohme PO Box PC Haarlem The Netherlands Merck Sharp & Dohme PO Box PC Haarlem The Netherlands Merck Sharp & Dohme Limited Hertford Road, Hoddesdon, Herts EN11 9BU United Kingdom Cozaar 12.5 mg Film-coated tablet Oral use Cozaar 50 mg Film-coated tablet Oral use Cozaar 100 mg Film-coated tablet Oral use Cozaar 12.5 mg Film-coated tablet Oral use Cozaar 50 mg Film-coated tablet Oral use Cozaar 100 mg Film-coated tablet Oral use COZAAR 50 mg Film-coated Tablets 50 mg Film-coated tablet Oral use 7

8 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Ireland Ireland Italy Italy Italy Italy Italy Italy Italy Merck Sharp & Dohme Limited Hertford Road, Hoddesdon, Herts EN11 9BU United Kingdom Merck Sharp & Dohme Limited Hertford Road, Hoddesdon, Herts EN11 9BU United Kingdom Merck Sharp & Dohme (Italia) S.p.A. Via G. Fabbroni 6, Rome, Italy Merck Sharp & Dohme (Italia) S.p.A. Via G. Fabbroni 6, Rome, Italy Merck Sharp & Dohme (Italia) S.p.A. Via G. Fabbroni 6, Rome, Italy Neopharmed SpA Via G. Fabbroni 6, Rome, Italy Neopharmed SpA Via G. Fabbroni 6, Rome, Italy Neopharmed SpA Via G. Fabbroni 6, Rome, Italy Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.- Viale Shakespeare 47, Rome Italy COZAAR 100 mg Film-coated Tablets COZAAR 12.5mg Film-coated Tablets LORTAAN 50 mg compresse rivestite con film LORTAAN 12,5 mg compresse rivestite con film LORTAAN 100 mg compresse rivestite con film NEO-LOTAN 50 mg compresse rivestite con film NEO-LOTAN 12,5 mg compresse rivestite con film NEO-LOTAN 100 mg compresse rivestite con film LOSAPREX 50 mg compresse rivestite con film 100 mg Film-coated tablet Oral use 12.5mg Film-coated tablet Oral use 50 mg Film-coated tablet Oral use 12.5 mg Film-coated tablet Oral use 100 mg Film-coated tablet Oral use 50 mg Film-coated tablet Oral use 12.5 mg Film-coated tablet Oral use 100 mg Film-coated tablet Oral use 50 mg Film-coated tablet Oral use 8

9 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Italy Italy Latvia Lithuania Lithuania Lithuania Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.- Viale Shakespeare 47, Rome Italy Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.- Viale Shakespeare 47, Rome Italy SIA Merck Sharp & Dohme Latvia, Latvija; Skanstes street 13, LV-1013, Riga Latvia SIA Merck Sharp & Dohme Latvia, Latvija; Skanstes street 13, LV-1013, Riga Latvia UAB Merck Sharp & Dohme, Geležinio Vilko 18A, LT Vilnius Lithuania UAB Merck Sharp & Dohme, Geležinio Vilko 18A, LT Vilnius Lithuania UAB Merck Sharp & Dohme, Geležinio Vilko 18A, LT Vilnius Lithuania LOSAPREX 12,5 mg compresse rivestite con film LOSAPREX 100 mg compresse rivestite con film Cozaar 50 mg film-coated tablets Cozaar 100 mg film-coated tablets Cozaar (Losartan) Cozaar (Losartan) Cozaar (Losartan) 12.5 mg Film-coated tablet Oral use 100 mg Film-coated tablet Oral use 50 mg Film-coated tablet Oral use 100 mg Film-coated tablet Oral use 12.5 mg Film-coated tablet oral use 50 mg Film-coated tablet oral use 100 mg Film-coated tablet oral use 9

10 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Luxembourg Merck Sharp & Dohme BV - Chaussée de Waterloo 1135 B-1180 Brussels Belgium Luxembourg Merck Sharp & Dohme BV - Chaussée de Waterloo 1135 B-1180 Brussels Belgium Luxembourg Merck Sharp & Dohme BV - Chaussée de Waterloo 1135 B-1180 Brussels Belgium Luxembourg Merck Sharp & Dohme BV - Chaussée de Waterloo 1135 B-1180 Brussels Belgium Luxembourg Therabel Pharma S.A. - Rue Egide Van Ophem 108 B-1180 Brussels Belgium Luxembourg Therabel Pharma S.A. - Rue Egide Van Ophem 108 B-1180 Brussels Belgium Luxembourg Therabel Pharma S.A. - Rue Egide Van Ophem 108 B-1180 Brussels Belgium COZAAR 100 mg 100 mg Film-coated tablet Oral use COZAAR 50 MG 50 mg Film-coated tablet Oral use COZAAR 12,5 mg 12.5 mg Film-coated tablet Oral use COZAAR CARDIO START 21 x 12.5 mg + 14 x 50 mg Film-coated tablet Oral use LOORTAN 100 mg 100 mg Film-coated tablet Oral use LOORTAN 50 mg 50 mg Film-coated tablet Oral use LOORTAN 12,50 mg 12.5mg Film-coated tablet Oral use 10

