How Cause Related Marketing Influence Customer Value in

Annex I

List of the names, pharmaceutical form, strengths of the medicinal products, route of administration, marketing authorisation holders in the

member states

1

Member State

Marketing authorisation

holder Product name Strength

Pharmaceutical form

Route of administration

Austria Baxter Healthcare GmbH, Stella-Klein-Löw-Weg 15, A-1020 Wien, Austria

Dianeal PD4 Glucose 1,36% w/v/13,6 mg/ml - Peritonealdialyselösung

Anhydrous glucose 13.6 g/L, sodium chloride 5.38 g/L, sodium-L(+) lactate 4.48 g/L, calcium chloride dihydrate 0.184 g/L, magnesium chloride hexahydrate 0.051 g/L

Solution for peritoneal dialysis

Intraperitoneal use


Dianeal PD4 Glucose 2,27% w/v/22,7 mg/ml - Peritonealdialyselösung



Intraperitoneal use


Dianeal PD4 Glucose 3,86 % w/v/38,6 mg/ml - Peritonealdialyselösung



Intraperitoneal use


EXTRANEAL - Peritonealdialyselösung

75 g/L Solution for peritoneal dialysis

Intraperitoneal use

Belgium Baxter SA Bld R Branquart 80 7860 Lessines Belgium

Dianeal PD4 Glucose 1,36 % (13,6 mg/ml), solution pour dialyse péritonéale.

13.6 g/l glucose anhydrate Solution for peritoneal dialysis

Intraperitoneal use




Intraperitoneal use




Intraperitoneal use


EXTRANEAL 7,5 %, solution pour dialyse péritonéale

75.00 g/l Icodextrine Solution for peritoneal dialysis

Intraperitoneal use

2

Member State



Pharmaceutical form


Bulgaria BAXTER d.o.o.,Zelezna cesta 18, 1000 Ljubljana,Slovenia

Dianeal PD4 Glucose 2.27% w/v/ 22.7mg/ml Solution for peritoneal dialysis

Intraperitoneal use


Dianeal PD4 Glucose 3.86% w/v/ 38.6mg/ml Solution for peritoneal dialysis

Intraperitoneal use


Dianeal PD4 Glucose 1.36% w/v/ 13.6mg/ml

1.36% w/v/ 13.6mg/ml Solution for peritoneal dialysis

Intraperitoneal use


Extraneal 7.50% Solution for peritoneal dialysis

Intraperitoneal use

Czech Republic

Baxter Healthcare S.A. Moneen Road Castlebar, Co. Mayo Ireland

Dianeal PD4 Glucose 1,36 % w/v / 13,6 mg/ml

1,36 % w/v / 13,6 mg/ml Solution for peritoneal dialysis

Intraperitoneal use

Czech Republic




Intraperitoneal use

Czech Republic




Intraperitoneal use

Czech Republic


EXTRANEAL 7,5 % 75 g / 1000 ml Solution for peritoneal dialysis

Intraperitoneal use

Denmark Baxter A/S, Gydevang 43, DK-3450 Allerød, Denmark

Dianeal PD4 med Glucos 13,6 mg/ml Solution for peritoneal dialysis

Intraperitoneal use

3

Member State



Pharmaceutical form




Intraperitoneal use



Intraperitoneal use


Extraneal 75 mg/ml Solution for peritoneal dialysis

Intraperitoneal use

Estonia Baxter OY P.O box 270, Valimotie 15A, Helsinki 00381 Finland

EXTRANEAL 7.50% Solution for peritoneal dialysis

Intraperitoneal use

Finland Baxter Healthcare S.A. Moneen Road, Castlebar County Mayo Ireland

Dianeal PD4 Glucose 13.6 mg/ml Solution for peritoneal dialysis

Intraperitoneal use


Dianeal PD4 Glucose

22.7 mg/ml Solution for peritoneal dialysis

Intraperitoneal use



Intraperitoneal use

Finland Baxter Oy Valimotie 15 A 00380 Helsinki Finland

Extraneal 7.5 % Solution for peritoneal dialysis

Intraperitoneal use

4

Member State



Pharmaceutical form


France Baxter SAS Avenue louis Pasteur ZA de Coignères Maurepas 78310 Maurepas France

