Paul-Ehrlich-Institut

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1 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 1 Paul-Ehrlich-Institut Federal Institute for Vaccines and Biomedicines FINALISATION REPORT ON VARIATION TYPE II PRODUCT DETAILS Name of products Active ingredient(s) Target Species APPLICATION(S) DETAILS Type of application Name and address of Applicant List of CMS Rispoval IBR-Marker Inactivatum Inactivated Bovine Herpes Virus Type 1 (BoHV-1), strain Difivac (ge-negative) Cattle Variation Type II: Change the recommendations for booster vaccinations (C.I.4, Typ II) Pfizer Limited Ramsgate Road Sandwich, Kent CT13 9NJ United Kingdom +32 (0) frederic.descamps@pfizer.com BE, BG, CZ, EE, ES, FR, HU, IE, IT, LT, LU, LV, NL, PL, PT, RO, SI, SK, UK ORIGINATING MEMBER STATE DETAILS RMS Germany Date of preparation and assessor 02. October, 2012 / Dr Brigitte Küchler Marketing authorisation number 497a/93 Decentralised Procedure DE/V/0021/001/II/014 Reference Number CONTACT WITH THE ORIGINATING MEMBER STATE Contact name Dr Brigitte Küchler / Dr Ingun Lemke Address Paul-Ehrlich-Institut Paul-Ehrlich-Str , D Langen Phone and fax numbers / address (if available) Brigitte.Kuechler@pei.de, Ingun.Lemke@pei.de Paul-Ehrlich-Institut Paul-Ehrlich-Straße Telefon /77-0 Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel D Langen Telefax / Federal Institute for Vaccines and Biomedcines Postfach D Langen

2 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 2 KEY DATES Variation Procedure Start Date (day 0) Date of Preparation of PVAR (day 40) Deadline for comment to RMS (day 55) RSI clock stop (day 59) Restart of procedure, RMS circulates FVAR (day 60) CMSs send comments on the FVAR to RMS (day 80) End of procedure (day 90) (Wed) (Mon) (Tue) (Sat) (Tue) (Mon) (Thu) Conclusion The data presented support the proposed SPC changes concerning change of recommendations for booster vaccinations for Rispoval IBR-Marker Inactivatum to be consistent with the recently approved modified SPC for Rispoval IBR-Marker Vivum, by adding the option for using Rispoval IBR-Marker Inactivatum for booster vaccinations in animals initially vaccinated with Rispoval IBR-Marker Vivum. There are no adequate and objective reasons not to amend the national marketing authorisations. The revised SPC, leaflet and labels are attached in Annex 1 to this finalisation report. Overall Conclusion The Member States are of the opinion that the requested variations to the product Rispoval IBR- Marker Inactivatum can be accepted. Therefore the Member States are prepared to amend the national marketing authorisations for Rispoval IBR-Marker Inactivatum. Thus, the RMS declares the variation type II procedure finalised. The date of effect of this decision is fixed on 04. October, Dr Brigitte Küchler

3 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 3 Annex 1: Day 90 SPC and PL SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE VETERINARY MEDICINAL PRODUCT Rispoval IBR-Marker Inactivatum Suspension for injection for cattle Rispoval IBR-Marker Inactivated (only UK and Ireland) Rispoval IBR-Marker (only FR) Rispoval IBR-Marker Inattivato (only IT) 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One dose (2 ml) contains: Immunologically Active Substances: Bovine Herpes Virus type 1 (BHV-1), strain Difivac ( ge-negative), to produce a geometrical mean serum neutralising titre of min. 1:160 in cattle Adjuvants Aluminium hydroxide mg mg Quil A 0.25 mg 0.25 mg Other components: Preservative Thiomersal 0.2 mg For a complete list of excipients please refer to section PHARMACEUTICAL FORM Suspension for injection. 4. CLINICAL PARTICULARS 4.1 Target species Cattle. 4.2 Indications for use, specifying the target species For active immunisation of cattle against Infectious Bovine Rhinotracheitis (IBR), to reduce the clinical signs and virus shedding and to prevent abortions associated with BHV-1 infection in female cattle. Vaccination of gestating cattle prevents abortions as proven by challenge infection 28 days after vaccination during the second trimester of gestation. Vaccinated cattle can be