11 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Luxembourg Therabel Pharma S.A. - Rue Egide Van Ophem 108 B-1180 Brussels Belgium Malta Merck Sharp & Dohme Ltd., Hertford Road, Hoddesdon, Hertfordshire EN11 9BU United Kingdom Malta Merck Sharp & Dohme Ltd., Hertford Road, Hoddesdon, Hertfordshire EN11 9BU United Kingdom The Netherlands The Netherlands Norway Norway Merck Sharp & Dohme PO Box PC Haarlem The Netherlands Merck Sharp & Dohme PO Box PC Haarlem The Netherlands Merck Sharp & Dohme PO Box PC Haarlem The Netherlands Merck Sharp & Dohme PO Box PC Haarlem The Netherlands LOORTAN CARDIO START 21 x 12.5 mg + 14 x 50 mg Film-coated tablet Oral use "Cozaar 100 mg" pilloli miksija b rita "Cozaar 50 mg" pilloli miksija b rita 100mg Film-coated tablet Oral use 50mg Film-coated tablet Oral use Cozaar mg Film-coated tablet Oral use Cozaar mg Film-coated tablet Oral use Cozaar 12.5 mg Film-coated tablet Oral use Cozaar 50 mg Film-coated tablet Oral use 11

12 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Norway Poland Poland Poland Portugal Portugal Merck Sharp & Dohme PO Box PC Haarlem The Netherlands MSD Polska Sp. z o.o. Chłodna Warsaw Poland MSD Polska Sp. z o.o. Chłodna Warsaw Poland MSD Polska Sp. z o.o. Chłodna Warsaw Poland Merck Sharp & Dohme, Lda. Quinta da Fonte - Edifício Vasco da Gama, 19 - Porto Salvo P.O. Box Paço d' Arcos Portugal Merck Sharp & Dohme, Lda. Quinta da Fonte - Edifício Vasco da Gama, 19 - Porto Salvo P.O. Box Paço d' Arcos Portugal Cozaar 100 mg Film-coated tablet Oral use COZAAR 12.5 mg Film-coated tablet Oral use COZAAR 50 mg Film-coated tablet Oral use COZAAR 100 mg Film-coated tablet Oral use COZAAR 50 mg Film-coated tablet Oral use COZAAR 100 mg 100 mg Film-coated tablet Oral use 12

13 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Portugal Portugal Portugal Portugal Portugal Merck Sharp & Dohme, Lda. Quinta da Fonte - Edifício Vasco da Gama, 19 - Porto Salvo P.O. Box Paço d' Arcos Portugal Merck Sharp & Dohme, Lda. Quinta da Fonte - Edifício Vasco da Gama, 19 - Porto Salvo P.O. Box Paço d' Arcos Portugal LABORATÓRIO MEDINFAR, Produtos Farmacêuticos, SA Rua Manuel Ribeiro de Pavia, 1-1 Venda Nova Amadora Portugal LABORATÓRIO MEDINFAR, Produtos Farmacêuticos, SA Rua Manuel Ribeiro de Pavia, 1-1 Venda Nova Amadora Portugal LABORATÓRIO MEDINFAR, Produtos Farmacêuticos, SA Rua Manuel Ribeiro de Pavia, 1-1 Venda Nova Amadora Portugal COZAAR IC 12.5 mg Film-coated tablet Oral use COZAAR IC Titulação 12.5 mg + 50 mg Film-coated tablet Oral use LORTAAN IC 12.5 mg Film-coated tablet Oral use LORTAAN IC- Titulação 12.5 mg + 50 mg Film-coated tablet Oral use LORTAAN 50 mg Film-coated tablet Oral use 13

14 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Portugal Romania Slovenia Slovenia Slovenia Spain LABORATÓRIO MEDINFAR, Produtos Farmacêuticos, SA Rua Manuel Ribeiro de Pavia, 1-1 Venda Nova Amadora Portugal Merck Sharp & Dohme Romania S.R.L. Bucharest Business Park Şos. Bucureşti-Ploieşti, Nr. 1A, Clădirea C1, Etaj 3 Sector 1, Bucureşti Romania Merck Sharp & Dohme, inovativna zdravila d.o.o., Šmartinska cesta 140, 1000 Ljubljana Slovenia Merck Sharp & Dohme, inovativna zdravila d.o.o., Šmartinska cesta 140, 1000 Ljubljana Slovenia Merck Sharp & Dohme, inovativna zdravila d.o.o., Šmartinska cesta 140, 1000 Ljubljana Slovenia MERCK SHARP AND DOHME DE ESPAÑA, S.A. C/ Josefa Valcárcel, Madrid Spain LORTAAN 100mg 100 mg Film-coated tablet Oral use COZAAR, comprimate filmate, 50 mg Cozaar 12,5 mg filmsko obložene tablete Cozaar 50 mg filmsko obložene tablete Cozaar 100 mg filmsko obložene tablete 50 mg Film-coated tablet Oral use 12.5 mg Film-coated tablet Oral use 50 mg Film-coated tablet Oral use 100 mg Film-coated tablet Oral use Cozaar 12.5 mg Inicio 12.5 mg Film-coated tablet Oral use 14