DIANEAL PD4 GLUCOSE 1,36 %, solution pour dialyse péritonéale en poche

1.36% Solution for peritoneal dialysis

Intraperitoneal use




Intraperitoneal use




Intraperitoneal use


EXTRANEAL, solution pour dialyse péritonéale


Intraperitoneal use

Germany Baxter Deutschland GmbH Edisonstr. 4 D-85716 Unterschleißheim Germany

Dianeal PD4 Glucose 1.36% w/v

13.6 g / l 5.4 g / l 4.5 g / l 0.184 g / l 0.051 g / l


Intraperitoneal use

5

Member State



Pharmaceutical form




22.7 g / l 5.4 g / l 4.5 g / l 0.184 g / l 0.051 g / l


Intraperitoneal use



38.6 g / l 5.4 g / l 4.5 g / l 0.184 g / l 0.051 g / l


Intraperitoneal use


Dianeal PDG4 1,36 % 13.6g / l 5.38 g / l 4.48 g/ l 0.184 g / l 0.051 g / l


Intraperitoneal use


Dianeal PDG4 2,27 % 22.7 g / l 5.38 g / l 4.48 g/ l 0.184 g / l 0.051 g / l


Intraperitoneal use


Extraneal 75 g / l 5.4. g / l 4.5 g / l 0.257 g / l 0.051 g / l


Intraperitoneal use

6

Member State



Pharmaceutical form


Greece DIOPHAR S.A. Kifissias Avenue 368, Halandri, 152 33 Greece

DIANEAL PD4 1.36% Solution for peritoneal dialysis

Intraperitoneal use

Greece DIOPHAR S.A. Kifissias Avenue 368, Halandri, 152 33 Greece

EXTRANEAL (7,5+0,54+0,45+0,0257+0,0051)% w/v Solution for peritoneal dialysis

Intraperitoneal use

Hungary Baxter Hungary Kft. Népfürdő u. 22. 1138, Budapest Hungary

DIANEAL PD 4 Glucose 1,36% peritoneális dializáló oldat


Intraperitoneal use




Intraperitoneal use




Intraperitoneal use


EXTRANEAL peritoneális dializáló oldat

7,5% (icodextrin) Solution for peritoneal dialysis

Intraperitoneal use

Iceland Baxter Healthare SA Moneen Road Castlebar County Mayo Irland


Intraperitoneal use


Dianeal PD4 Glucose 22,7 mg/ml Solution for peritoneal dialysis

Intraperitoneal use

7

Member State



Pharmaceutical form



Dianeal PD4 Glucose 38,6 mg/ml Solution for peritoneal dialysis

Intraperitoneal use

Ireland Baxter Healthcare Limited, Caxton Way, Thetford, Norfolk, IP24 3SE, United Kingdom