4 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 4 differentiated from field virus infected animals due to the marker deletion, unless the cattle were previously vaccinated with a conventional vaccine or infected with field virus. Duration of immunity: - For booster immunisation after primovaccination with Rispoval IBR Marker Vivum (in member states where this product is authorized) to reduce the virus shedding and the clinical signs associated with BHV-1 infection in cattle. When using the combined vaccination scheme, protection against abortions has not been investigated. Duration of immunity : 6 month after complete primovaccination with Rispoval IBR Marker Vivum followed by 12 month after annual booster with Rispoval IBR Marker Inactivatum 4.3 Contra-Indications Do not use in diseased or weak cattle Special warnings None. 4.5 Special precautions for use Special precautions for use in animals None. Special precautions to be taken by the person administering the medicinal product to animals In case of accidental self-injection, seek medical advice immediately and show the package insert or the label to the physician. 4.6 Undesirable effects (frequency and seriousness) In very rare cases, transient subcutaneous swelling of up to 5 cm diameter may occur at the injection site, which subsides within 14 days. In very rare cases allergic reactions may occur as with other vaccines, therefore vaccinates should be supervised for approx. 30 min. following immunisation. In those cases, antiallergics should be administered. 4.7 Use during pregnancy and lactation Can be used during pregnancy and lactation.

5 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page Interaction with other vaccines and medicinal products when administered in combination with the product Immunosuppressive substances, i.e. corticosteroids or Bovine Virus Diarrhoea modified live vaccines, should be avoided during a period of 7 days prior to and after vaccination as these may impair the development of the immunity. No data is available on safety and efficacy of concomitant use with other veterinary medicinal products. Therefore a decision to use the vaccine with other veterinary drugs should be made on a case by case basis. 4.9 Posology and method of administration Posology One dose of the vaccine for subcutaneous injection is 2 ml for cattle over 3 months of age. The vaccination scheme consists of basic immunisation and booster vaccinations. Basic immunisation: Two injections of 1 dose (2 ml) each 3-5 weeks apart. Booster vaccinations of cattle having been administered the primary vaccination scheme using Rispoval IBR-Marker Inactivatum: 1 dose (2 ml) apart. Booster Vaccinations of cattle having been administered the primary vaccination scheme using Rispoval IBR-Marker Vivum (in member states where this product is authorized): Cattle having been administered the primary vaccination scheme using Rispoval IBR-Marker Vivum (according to the product information for this product) may be given booster vaccinations with Rispoval IBR-Marker Inactivatum. These animals should be given a single dose booster vaccination with Rispoval IBR-Marker Inactivatum after their initial vaccination course with Rispoval IBR-Marker Vivum. Thereafter, single dose booster vaccinations with Rispoval IBR- Marker Inactivatum should be administered every 12 months. In case of vaccination of calves under the age of 3 months the development of an immunity may be impaired by maternal antibodies. These calves should be revaccinated at an age of over 3 months. It is recommended to vaccinate all cattle of a herd. Method of administration Shake the vaccine well before use. The liquid suspension is injected aseptically via the subcutaneous route.

6 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 6 Vaccination schemes summary From 2 weeks to 3 months of age Rispoval IBRm vaccine used Primary Booster vaccination vaccination (number of at 3 months doses) of age (number of doses) Vivum Vivum (once) Vivum (once) (once) Vivum (once) Revaccination intervals Interval to next booster vaccination (vaccine) (Vivum) All subsequent booster vaccinations (vaccine) (Vivum) 12 months From 3 months of age Rispoval IBRm vaccine used Revaccination intervals Primary vaccination (number of doses) Interval to first booster vaccination (vaccine) All subsequent booster vaccinations (vaccine) Vivum (once) (Vivum) (Vivum) Vivum (once) 12 months Inactivatum (twice with 3-5 week interval) 4.10 Overdose (symptoms, emergency procedures, antidotes) (if necessary) Reactions observed after administration of a twofold overdose do not differ from the reactions after administration of a single dose Withdrawal period(s) Zero days 5. IMMUNOLOGICAL PROPERTIES Inactivated virus vaccine ATCvet Code: QI02AA03 The vaccine induces immunity in cattle against clinical respiratory signs caused by the Infectious Bovine Rhinotracheitis (IBR) virus. Following infection, the intensity and duration of clinical signs as well as the titre and duration of virus shedding are significantly reduced. As with other vaccines, vaccination may not completely prevent an infection but does reduce the risk of infection. The product induces in vaccinated cattle antibodies, which are detected in the serum neutralisation test and in conventional ELISA. With specific test kits these antibodies can be