15 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration Spain Spain Sweden Sweden Sweden Sweden United Kingdom MERCK SHARP AND DOHME DE ESPAÑA, S.A. C/ Josefa Valcárcel, Madrid Spain MERCK SHARP AND DOHME DE ESPAÑA, S.A. C/ Josefa Valcárcel, Madrid Spain Merck Sharp & Dohme PO Box PC Haarlem The Netherlands Merck Sharp & Dohme PO Box PC Haarlem The Netherlands Merck Sharp & Dohme PO Box PC Haarlem The Netherlands Merck Sharp & Dohme PO Box PC Haarlem The Netherlands Merck Sharp & Dohme Limited Hertford Road, Hoddesdon, Herts EN11 9BU United Kingdom Cozaar 50 mg 50 mg Film-coated tablet Oral use Cozaar 100 mg 100 mg Film-coated tablet Oral use Cozaar 12,5 mg filmdragerade tabletter Cozaar 12,5 mg + 50 mg filmdragerade tabletter Cozaar 50 mg filmdragerade tabletter Cozaar 100 mg filmdragerade tabletter COZAAR 50 mg film-coated tablets 12.5 mg Film-coated tablet Oral use 12.5 mg + 50 mg Film-coated tablet Oral use 50 mg Film-coated tablet Oral use 100 mg Film-coated tablet Oral use 50 mg Film-coated tablet Oral use 15

16 Member State Marketing Authorisation Holder Invented name Strength Pharmaceutical Form Route of administration United Kingdom United Kingdom Merck Sharp & Dohme Limited Hertford Road, Hoddesdon, Herts EN11 9BU United Kingdom Merck Sharp & Dohme Limited Hertford Road, Hoddesdon, Herts EN11 9BU United Kingdom COZAAR 25 mg film-coated tablets COZAAR 100 mg film-coated tablets 25 mg Film-coated tablet Oral use 100 mg Film-coated tablet Oral use 16

17 ANNEX II SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARIES OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET PRESENTED BY THE EMEA 17

18 SCIENTIFIC CONCLUSIONS OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF COZAAR AND ASSOCIATED NAMES (SEE ANNEX I) Cozaar (losartan) was included in the list of products for Product Information harmonisation, drawn up by the CMD(h), in accordance with Article 30(2) of the Directive 2001/83/EC in order to resolve divergences amongst the nationally authorised SPCs and therefore to harmonise these divergent SPCs across the European Union. Losartan is an orally active angiotensin II (Ang- II) receptor antagonist acting on the AT1 receptor subtype, thus blocking the effect of Ang-II in the renin angiotensin system (RAS) cascade. Losartan is indicated for the treatment of hypertension. Losartan may also delay progression of diabetic nephropathy and is also indicated for the reduction of renal disease progression in patients with type 2 diabetes, hypertension and microalbuminuria (>30 mg/24 hours) or proteinuria (>900 mg/24 hours). The main areas of disharmony of the existing Summary of Product Characteristics were section 4.1 Therapeutic Indications, section 4.3 Contraindications, and section 4.4 Special Warnings and Precautions for Use. Therapeutic Indications (SPC section 4.1) - Treatment of essential hypertension. The efficacy and safety are well established for the indication treatment of essential hypertension. Therefore, the CHMP considered that this is an acceptable indication. -Reduction in risk of cardiovascular morbidity and mortality in hypertensive patients with left ventricular hypertrophy ( LIFE indication ) During the referral procedure, the MAH proposed amending the indication to substitute cardiovascular morbidity and mortality with stroke. After careful evaluation, the CHMP considered that this indication is acceptable. The LIFE study has been assessed in the past and this has led to the registration of the more extensive indication, i.e. the reduction of the cardiovascular morbidity and mortality (as measured by the combined incidence of CV death, stroke and MI) instead of stroke only. This is the indication currently proposed by the applicant and has been registered in 15 member states of the EU. The reason for this broader indication is that the LIFE study was not a placebo-controlled study, studying the effect on stroke only compared to placebo, but an actively controlled study, comparing a losartan based with an atenolol based antihypertensive treatment using a primary composite endpoint of CV death, stroke and MI. This composite endpoint can be considered as representative for CV morbidity and mortality, and has translated into this indication in many medicinal products that have been discussed in the CHMP (e.g. statins). At the time of the study, beta-blockade alone, or in combination with diuretics had shown to reduce rates of many CV events by 15-45%. In the LIFE study an additional benefit was noted with regards to stroke for the losartan based strategy, and effects were similar with regard to MI and CV mortality, indicating that the demonstrated beneficial effect of beta-blockade on CV morbidity and mortality in general was also present for losartan. Since then the beneficial effect of atenolol regarding CV morbidity and mortality has been questioned. A recent review in the BMJ shows that specifically the preventive effect on stroke of atenolol is lower than for other antihypertensives; RR of 1.26 (95%CI: 1.15 to 1.38). As a consequence the observed 25% risk reduction with losartan versus atenolol brings the protective effect of losartan on stroke in the same range as for other antihypertensives. Therefore, the proposed indication was considered approvable after a majority vote by the CHMP plenum and is supported with the following wording: reduction of risk of stroke in hypertensive patients with left ventricular hypertrophy, documented by ECG. 18