Dianeal PD4 Glucose 1.36 % w/v (13.6 mg/ml) Solution for peritoneal dialysis

1.36 % w/v (13.6 mg/ml) Solution for peritoneal dialysis

Intraperitoneal use




Intraperitoneal use




Intraperitoneal use


EXTRANEAL Solution for peritoneal dialysis


Intraperitoneal use

Italy Baxter SPA piazzale dell' industria 20 - 00144-Roma Italy

EXTRANEAL 7.5% Solution for dialysis peritoneal

Intraperitoneal use

Italy Baxter SPA piazzale dell' industria 20 - 00144-Roma Italy

SOLUZIONI PER DIALISI PERITONEALE BAXTER

4,95 g/l - 49,54 g/l; Solution for dialysis peritoneal

Intraperitoneal use

8

Member State



Pharmaceutical form


Latvia Baxter Healthcare S.A. Moneen Road Castlebar County Mayo IRELAND

Dianeal PD4 Glucose 1,36 % w/v/13,6 mg/ml solution for peritoneal dialysis

1,36% w/v 0,538% w/v 0,448% w/v 0,0184% w/v 0,0051% w/v


Intraperitoneal use


Dianeal PD4 Glucose 2,27% w/v//22,7 mg/ml solution for peritoneal dialysis

2,27 % w/v 0,538% w/v 0,448% w/v 0,0184% w/v 0,0051% w/v


Intraperitoneal use


Dianeal PD4 Glucose 3,86 % w/v/38,6 mg/ml solution for peritoneal dialysis

3,86% w/v 0,538% w/v 0,448% w/v 0,0184% w/v 0,0051% w/v


Intraperitoneal use

Latvia Baxter Oy Valimotie 15 A 00380 Helsinki Finland FINLAND

Extraneal solution for peritoneal dialysis

75g/L 5,4g/L 4,5g/L 0,257g/L 0,051g/L


Intraperitoneal use

Lithuania Baxter Healthcare S.A., Moneen Road, Castlebar County Mayo, Ireland

Dianeal PD4 Glucose 13,6g+5,38g+4,48g+0,184g+0,051g/l Solution for peritoneal dialysis

Intraperitoneal use



Intraperitoneal use



Intraperitoneal use

9

Member State



Pharmaceutical form


Lithuania Baxter Oy, P.O. Box 270 Valimotie 15A 00381 Helsinki, Finland

EXTRANEAL 75g+5,4g+4,5g+0,257g+0,051g/1000ml Solution for peritoneal dialysis

Intraperitoneal use

Luxembourg Baxter SA, Bd René Branquart 80, B-7860 Lessines Belgium

Dianeal PD4 Glucose 1,36%/2,27%/3,86% dextrose anydre Solution for peritoneal dialysis

Intraperitoneal use

Luxembourg Baxter SA, Bd René Branquart 80, B-7860 Lessines Belgium

Extraneal 75.00 g/l Icodextrine Solution for peritoneal dialysis

Intraperitoneal use

Malta Baxter Healthcare Ltd., Caxton Way, Thetford, Norfolk, IP24 3SE United Kingdom

Dianeal PD4 Glucose 1.36%w/v 13.6mg/ml

Anhydrous Glucose Ph.Eur. 1.36 % w/v or Glucose Monohydrate Ph.Eur. 1.50 % w/v Sodium Chloride Ph.Eur. 0.538 % w/v Sodium Lactate Ph.Eur. 0.448 % w/v Calcium Chloride Ph.Eur. 0.0184 % w/v Magnesium Chloride Ph.Eur. 0.0051 % w/v


Intraperitoneal use





Intraperitoneal use





Intraperitoneal use

10

Member State



Pharmaceutical form



Extraneal (Icodextrin 7.5%)

Icodextrin (75 g/l), Sodium chloride (5.4 g/l), Calcium chloride (0.257 g/l), Magnesium chloride (0.051 g/l), Sodium lactate solution (4.5 g/l)


Intraperitoneal use

Norway Baxter AS Gjerdrumsvei 11 0484 Oslo, Norway

Extraneal 75 mg/ml Solution for peritoneal dialysis

Intraperitoneal use

Poland Baxter Polska SP. z o.o. Kruczkowskiego 8 st., 00-380 Warsawa, Poland

Dianeal PD4 (glukoza 1,36%). Zestaw do dializy otrzewnowej


Intraperitoneal use




Intraperitoneal use




Intraperitoneal use


Extraneal Zestaw do dializy otrzewnowej


Intraperitoneal use

11

Member State



Pharmaceutical form



Extraneal Zestaw do dializy otrzewnowej


Intraperitoneal use

Portugal Baxter Médico-Farmacêutica, Lda. Zona Industrial da Abrunheira - Edifício 10 - Sintra Business Park, 2710-089 Sintra Portugal

Dianeal Pd4 42,5 mg/ml Glucose Monohydrate; 5,38 mg/ml Sodium Chloride; 0,184 mg/ml Calcium Chloride Dihydrate; 0,051 mg/ml Magnesium Chloride Hexahydrate; 4,48 mg/ml Sodium Lactate.


Intraperitoneal use


Dianeal Pd4 25 mg/ml Glucose Monohydrate; 5,38 mg/ml Sodium Chloride; 0,184 mg/ml Calcium Chloride Dihydrate; 0,051 mg/ml Magnesium Chloride Hexahydrate; 4,48 mg/ml Sodium Lactate.