7 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 7 differentiated - due to the lack of antibodies against ge - from those of animals infected by field virus or animals vaccinated with conventional vaccines. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Phenolsulfonphthalein HEPES-Sodium Sodium Thiosulfat Thiomersal Minimal medium with Earle saline 6.2 Incompatibilities Do not mix with any other veterinary products. 6.3 Shelf-life Shelf-life of the veterinary drug according to label: 24 months. Shelf life after broaching the primary packaging : 8 hours 6.4. Special precautions for storage Store in a refrigerator (+ 2 C to + 8 C). Protect from frost and light. Do not freeze. 6.5 Nature and contents of container Multidose containers: 10 doses: 1 glass vial with 20 ml (10 doses) inactivated vaccine, closed with bromobytyl stoppers and sealed with an aluminium ring with a flip-off cap, packed as 1 vial in a folding carton. 50 doses: 1 glass vial with 100 ml (50 doses) inactivated vaccine, closed with bromobytyl stoppers and sealed with an aluminium ring with a flip-off cap, packed as 1 vial in a folding carton 6.6 Special precautions for the disposal of unused medicinal product or waste materials, if any Any unused product or waste material should be disposed of in accordance with national requirements.

8 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 8 7. NAME OR CORPORATE NAME AND ADDRESS OR REGISTERED PLACE OF BUSINESS OF THE MARKETING AUTHORISATION HOLDER Pfizer GmbH Linkstraße Berlin 8. MARKETING AUTHORISATION NUMBER Zul.-Nr.: 497a/93 9. DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION 28 October 1994 / 26 October DATE OF REVISION OF THE TEXT October 2012 Prohibition of sale, supply and/or use Not applicable.

9 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 9 <PARTICULARS TO APPEAR ON THE OUTER PACKAGE> <PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGE> Folding Carton 1x 20 ml (10 doses), 1x100 ml (50 doses) 1. NAME OF THE VETERINARY MEDICINAL PRODUCT Rispoval IBR-Marker Inactivatum Suspension for injection for cattle 2. STATEMENT OF ACTIVE AND OTHER SUBSTANCES One dose (2 ml) contains BHV-1, strain Difivac ( ge-negative), to produce a geometrical mean serum neutralising titre of min. 1:160 in cattle Aluminium hydroxide Quil A Thiomersal 3. PHARMACEUTICAL FORM Suspension for injection 4. PACKAGE SIZE 1 x 20 ml (10 doses) 1 x 100 ml (50 doses) 5. TARGET SPECIES Cattle 6. INDICATION(S) For active immunisation of cattle against Infectious Bovine Rhinotracheitis (IBR), to reduce the clinical signs and virus shedding, and to prevent abortions associated with BHV-1 infections in female cattle. 7. METHOD AND ROUTE(S) OF ADMINISTRATION Dosage: 2 ml for cattle at an age of 3 months. Route of administration: subcutaneous injection. Vaccination scheme: Two injections 3 5 weeks apart. Booster vaccination every 6-12months (depending on vaccine used for primary vaccination). Shake well before use. Read the package leaflet before use. 8. WITHDRAWAL PERIOD Zero days.

10 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page SPECIAL WARNING(S), IF NECESSARY 10. EXPIRY DATE <EXP {month/year}> Once broached use within 8 hours. 11. SPECIAL STORAGE CONDITIONS Store in a refrigerator (+ 2 C to + 8 C). Protect from frost and light. Do not freeze. 12. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCTS OR WASTE MATERIALS, IF ANY Any unused product or waste material should be disposed of in accordance with national requirements. 13. THE WORDS FOR ANIMAL TREATMENT ONLY AND CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE, IF APPLICABLE For animal treatment only. To be supplied only on veterinary prescription. 14. THE WORDS KEEP OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 15. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Pfizer GmbH Linkstraße Berlin 16. MARKETING AUTHORISATION NUMBER(S) Zul.-Nr.: 497a/ MANUFACTURER S BATCH NUMBER <Batch> {number}

11 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 11 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Label on the glass vial 20 ml (10 doses), 100 ml (50 doses) 1. NAME OF THE VETERINARY MEDICINAL PRODUCT Rispoval IBR-Marker Inactivatum Suspension for injection for cattle 2. QUANTITY OF THE ACTIVE SUBSTANCE(S) One dose (2 ml) contains BHV-1, strain Difivac ( ge-negative), to produce a geometrical mean serum neutralising titre of min. 1:160 in cattle Aluminium hydroxide Quil A Thiomersal 3. PHARMACEUTICAL FORM Suspension for injection 4. CONTENTS BY WEIGHT, BY VOLUME OR BY NUMBER OF DOSES 20 ml (10 doses) 100 ml (50 doses) 5. TARGET SPECIES Cattle 6. INDICATION(S) For active immunisation of cattle against Infectious Bovine Rhinotracheitis (IBR), to reduce the clinical signs and virus shedding, and to prevent abortions associated with BHV-1 infections in female cattle. 7. METHOD AND ROUTE(S) OF ADMINISTRATION Dosage: 2 ml for cattle at an age of 3 months. Route of administration: subcutaneous injection. Shake well before use. Read the package leaflet before use. 8. WITHDRAWAL PERIOD Zero Days