19 - Renal protection in patients with Type-2 diabetes and proteinuria The CHMP considered the benefit/risk ratio of this indication is positive. The proposed indication is based on the results from the RENAAL study, where the effect of losartan was investigated on a composite primary endpoint of renal endpoints and mortality in patients with Type II diabetes mellitus with proteinuria. Treatment with losartan, as compared with placebo, resulted in a 16.1% risk reduction in the number of patients reaching the primary composite endpoint. There was also a significant risk reduction for doubling of the serum creatinine and for end-stage renal failure in the patient group treated with losartan. These findings were regarded as clinically relevant for this group of patients. Therefore, the CHMP proposed that the indication should be re-worded to Treatment of renal disease in patients with hypertension and Type II diabetes mellitus with proteinuria > 0.5g/day as part of an antihypertensive treatment to reflect the inclusion criteria of the RENAAL study. - Heart Failure (as second line, when ACE inhibitors are unsuitable). The CHMP was concerned that the benefit/risk ratio of this indication could not be adequately established. This indication is primarily based on the results of the clinical trials ELITE I and II. The CHMP considered that the data from these trials may not be sufficient to demonstrate the claimed benefit. Whilst the ELITE I indicated an reduction in risk of mortality due to heart failure in patients taking losartan, as compared to captopril, the ELITE II study was not powered to establish equal efficacy between losartan and captopril. Furthermore, the study provided no information on the effect that higher doses of losartan (greater than 50mg) could have on improving efficacy. Importantly, an ongoing study (HEAAL) comparing 50mg with 150mg losartan in patients with heart failure, may give relevant information on the dosing issue and address other open issues such as the negative results observed in patients on beta-blockers and losartan. After a majority voting at the CHMP plenum, the CHMP recommended that the following wording be proposed to reflect the data from the ELITE I and II studies, within a second-line indication: Treatment of chronic heart failure (in patients aged 60 or over), when treatment with ACE inhibitors is not considered suitable due to incompatibility or contraindications. Patients with heart failure who have been stabilised with an ACE inihibitor should not be switched to losartan. The patients should have a left ventricular ejection fraction equal to or greater than 40% and should be stabilised under the treatment of the chronic heart failure. The combination of losartan with a beta-blocker should be used with caution. Contra-indications (SPC section 4.3) The CHMP considered that the following contra-indications needed to be included in the SPC for Cozaar in all MSs: Pregnancy and lactation; Severely reduced liver function; Angina pectoris; Myocardial infraction; Cerebrovascular disease; Renal artery stenosis; Kidney transplant patients. Special warnings and precautions for use (SPC section 4.4) The CHMP considered that the following warnings needed to be included in the SPC for Cozaar in all MSs: Hypersensitivity; Angioedema; Surgery; Anaesthesia; Haemodialysis; Kidney transplant; Black patients; Obstructive valvular disease. Pregnancy and Lactation The CHMP considered that the text concerning pregnancy and lactation in the SPC (sections 4.3, 4.4 and 4.6) needed to be amended to include the outcome of the PhVWP report on ACE Inhibitors and angiotensin II receptors antagonists (AIIRAs) and recommendations on the use during the first trimester of pregnancy (EMEA/CHMP/PhVWP/474692/2007). Pregnancy and Lactation should be contraindicated and the appropriate wording included in sections 4.3, 4.4 and 4.6 of the SPC, and the relevant sections of the Package Leaflet. Use of losartan in children and adolescents 19