Intraperitoneal use


Dianeal Pd4 15 mg/ml Glucose Monohydrate; 5,38 mg/ml Sodium Chloride; 0,184 mg/ml Calcium Chloride Dihydrate; 0,051 mg/ml Magnesium Chloride Hexahydrate; 4,48 mg/ml Sodium Lactate.


Intraperitoneal use

Portugal Baxter Médico-Farmacêutica, Lda. Zona Industrial da Abrunheira - Edifício 10 - Sintra Business Park, 2710-

Extraneal 75 mg/ml Icodextrin; 5,4 mg/ml Sodium Chloride; 4,5 mg/ml Sodium (S) - lactate solution; 0,051 mg/ml Magnesium Chloride; 0,257 mg/ml Calcium Chloride.


Intraperitoneal use

12

Member State



Pharmaceutical form


089 Sintra Portugal

Romania BAXTER HEALTHCARE S.A. Moneen Road, Castelbar, County Mayo, Ireland

DIANEAL PD4 GLUCOSE 1,36% m/v (13,6 mg/ml),

13,6 mg/ml Solution for peritoneal dialysis

Intraperitoneal use


DIANEAL PD4 GLUCOSE 2,27% m/v (22,7 mg/ml)


Intraperitoneal use


DIANEAL PD4 GLUCOSE 3,86% m/v (38,6 mg/ml)


Intraperitoneal use

Romania BAXTER HEALTHCARE Ltd., Caxton Way, Thetford, Norfolk, 1P24 3SE, Thetford, United Kingdom