12 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page SPECIAL WARNING(S), IF NECESSARY 10. EXPIRY DATE <EXP {month/year}> Once broached use within 8 hours. 11. SPECIAL STORAGE CONDITIONS Store in a refrigerator (+ 2 C to + 8 C). Protect from frost and light. Do not freeze. 12. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCTS OR WASTE MATERIALS, IF ANY Any unused product or waste material should be disposed of in accordance with national requirements. 13. THE WORDS FOR ANIMAL TREATMENT ONLY AND CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE, IF APPLICABLE For animal treatment only. To be supplied only on veterinary prescription. 14. THE WORDS KEEP OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 15. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Pfizer GmbH Linkstraße Berlin 16. MARKETING AUTHORISATION NUMBER(S) Zul.-Nr.: 497a/ MANUFACTURER S BATCH NUMBER <Batch> {number}

13 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 13 Rispoval IBR-Marker Inactivatum Suspension for injection for cattle PACKAGE LEAFLET 1. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER AND OF THE MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE, IF DIFFERENT Marketing authorisation holder: Pfizer GmbH Linkstraße Berlin Manufacturer for the batch release: Pfizer Animal Health s.a. Rue Laid Burniat, 1 B-1348 Louvain-la-Neuve Belgien 2. NAME OF THE VETERINARY MEDICINAL PRODUCT Rispoval IBR-Marker Inactivatum Suspension for injection for cattle. 3. STATEMENT OF THE ACTIVE SUBSTANCE(S) AND OTHER INGREDIENT(S) One dose (2 ml) contains: Bovine Herpes Virus Type 1 (BHV-1), strain Difivac (ge-negative), to produce a geometrical mean serum neutralising titre of min. 1:160 in cattle. Adjuvants: Aluminium hydroxide Quil A Excipients: Thiomersal mg 0.25 mg 0.2 mg 4. INDICATION(S) For active immunisation of cattle against Infectious Bovine Rhinotracheitis (IBR), to reduce the clinical signs and virus shedding and to prevent abortions associated with BHV-1 infection in female cattle. Vaccination of gestating cattle prevents abortions as proven by challenge infection 28 days after vaccination during the second trimester of gestation. Vaccinated cattle can be differentiated from field virus infected animals due to the marker deletion, unless the cattle were previously vaccinated with a conventional vaccine or infected with field virus. Duration of immunity:

14 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 14 - For booster immunisation after primovaccination with Rispoval IBR Marker Vivum (in member states where this product is authorized) to reduce the virus shedding and the clinical signs associated with BHV-1 infection in cattle. When using the combined vaccination scheme, protection against abortions has not been investigated. Duration of immunity : 6 month after complete primovaccination with Rispoval IBR Marker Vivum followed by 12 month after annual booster with Rispoval IBR Marker Inactivatum 5. CONTRAINDICATIONS Do not use in diseased or weak cattle. 6. ADVERSE REACTIONS In very rare cases, transient subcutaneous swelling of up to 5 cm diameter may occur at the injection site, which subsides within 14 days. In very rare cases allergic reactions may occur as with other vaccines, therefore vaccinates should be supervised for approx. 30 min. following immunisation. In those cases, antiallergics should be administered. If you notice any serious effects or other effects not mentioned in this leaflet, please inform your veterinary surgeon. 7. TARGET SPECIES Cattle 8. DOSAGE FOR EACH SPECIES, ROUTE(S) AND METHOD OF ADMINISTRATION Posology: 2 ml for cattle over 3 months of age. Method of administration: subcutaneous injection. Vaccination scheme: The vaccination scheme consists of a basic immunisation and booster vaccinations. Basic immunisation: Two injections of 1 dose (2 ml) each 3-5 weeks apart. Booster vaccinations of cattle having been administered the primary vaccination scheme using Rispoval IBR-Marker Inactivatum: One single dose of 2 ml in intervals of. Booster Vaccinations of cattle having been administered the primary vaccination scheme using Rispoval IBR-Marker Vivum (in member states where this product is authorized): Cattle having been administered the primary vaccination scheme using Rispoval IBR-Marker Vivum (according to the product information for this product) may be given booster vaccinations with Rispoval IBR-Marker Inactivatum. These animals should be given a single dose booster vaccination with Rispoval IBR-Marker Inactivatum after their initial vaccination course with Rispoval IBR-Marker Vivum. Thereafter, single dose booster vaccinations with Rispoval IBR- Marker Inactivatum should be administered every 12 months.