20 Based on the data submitted during the Article 30 Referral procedure and the outcome of the EU worksharing project assessment of these paediatric data, the CHMP considered that the conclusions of the European Paediatric Worksharing Project on losartan needed to be incorporated into sections 4.2, 4.4, 4.8, 5.1 and 5.2 of Summary of Product Characteristics and the relevant sections of the Package Leaflet. The following wording has been added to SPC section 4.2 Posology and Method of Administration: Paediatric hypertension There are limited data on the efficacy and safety of losartan in children and adolescents aged 6-16 years old for the treatment of hypertension (see 5.1: Pharmacodynamic properties). Limited pharmacokinetic data are available in hypertensive children above one month of age (see 5.2 : Pharmacokinetic properties). For patients who can swallow tablets, the recommended dose is 25 mg once daily in patients >20 to <50 kg. In exceptional cases the dose can be increased to a maximum of 50 mg once daily. Dosage should be adjusted according to blood pressure response. In patients >50 kg, the usual dose is 50 mg once daily. In exceptional cases the dose can be adjusted to a maximum of 100 mg once daily. Doses above 1.4 mg/ kg (or in excess of 100 mg) daily have not been studied in paediatric patients. Losartan is not recommended for use in children under 6 years old, as limited data are available in these patient groups. It is not recommended in children with glomerular filtration rate < 30 ml/ min / 1.73 m 2, as no data are available (see also section 4.4). Losartan is also not recommended in children with hepatic impairment (see also section 4.4). The following wording has been added to SPC Section 4.4 Special warnings and precautions for use: Hypotension and Electrolyte/Fluid Imbalance Symptomatic hypotension, especially after the first dose and after increasing of the dose, may occur in patients who are volume- and/or sodium-depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. These conditions should be corrected prior to administration of <COZAAR>, or a lower starting dose should be used (see section 4.2). This also applies to children. Liver Function Impairment Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with a history of hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment. Therefore losartan must not be administered in patients with severe hepatic impairment (see sections 4.2, 4.3and 5.2). Losartan is also not recommended in children with hepatic impairment (see section 4.2). Renal Function Impairment As a consequence of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported (in particular, in patients whose renal function is dependent on the renin angiotensin aldosterone system such as those with severe cardiac insufficiency or pre-existing renal dysfunction). As with other drugs that affect the renin-angiotensin-aldosterone system, increases in blood urea and serum creatinine have also been reported in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney; these changes in renal function may be reversible upon 20

21 discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Losartan is not recommended in children with glomerular filtration rate < 30ml/ min/ 1.73 m 2 as no data are available (see section 4.2). Renal function should be regularly monitored during treatment with losartan as it may deteriorate. This applies particularly when losartan is given in the presence of other conditions (fever, dehydratation) likely to impair renal function. Concomitant use of losartan and ACE-inhibitors has shown to impair renal function. Therefore, concomitant use is not recommended. The following wording has been added to SPC Section 4.8 Undesirable effects: The adverse experience profile for paediatric patients appears to be similar to that seen in adult patients. Data in the paediatric population are limited. The following wording has been added to SPC Section 5.1.Pharmacodynamic Properties: Paediatric Hypertension The antihypertensive effect of Cozaar was established in a clinical study involving 177 hypertensive paediatric patients 6 to 16 years of age with a body weight > 20 kg and a glomerular filtration rate > 30 ml/ min/ 1.73 m 2. Patients who weighted >20kg to < 50 kg received either 2.5, 25 or 50 mg of losartan daily and patients who weighted > 50 kg received either 5, 50 or 100 mg of losartan daily. At the end of three weeks, losartan administration once daily lowered trough blood pressure in a dosedependent manner. Overall, there was a dose-response. The dose-response relationship became very obvious in the low dose group compared to the middle dose group (period I: -6.2 mmhg vs mmhg), but was attenuated when comparing the middle dose group with the high dose group (period I: mmhg vs mmhg). The lowest doses studied, 2.5 mg and 5 mg, corresponding to an average daily dose of 0.07 mg/ kg, did not appear to offer consistent antihypertensive efficacy. These results were confirmed during period II of the study where patients were randomized to continue losartan or placebo, after three weeks of treatment. The difference in blood pressure increase as compared to placebo was largest in the middle dose group (6.70 mm Hg middle dose vs mmhg high dose). The rise in trough diastolic blood pressure was the same in patients receiving placebo and in those continuing losartan at the lowest dose in each group, again suggesting that the lowest dose in each group did not have significant antihypertensive effect. Long-term effects of losartan on growth, puberty and general development have not been studied. The long-term efficacy of antihypertensive therapy with losartan in childhood to reduce cardiovascular morbidity and mortality has also not been established. The following wording has been added to SPC Section 5.2 Pharmacokinetic properties: Pharmacokinetics in paediatric patients The pharmacokinetics of losartan have been investigated in 50 hypertensive paediatric patients > 1 month to < 16 years of age following once daily oral administration of approximately 0.54 to 0.77 mg/ kg of losartan (mean doses). The results showed that the active metabolite is formed from losartan in all age groups. The results showed roughly similar pharmacokinetic parameters of losartan following oral administration in infants and toddlers, preschool children, school age children and adolescents. The pharmacokinetic parameters for the metabolite differed to a greater extent between the age groups. When comparing preschool children with adolescents these differences became statistically significant. Exposure in infants/ toddlers was comparatively high. 21