EXTRANEAL 75 mg/ml Solution for peritoneal dialysis

Intraperitoneal use

Slovak Republic

Baxter Healthcare SA Moneen Rd Castlebar, Co. Mayo Ireland

DIANEAL PD4 glucose 1,36 % w/v/13,6 mg/ ml

13,6 mg/1 ml Solution for peritoneal dialysis

Intraperitoneal use

Slovak Republic




Intraperitoneal use

13

Member State



Pharmaceutical form


Slovak Republic




Intraperitoneal use

Slovak Republic

Baxter Healthcare Ltd.Caxton Way Thetford Norfolk IP24 3SE United Kingdom

EXTRANEAL 7.5% Solution for peritoneal dialysis

Intraperitoneal use

Slovenia Baxter d.o.o., Zelezna cesta 18, Ljubljana, SI-1000, Slovenia

Dianeal PD4 13,6 mg/ml glukoze raztopina za peritonelano dializo


Intraperitoneal use




Intraperitoneal use




Intraperitoneal use


Extraneal 75 mg/ml ikodekstrina raztopina za peritonealno dializo

75 mg/ml Solution for peritoneal dialysis

Intraperitoneal use

Spain BAXTER S.L. Pouet de Camilo 2 Ribarroja del Turia (Valencia) 46394 Spain

Dianeal PD4 Glucosa 1,36%

15,0 g/l; 5,38 g/l; 4,48 g/l; 0,184 g/l; 0,051 g/l


Intraperitoneal use

14

Member State



Pharmaceutical form



Dianeal PD4 Glucosa 1,36% con sistema de desconexión integrado

15,0 g/l; 5,38 g/l; 4,48 g/l; 0,184 g/l; 0,051 g/l


Intraperitoneal use



25,0 g/l; 5,38 g/l; 4,48 g/l; 0,184 g/l; 0,051 g/l


Intraperitoneal use



25,0 g/l; 5,38 g/l; 4,48 g/l; 0,184 g/l; 0,051 g/l


Intraperitoneal use



42,50 g/l; 5,38 g/l; 4,48 g/l; 0,184 g/l; 0,051 g/l


Intraperitoneal use



42,50 g/l; 5,38 g/l; 4,48 g/l; 0,184 g/l; 0,051 g/l


Intraperitoneal use

Spain BAXTER S.L. Pouet de Camilo 2 46394 Ribarroja del Turia (Valencia) Spain

EXTRANEAL Solución para diálisis peritoneal

75 g/l; 5,4 g/l; 4,5 g/l; 0,257 g/l; 0,051 g/l


Intraperitoneal use

15

Member State



Pharmaceutical form


Sweden Baxter Healthare SA Moneen Road Castlebar County Mayo Irland

Dianeal PD4 med glucos 13,6 mg/ml


Intraperitoneal use




Intraperitoneal use




Intraperitoneal use

Sweden Baxter Medical AB Box 63 164 94 Kista Sverige Sweden

Extraneal 7.5% Solution for peritoneal dialysis

Intraperitoneal use

The Netherlands

Baxter B.V., Kobaltweg 49, 3542 CE Utrecht, the Netherlands

Dianeal PD4 Glucose 1.36%/13,6 mg/ml, peritoneaaldialysevloeistof

13,6 g/l glucose anhydrate Solution for peritoneal dialysis

Intraperitoneal use

The Netherlands




Intraperitoneal use

The Netherlands




Intraperitoneal use

16

17

Member State



Pharmaceutical form


The Netherlands


EXTRANEAL 7,5 %, oplossing voor peritoneale dialyse

75 g/l icodextrine Solution for peritoneal dialysis

Intraperitoneal use

United Kingdom

Baxter Healthcare Limited, Caxton Way, Thetford, Norfolk IP24 3SE, United Kingdom

Dianeal PD4 Glucose 1.36% w/v /13.6mg/ml

magnseium chloride 0.005%w/v; glucose 1.36%w/v; sodium lactate 0.45%w/v; calcium chloride 0.018%w/v; sodium chloride 0.54%w/v


Intraperitoneal use

United Kingdom





Intraperitoneal use

United Kingdom





Intraperitoneal use

United Kingdom


Extraneal (Icodextrin 7.5%) Solution for peritoneal dialysis

icodextrin 75g/l; sodium chloride 5.4g/l; calcium chloride 0,257g/l; magnesium chloride 0.051g/l; sodium s-lactate 4.5g/l


Intraperitoneal use

Annex II

Scientific conclusions and grounds for the addition of a manufacturing site to the marketing authorisations and amendment of the summaries of product characteristics and package leaflets presented by the EMA

18

Scientific conclusions

Overall summary of the scientific evaluation on the inclusion of an additional site into the existing licenses of dialysis solutions (Dianeal PD4 and Extraneal) from Baxter group of companies and associated companies (see Annex I) An article 31 referral procedure of Directive 2001/83/EC, as amended was initiated by the European Commission (EC) following reports of out-of-specifications results for endotoxins in dialysis solutions from Baxter group of companies and associated companies produced at Castlebar. In particular, the peritoneal dialysis (PD) Dianeal, Extraneal and Nutrineal were affected by this procedure. Taking into account the crucial nature of these medicinal products, unaffected batches of PD solutions had to be made available to patients across the EU in the shortest possible timeframe, and thus alternatives were sought. In view of severe supply limitations for Dianeal, Extraneal and Nutrineal and the risk of switching patients to alternative PD solutions or therapies, the CHMP considered that the use of comparable products produced by Baxter at alternative manufacturing sites outside the EEA (European Economic Area) should be prioritised. These dialysis solutions were thus imported from Canada, Singapore, Turkey and USA. To meet supply demands, the unprecedented importation of PD solutions from Canada, Turkey and USA increased. The Singaporean manufacturing plant was only used once and no longer considered as an alternative. Considering the likelihood of prolonged use of large quantities of unlicensed (imported) PD solutions on the EU market, and in order to ensure continued supply of licensed medicinal products to the EU, the necessary data packages to support the inclusion of additional manufacturing sites were expedited within the ongoing article 31 referral procedure. The available data to support inclusion of sites from which products are currently being imported (Canada, Turkey and USA) into the existing PD solutions marketing authorisations were submitted. The necessary data packages to support the inclusion of one more additional manufacturing site located in Europe (Poland) which is expected to become fully operational soon, was also expedited. In light of the current uncertainty over the root cause and the future re-instatement of supply from Castlebar, the addition of manufacturing sites to the marketing authorisations aimed at mitigating future supply problems arising for PD solutions in Europe, ensuring that sufficient PD solutions are available. The CHMP reviewed all the data available for each of the sites concerned. In April 2011, the Committee considered that sufficient information was available to issue a first opinion for this Article 31 procedure recommending the addition of Canada, Poland and Turkey manufacturing sites to the existing PD solutions’ marketing authorisations. The corresponding decision from the commission was issued on 12 May 2011. At this stage of the article 31 procedure, sufficient data is available to recommend the variation to the marketing authorisations consisting in the inclusion of the site located in the USA as additional manufacturing site, as no major quality issues were identified. The opinion on the Castlebar site cannot be finalised at this stage as issues remain for resolution by the marketing authorisation holder. The review of the issues identified at Castlebar, with the interruption of supply from this site, led to the need to authorise additional manufacturing sites to ensure supply of PD solutions in Europe. Whilst all data to finalise the ongoing article 31 is not available, a stepwise approach is followed for the assessment, resulting in subsequent opinions being adopted by the CHMP. Therefore, without prejudice to the ongoing article 31 procedure, the CHMP considers that sufficient information is available to issue a second opinion for this Article 31 procedure recommending the addition of the USA manufacturing site to the relevant PD solutions’ marketing authorisations, subject to conditions set out in the Annex IV. Overall, the following should be taken into account: - All drug substances should be supported by active substance master files or appropriate data and comply with Ph Eur requirements. - All starting materials (including excipients) should be subject to satisfactory routine control of microbial contamination and, unless justified, endotoxin testing. - Water for injections, and other excipients, should fully comply with Ph Eur monograph requirements, where applicable. - The current minimum standards for critical process parameters and limits e.g. for terminal sterilisation should be reviewed and improved, in compliance with process capabilities and best