15 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 15 It is recommended to vaccinate all cattle of a herd. Shake the vaccine well before use. For administration of the vaccine always use sterile needles and syringes. Avoid entry of extraneous agents during administration. In case of vaccination of calves under the age of 3 months the development of an immunity may be impaired by maternal antibodies. These calves should be revaccinated at an age of over 3 months. Vaccination schemes summary From 2 weeks to 3 months of age Rispoval IBRm vaccine used Primary Booster vaccination vaccination (number of at 3 months doses) of age (number of doses) Vivum Vivum (once) (once) Vivum (once) Vivum (once) Revaccination intervals Interval to next booster vaccination (vaccine) (Vivum) All subsequent booster vaccinations (vaccine) (Vivum) 12 months From 3 months of age Rispoval IBRm vaccine used Revaccination intervals Primary vaccination (number of doses) Interval to first booster vaccination (vaccine) All subsequent booster vaccinations (vaccine) Vivum (once) (Vivum) (Vivum) Vivum (once) 12 months Inactivatum (twice with 3-5 week interval) 9. ADVICE ON CORRECT ADMINISTRATION None 10. WITHDRAWAL PERIOD Zero Days. 11. SPECIAL STORAGE PRECAUTIONS Keep out of the reach and sight of children.

16 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 16 Store in a refrigerator (+ 2 C to + 8 C). Protect from frost and light. Do not freeze. Do not use the veterinary medicinal product after the expiry date indicated on the label. Once broached use within 8 hours. 12. SPECIAL WARNING(S) For animal treatment only. To be supplied only on veterinary prescription. Can be used during pregnancy and lactation. Immunosuppressive substances, i.e. corticosteroids or Bovine Virus Diarrhoea modified live vaccines, should be avoided during a period of 7 days prior to and after vaccination as these may impair the development of the immunity. No data is available on safety and efficacy of concomitant use with other veterinary medicinal products. Therefore a decision to use the vaccine before or after other veterinary drugs should be made on a case by case basis. Do not mix with other veterinary drugs. Reactions observed after administration of an overdose do not differ from the reactions after administration of a single dose. Special precautions to be taken by the person administering the medicinal product to animals In case of accidental self-injection, seek medical advice immediately and show the package insert or the label to the physician. 13. SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCT OR WASTE MATERIALS, IF ANY Any unused product or waste material should be disposed of in accordance with national requirements. 14. DATE ON WHICH THE PACKAGE LEAFLET WAS LAST APPROVED October OTHER INFORMATION> Rispoval IBR-Marker Inactivatum can be used during pregnancy and lactation. The virus particles in Rispoval IBR-Marker Inactivatum are lacking the glycoprotein ge. Therefore the vaccine virus and the antibodies produced against it can be clearly distinguished from field virus strains or antibodies against them by serological methods, as long as the animals were not previously infected by field virus or vaccinated with conventional vaccines. The vaccine induces immunity in cattle against clinical respiratory signs caused by the Infectious Bovine Rhinotracheitis (IBR) virus. Intensity and duration of clinical signs as well as the titre and duration of virus shedding are significantly reduced. As with other vaccines, vaccination may not completely prevent an infection, but does reduce the risk of infection. The product induces in

17 Paul-Ehrlich-Institut DE/V/0021/001/II/014 Page 17 vaccinated cattle antibodies, which are detected in the serum neutralisation test and in conventional ELISA. By using specific ge test kits, these antibodies can be differentiated from those antibodies found in animals infected by field virus or in animals vaccinated with conventional vaccines. Vaccination of all cattle in a herd, infected and non-infected alike, is recommended. After use of Rispoval IBR-Marker Inactivatum the risk of infection as well as titre and duration of virus shedding are reduced. The duration of a vaccination scheme until the status of a BHV-1 free herd is reached depends upon the original extent of the BHV-1 infection in the herd and the culling of persistently BHV-1 positive animals. Pack sizes: 1 x 20 ml (10 doses) 1 x 100 ml (50 doses) Not all pack sizes may be marketed. For any information about this veterinary medicinal product, please contact the local representative of the marketing authorisation holder.