22 The following wording has been added to the Package Leaflet Section 2 Before you take Cozaar: Use in children and adolescents <COZAAR> has been studied in children. For more information, talk to your doctor. GROUNDS FOR AMENDMENT OF THE SUMMARIES OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET Whereas - the scope of the referral was the harmonisation of the Summaries of Products Characteristics, labelling and package leaflet. - the Summaries of Products Characteristic, labelling and package leaflet proposed by the Marketing Authorisation Holders have been assessed based on the documentation submitted and the scientific discussion within the Committee, - the CHMP concluded that the Marketing Authorisation could be harmonised on the following indications: - Treatment of essential hypertension - Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus with proteinuria > 0.5 g/day as part of an antihypertensive treatment - Reduction of risk of stroke in hypertensive patients with left ventricular hypertrophy documented by ECG ( See section 5.1 Life Study, Race) - Treatment of chronic heart failure (in patients 60 years), when treatment with ACE inhibitors is not considered suitable due to incompatibility, especially cough, or contraindication. Patients with heart failure who have been stabilised with an ACE inhibitor should not be switched to losartan. The patients should have a left ventricular ejection fraction 40% and should be stabilised under the treatment of the chronic heart failure - Pregnancy and Lactation should be contraindicated and the appropriate wording included in sections 4.3, 4.4 and 4.6 of the SPC, and the relevant sections of the Package Leaflet. - The use of losartan in paediatric patients should be included in sections 4.2, 4.4, 4.8, 5.1 and 5.2 of the SPC, and the relevant sections of the Package Leaflet. the CHMP has recommended the amendment of the Marketing Authorisations for which the Summary of Product Characteristics, labelling and package leaflet are set out in Annex III for Cozaar and associated names (see Annex I). 22

23 ANNEX III SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET 23

24 SUMMARY OF PRODUCT CHARACTERISTICS 24

25 1. NAME OF THE MEDICINAL PRODUCT Cozaar and associated names (see Annex I) 12.5 mg film-coated tablets Cozaar and associated names (see Annex I) 25 mg film-coated tablets Cozaar and associated names (see Annex I) 50 mg film-coated tablets Cozaar and associated names (see Annex I) 100 mg film-coated tablets [To be implemented nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each Cozaar 12.5 mg Tablet contains 12.5 mg of losartan (as potassium salt). Each Cozaar 25 mg Tablet contains 25 mg of losartan (as potassium salt). Each Cozaar 50 mg Tablet contains 50 mg of losartan (as potassium salt). Each Cozaar 100 mg Tablet contains mg of losartan (as potassium salt). Each Cozaar 12,5 mg tablet contains 25.5 mg lactose monohydrate. Each Cozaar 25 mg tablet contains12.75 mg lactose monohydrate. Each Cozaar 50 mg tablet contains 25.5 mg lactose monohydrate. Each Cozaar 100 mg tablet contains 51.0 mg lactose monohydrate. For a full list of excipients, see section 6.1. [To be implemented nationally] 3. PHARMACEUTICAL FORM Film-coated tablets Cozaar 12,5 mg tablet Blue, oval film-coated tablets marked 11 on one side and plain on the other. Cozaar 25 mg tablet White, oval unscored film-coated tablets marked 951 on one side and plain on the other.. Cozaar 50 mg tablet White, oval film-coated tablets marked 952 on one side and scored on the other. <The tablet can be divided into equal halves.> Cozaar 100 mg tablet White, teardrop-shaped film-coated tablets marked 960 on one side and plain on the other. [To be implemented nationally] 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment of essential hypertension. Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus with proteinuria 0.5 g/day as part of an antihypertensive treatment. 25