19

practice. Terminal sterilisation has to be expressed as a minimum exposure time to a minimum temperature as per Ph. Eur. and should be harmonised at all involved sites. Consequently bioburden specifications of the filled containers should also be harmonised. The sterilisation process should be re-validated using biological indicators as per Ph. Eur.. Standard QP release should apply for all products released under the terms of EU marketing authorisations; in particular the QPs must be satisfied that the active substances are manufactured in accordance with EU GMP requirements. Pending conclusion of the ongoing Article 31, it is expected that the MAH implements in all its sites the outcome of lessons learned from the findings at Castlebar, to ensure a safe product supply. The introduction of a more sensitive kinetic turbidimetric limulus amebocyte lysate (LAL) method for endotoxin testing and the re-submission of the full description of the manufacturing processes for all sites together with its critical review should thus be undertaken. Additional measures may be requested subsequently for these sites, but pending conclusion of the ongoing article 31 these cannot be identified. The CHMP considers of extreme importance to retain coordination of the review of the conditions presently identified for the site in the USA. A harmonised European approach to supply has been in place since identification of the concern at Castlebar and the article 31 procedure remains ongoing pending resolution of the outstanding issues. The present opinion is the second of a series of entwined opinions, which may result subsequently in additional measures being requested for the site subject of the current opinion. The coordinated review of the conditions by the CHMP will enable the appropriate harmonious adjustments with minimum impact on supply of PD solutions to the EU market. Grounds for the addition of an additional manufacturing site to the marketing authorisations and amendment of the summaries of product characteristics and package leaflets Whereas The CHMP considered the referral under Article 31 of Directive 2001/83/EC, as amended, for

dialysis solutions from Baxter group of companies and associated companies produced at Castlebar.

The review of the issues identified at Castlebar is ongoing, and peritoneal dialysis solutions are not

being released from this manufacturing plant which is the main marketing authorisation holder’s supplier in Europe.

Unaffected batches of peritoneal dialysis solutions needed to be made available to patients across

the EU in the shortest possible timeframe, thus alternative PD solutions produced by Baxter at alternative manufacturing sites outside the EEA (European Economic Area) were prioritised.

The CHMP considers that sufficient quality data is available to recommend the inclusion of the

manufacturing site located in the USA into the existing marketing authorisations for the peritoneal dialysis solutions, as applicable.

the CHMP recommends the variation to the terms of the marketing authorisations concerning the addition of the manufacturing site in the USA and for which the relevant amendments to sections of the summaries of product characteristics and package leaflets are set out in Annex III for dialysis solutions from Baxter group of companies and associated companies produced at Castlebar (see Annex I). The conditions affecting the marketing authorisations are set out in Annex IV of the opinion.

20

Annex III

Amendments to the relevant sections of the summaries of product characteristics and package leaflets

21

Amendments to be included in the relevant sections of the summary of product characteristics and package leaflets for Dianeal PD4 and Extraneal, as applicable. Changes are shown as greyed boxed wording Summary of Product Characteristics DIANEAL PD4 6.3 Shelf life

The shelf life of the product as packaged for sale is 24 months 12 months (for medicinal products manufactured at Alliston, Canada and North Cove, USA only). The product, once removed from its overpouch, should be used immediately EXTRANEAL 6.3 Shelf Life

2 years 12 months (for medicinal products manufactured at Alliston, Canada and North Cove, USA only). The product, once removed from its overpouch should be used immediately. 6.5 Nature and Contents of Container Flexible PVC container holding 1.5, 2.0 or 2.5 litres. The lineo connector that may equip the Y transfer line of the twin bag, contains 10.5% of Povidone iodine ointment 1.5 L 8 units per box Single bag Sy II (luer connector) 1.5 L 8 units per box Single bag Sy III (spike connector) 1.5 L 8 units per box Twin bag Sy II (luer connector) 1.5 L 8 units per box Twin bag Sy III (spike connector) 1.5 L 6 units per box Single bag Sy II (luer connector) 1.5 L 6 units per box Single bag Sy III (spike connector) 1.5 L 6 units per box Twin bag Sy II (luer connector) 1.5 L 6 units per box Twin bag Sy III (spike connector) 1.5 L 6 units per box Twin bag (lineo connector) 2.0 L 8 units per box Single bag Sy II (luer connector) 2.0 L 8 units per box Single bag Sy III (spike connector) 2.0 L 8 units per box Twin bag Sy II (luer connector) 2.0 L 8 units per box Twin bag Sy III (spike connector) 2.0 L 6 units per box Single bag Sy II (luer connector) 2.0 L 6 units per box Single bag Sy III (spike connector) 2.0 L 6 units per box Twin bag Sy II (luer connector) 2.0 L 6 units per box Twin bag Sy III (spike connector) 2.0 L 5 units per box Single bag Sy II (luer connector) 2.0 L 5 units per box Single bag Sy III (spike connector) 2.0 L 5 units per box Twin bag Sy II (luer connector) 2.0 L 5 units per box Twin bag Sy III (spike connector) 2.0 L 5 units per box Twin bag (lineo connector) 2.5 L 5 units per box Single bag Sy II (luer connector) 2.5 L 5 units per box Single bag Sy III (spike connector) 2.5 L 5 units per box Twin bag Sy II (luer connector) 2.5 L 5 units per box Twin bag Sy III (spike connector) 2.5 L 4 units per box Single bag Sy II (luer connector) 2.5 L 4 units per box Single bag Sy III (spike connector) 2.5 L 4 units per box Twin bag Sy II (luer connector) 2.5 L 4 units per box Twin bag Sy III (spike connector) 2.5 L 4 units per box Twin bag (lineo connector) Not all pack sizes may be marketed.

22

Patient Information Leaflet EXTRANEAL 5. How to store EXTRANEAL Keep out of the reach and sight of children. Store in the original package. Do not store below 4°C. Do not use EXTRANEAL after the expiry date. The date is stated on the carton label and on the bag

after the abbreviation Exp. and the symbol . The expiry date refers to the last day of that month. Dispose EXTRANEAL as you have been trained Patient Information Leaflet Volume Number of Product configuration Type of connector(s) units per box 1.5L 8 Single bag (APD) luer /spike 1.5L 8 Twin bag (CAPD) luer / spike 1.5L 6 Single bag (APD) luer /spike 1.5L 6 Twin bag (CAPD) luer / spike /lineo 2.0L 8 Single bag (APD) luer/spike 2.0L 8 Twin bag (CAPD) luer/spike 2.0L 6 Single bag (APD) luer/spike 2.0L 6 Twin bag (CAPD) luer/spike 2.0L 5 Single bag (APD) luer / spike 2.0L 5 Twin bag (CAPD) luer / spike / lineo 2.5L 5 Single bag (APD) luer/spike 2.5L 5 Twin bag (CAPD) luer/spike 2.5L 4 Single bag (APD) luer / spike 2.5L 4 Twin bag (CAPD luer / spike /lineo The Lineo connector contains iodine. Not all configurations may be marketed.