26 Treatment of chronic heart failure (in patients 60 years), when treatment with ACE inhibitors is not considered suitable due to incompatibility, especially cough, or contraindication. Patients with heart failure who have been stabilised with an ACE inhibitor should not be switched to losartan. The patients should have a left ventricular ejection fraction 40% and should be stabilised under the treatment of the chronic heart failure. Reduction in the risk of stroke in hypertensive patients with left ventricular hypertrophy documented by ECG (see section 5.1 LIFE study, Race). 4.2 Posology and method of administration Losartan tablets should be swallowed with a glass of water. Cozaar may be administered with or without food. Hypertension The usual starting and maintenance dose is 50 mg once daily for most patients. The maximal antihypertensive effect is attained 3-6 weeks after initiation of therapy. Some patients may receive an additional benefit by increasing the dose to 100 mg once daily (in the morning). Cozaar may be administered with other antihypertensive agents, especially with diuretics (e.g. hydrochlorothiazide). Pediatric hypertension There are limited data on the efficacy and safety of losartan in children and adolescents aged 6-16 years old for the treatment of hypertension (see 5.1: Pharmacodynamic properties). Limited pharmacokinetic data are available in hypertensive children above one month of age (see 5.2 : Pharmacokinetic properties). For patients who can swallow tablets, the recommended dose is 25 mg once daily in patients >20 to <50 kg. In exceptional cases the dose can be increased to a maximum of 50 mg once daily. Dosage should be adjusted according to blood pressure response. In patients >50 kg, the usual dose is 50 mg once daily. In exceptional cases the dose can be adjusted to a maximum of 100 mg once daily. Doses above 1.4 mg/ kg (or in excess of 100 mg) daily have not been studied in pediatric patients. Losartan is not recommended for use in children under 6 years old, as limited data are available in these patient groups. It is not recommended in children with glomerular filtration rate < 30 ml/ min / 1.73 m 2, as no data are available (see also section 4.4). Losartan is also not recommended in children with hepatic impairment (see also section 4.4). Hypertensive type II diabetic patients with proteinuria 0.5 g/day The usual starting dose is 50 mg once daily. The dose may be increased to 100 mg once daily based on blood pressure response from one month after initiation of therapy onwards. Cozaar may be administered with other antihypertensive agents (e.g. diuretics, calcium channel blockers, alpha- or beta-blockers, and centrally acting agents) as well as with insulin and other commonly used hypoglycemic agents (e.g. sulfonylureas, glitazones and glucosidase inhibitors). Heart Failure The usual initial dose of Cozaar in patients with heart failure is 12.5 mg once daily. The dose should generally be titrated at weekly intervals (i.e mg daily, 25 mg daily, 50 mg daily) to the usual maintenance dose of 50 mg once daily, as tolerated by the patient. 26

27 Reduction in the risk of stroke in hypertensive patients with left ventricular hypertrophy documented by ECG The usual starting dose is 50 mg of Cozaar once daily. A low dose of hydrochlorothiazide should be added and/ or the dose of Cozaar should be increased to 100 mg once daily based on blood pressure response. Use in patients with intravascular volume depletion: For patients with intravascular volume-depletion (e.g. those treated with high-dose diuretics), a starting dose of 25 mg once daily should be considered (see section 4.4). Use in patients with renal impairment and haemodialysis patients: No initial dosage adjustment is necessary in patients with renal impairment and in haemodialysis patients. Use in patients with hepatic impairment: A lower dose should be considered for patients with a history of hepatic impairment. There is no therapeutic experience in patients with severe hepatic impairment. Therefore, losartan is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 4.4). Use in Elderly Although consideration should be given to initiating therapy with 25 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients (see section 4.4 and 6.1). 2nd and 3rd trimester of pregnancy (see section 4.4 and 4.6) Lactation (see section 4.6) Severe hepatic impairment 4.4 Special warnings and precautions for use Hypersensitivity Angiooedema. Patients with a history of angiooedema (swelling of the face, lips, throat, and/ or tongue) should be closely monitored (See section 4.8). Hypotension and Electrolyte/Fluid Imbalance Symptomatic hypotension, especially after the first dose and after increasing of the dose, may occur in patients who are volume- and/or sodium-depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. These conditions should be corrected prior to administration of Cozaar, or a lower starting dose should be used (see section 4.2). This also applies to children. Electrolyte imbalances Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with nephropathy, the incidence of hyperkalemia was higher in the group treated with Cozaar as compared to the placebo group (see section 4.8, 'Hypertension and type 2 diabetes with renal disease - Investigations and Post-marketing experience - Investigations Therefore, the plasma concentrations of potassium as well as creatinine clearance values should be closely monitored, especially patients with heart failure and a Creatinine Clearance between ml/ min should be closely monitored. The concomitant use of potassium sparing diuretics, potassium supplements and potassium containing salt substitutes with losartan is not recommended (see section 4.5). Liver Function Impairment 27

28 Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with a history of hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment. Therefore losartan must not be administered in patients with severe hepatic impairment (see sections 4.2, 4.3 and 5.2). Losartan is also not recommended in children with hepatic impairment (see section 4.2). Renal Function Impairment As a consequence of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported (in particular, in patients whose renal function is dependent on the renin angiotensin aldosterone system such as those with severe cardiac insufficiency or pre-existing renal dysfunction). As with other drugs that affect the renin-angiotensin-aldosterone system, increases in blood urea and serum creatinine have also been reported in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney; these changes in renal function may be reversible upon discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Use in pediatric patients with renal function impairment Losartan is not recommended in children with glomerular filtration rate < 30ml/ min/ 1.73 m 2 as no data are available (see section 4.2). Renal function should be regularly monitored during treatment with losartan as it may deteriorate. This applies particularly when losartan is given in the presence of other conditions (fever, dehydration) likely to impair renal function. Concomitant use of losartan and ACE-inhibitors has shown to impair renal function. Therefore, concomitant use is not recommended. Renal transplantation There is no experience in patients with recent kidney transplantation. Primary hyperaldosteronism Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Losartan tablets is not recommended. Coronary heart disease and cerebrovascular disease As with any antihypertensive agents, excessive blood pressure decrease in patients with ischaemic cardiovascular and cerebrovascular disease could result in a myocardial infarction or stroke. Heart failure In patients with heart failure, with or without renal impairment, there is - as with other drugs acting on the renin-angiotensin system - a risk of severe arterial hypotension, and (often acute) renal impairment. There is no sufficient therapeutic experience with losartan in patients with heart failure and concomitant severe renal impairment, in patients with severe heart failure (NYHA class IV) as well as in patients with heart failure and symptomatic life threatening cardiac arrhythmias. Therefore, losartan should be used with caution in these patient groups. The combination of losartan with a beta-blocker should be used with caution (see section 5.1). Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorbtion Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine. 28

29 Pregnancy Losartan should not be initiated during pregnancy. Unless continued losartan therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with losartan should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). Other warnings and precautions As observed for angiotensin converting enzyme inhibitors, losartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population. 4.5 Interaction with other medicinal products and other forms of interaction Other antihypertensive agents may increase the hypotensive action of Losartan. Other substances inducing hypotension like tricyclic antidepressants, antipsychotics, baclofene, amifostine: Concomitant use with these drugs that lower blood pressure, as main or side-effect, may increase the risk of hypotension. Losartan is predominantly metabolised by cytochrome P450 (CYP) 2C9 to the active carboxy-acid metabolite. In a clinical trial it was found that fluconazole (inhibitor of CYP2C9) decreases the exposure to the active metabolite by approximately 50%. It was found that concomitant treatment of losartan with rifampicine (inducer of matabolism enzymes) gave a 40% reduction in plasma concentration of the active metabolite. The clinical relevance of this effect is unknown. No difference in exposure was found with concomitantly treatment with fluvastatin (weak inhibitor of CYP2C9). As with other drugs that block angiotensin II or its effects, concomitant use of other drugs which retain potassium (e.g. potassium-sparing diuretics: amiloride, triamterene, spironolactone) or may increase potassium levels (e.g. heparin), potassium supplements or salt substitutes containing potassium may lead to increases in serum potassium. Co-medication is not advisable. Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Very rare cases have also been reported with antiotensin II receptor antagonists. Co-administration of lithium and losartan should be undertaken with caution. If this combination proves essential, serum lithium level monitoring is recommended during concomitant use. When angiotensin II antagonists are administered simultaneously with NSAIDs (i.e. selective COX-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of angiotensin II antagonists or diuretics and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter. 4.6 Pregnancy and lactation Pregnancy The use of losartan is not recommended during the first trimester of pregnancy (see section 4.4). The use of losartan is contra-indicated during the 2nd and 3rd trimester of pregnancy (see section 4.3 and 4.4). Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk 29

30 cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Inhibitors (AIIRAs), similar risks may exist for this class of drugs. Unless continued ARB therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with losartan should be stopped immediately and, if appropriate, alternative therapy should be started. Losartan therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also 5.3 'Preclinical safety data'). Should exposure to losartan have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken losartan should be closely observed for hypotension (see also section 4.3 and 4.4). Lactation It is not known whether losartan is excreted in human milk. However, losartan is excreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, losartan is contraindicated during breast-feeding (see section 4.3). 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machinery it must be borne in mind that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy, in particular during initiation of treatment or when the dose is increased. 4.8 Undesirable effects The frequency of adverse events listed below is defined using the following convention: very common ( 1/10); common ( 1/100, < 1/10); uncommon ( 1/1,000, < 1/100); rare ( 1/10,000, < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). In controlled clinical trials for essential hypertension, hypertensive patients with left ventricular hypertrophy, chronic heart failure as well as for hypertension and type 2 diabetes mellitus with renal disease, the most common adverse event was dizziness. Hypertension In controlled clinical trials for essential hypertension with losartan the following adverse events were reported Nervous system disorders: Common: dizziness, vertigo Uncommon: somnolence, headache, sleep disorders Cardiac disorder: Uncommon: palpitations, angina pectoris Vascular disorders: Uncommon: symptomatic hypotension (especially in patients with intravascular volume depletion, e.g. patients with severe heart failure or under treatment with high dose diuretics), dose-related orthostatic effects, rash. Gastrointestinal disorders: Uncommon: abdominal pain, obstipation 30