23

Annex IV

Conditions of the marketing authorisation

24

The following conditions should be fulfilled by the marketing authorisation holder. The CHMP considers of extreme importance to retain coordination of the review of the conditions presently identified for the site in the USA. A harmonised European approach to supply has been in place since identification of the concern at Castlebar and the article 31 procedure remains ongoing pending resolution of the outstanding issues. The present opinion is the second1 of a series of entwined opinions, which may result subsequently in additional measures being requested for the site subject of the current opinion. The coordinated review by the CHMP of the conditions of the site in theUSA, as done for the sites subject to the first opinion, will enable the appropriate harmonious adjustments with minimum impact on supply of PD solutions to the EU market. Therefore, data relation to the following conditions should be submitted and reviewed b

in y the CHMP.

USA manufacturing site The MAH should address the following: 1. All drug substances should be supported by active substance master files or appropriate data and comply with European Pharmacopoeia (Ph. Eur.) requirements. Suppliers of active substance listed below have not previously been used in EU product and active substance master files (ASMF’s) or equivalent data packages should be submitted for these suppliers. A change management plan, including timelines for implementation should be submitted within one week of Commission Decision. In addition, where applicable, they should be tested and shown to comply with the European Pharmacopoeia (Ph.Eur.), prior to the release of PD solutions to the EU market under the EU marketing authorisation. In particular:

- Dextrose anhydrous; - sodium chloride;

- Sodium S-Lactate. 2. The excipients water for injections, hydrochloric acid and sodium hydroxide are controlled according to the United States Pharmacopoeia. These should be tested and results submitted to shown they comply with the Ph. Eur. prior to the release of PD solutions to the EU market under the EU marketing authorisation.

3. The current minimum standards for critical process parameters and limits e.g. for terminal sterilisation should be reviewed and improved, in compliance with process capabilities and best practice. Terminal sterilisation has to be expressed as a minimum exposure time to a minimum temperature as per Ph. Eur. and should be harmonised at all involved sites. Consequently bioburden specifications of the filled containers should also be harmonised. The sterilisation process should be re-validated using biological indicators as per Ph. Eur. A change management plan, including timelines for implementation should be submitted within one week of Commission Decision. 4. Routine microbial monitoring of all the starting materials (including excipients) should be undertaken and the appropriate change management plan, including timelines for implementation should be submitted within one week of Commission Decision. 5. Stability data, including long term and accelerated in products produced in accordance with EU specifications should be provided. An appropriate change management plan should be submitted within three weeks of Commission Decision. 6. Standard QP release should apply for all products released under the terms of EU marketing authorisations; in particular the QPs must be satisfied that the active substances are manufactured in accordance with EU GMP requirements. The declaration should be provided prior to the release of PD solutions to the EU market under the EU marketing authorisation. Pending conclusion of the ongoing Article 31, the MAH should implement in all its sites the outcome of lessons learned from the findings at Castlebar, to ensure a safe product supply. In particular 7. A more sensitive kinetic turbidimetric limulus amebocyte lysate (LAL) method for endotoxin testing should be introduced. A change management plan, including timelines for implementation should be submitted within three weeks of Commission Decision.

1 A first opinion regarding inclusion of sites located in Canada, Poland and Turkey was adopted by the CHMP in April. The corresponding European Commission decision was issued on 12 May 2011.

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8. The full description of manufacture (3.2.P.3) for the site together with its critical review should be submitted. A change management plan, including timelines for implementation should be submitted within three weeks of Commission Decision. Additional measures may be requested subsequently for all sites, but pending conclusion of the ongoing article 31 these cannot be identified.

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