DCMO letter11.02 BCG.doc

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abcdefghijklm Health Department To: 1. Directors of Public Health, NHS Boards 2. Immunisation Co-ordinators 3. Medical Directors of Trusts for cascade to GPs,

Respiratory Physicians, Chest Clinics, Infection Control Teams, School and Community Health colleagues

4. Specialists in Pharmaceutical Public Health for cascade to Trust Chief Pharmacists and Community Pharmacists

5. Directors of Nursing NHS Trusts and Boards for cascade to Practice and Community Nurses

6. Chief Executives of NHS Trusts 7. Director, SCIEH 8. NHS 24

St Andrew’s House Regent Road Edinburgh EH1 3DG Telephone: 0131-244 2270 Fax: 0131-244 2835 e.mail: andrew.fraser@scotland.gsi.gov.uk http://www.scotland.gov.uk 22 November 2002

Dear Colleague IMPORTANT INFORMATION FOR MEDICAL AND HEALTHCARE PROFESSIONALS ABOUT NEW BCG VACCINE STATENS SERUM INSTITUT (SSI) The Marketing Authorisation for BCG Vaccine SSI was granted by the Medicines Control Agency (MCA) under the Mutual Recognition Procedure on 9 September 2002 and this vaccine will shortly be available for use in the UK. The application was submitted under the Mutual Recognition Procedure prior to withdrawal of the BCG Vaccines manufactured by Evans Vaccines Ltd on 9 August 2002 (ref EL(02)A/14). Whilst BCG Vaccine SSI is essentially similar to the Evans BCG Vaccine Intradermal there are two major changes that medical, nursing and pharmacy staff must be aware of before using the SSI vaccine: • The recommended dose of BCG SSI vaccine for children is different. It is important to follow

the revised instructions given in the Summary of Product Characteristics • SSI does not produce a percutaneous preparation of BCG vaccine for administration by the

multiple puncture technique. All BCG vaccine, including that administered to babies, must now be given intradermally using a syringe and needle.

The attached information gives details of these and other important changes. Please ensure that you note this information. BCG vaccine SSI is supplied in boxes of 10 x multidose vials with a separate box of 10 x vials of diluent. A pad of patient information leaflets will also be supplied. The vaccine is available, through Childhood Vaccine Holding Centres, in the usual way. The order code is SCOBCG101. You need only use this one order code to automatically receive the vaccine, diluent and information leaflets.

DCMO letter11.02 BCG.doc

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There will be two deliveries of the vaccine to Farillon from SSI during November and December to meet the needs of the schools sessions, the higher-risk catch-up and to provide for on-going use thereafter. While there will be sufficient stock for all these requirements, you are asked to order only what you need for immediate use to allow everyone to have some access to the initial delivery. The information contained in this letter is also available on the SHOW website – www.show.scot.nhs.uk/sehd/publications. If you have further enquires please write to the relevant member of the Immunisation Team at the Department as follows: On vaccine supply issues contact Siobhan Souness at Scottish Healthcare Supplies, tel: 0131 551 8890 or fax: 0131 551 8890 e-mail: siobhan.souness@shs.csa.scot.nhs.uk On clinical issues write to Dr Elizabeth Stewart, Public Health Professional Group, Room 2N.14, St Andrew’s House, Regent Road, Edinburgh EH1 3DG. On vaccine policy issues write to Wendy McKendrick, Area 3E(S) in St Andrew’s House. On pharmacy issues write to Mrs Norma Darroch, Room 1E.16 in St Andrew’s House. Yours sincerely

Dr Andrew Fraser DEPUTY CHIEF MEDICAL OFFICER

INFORMATION FOR MEDICAL AND HEATHCARE PROFESSIONALS ABOUT BCG VACCINE STATENS SERUM INSTITUT (SSI).

This information sheet contains the following details and advice:

1. Comparison table of the Summary of Product Characteristics (SPC) of the 1.0ml Intradermal BCG vaccine manufactured by Statens Serum Institut (SSI) and the 10-dose Intradermal BCG vaccine from Evans Vaccines.

2. A copy of the approved SPC for the BCG Vaccine SSI

(Appendix 1).

3. A copy of the approved text of the Patient Information Leaflet (PIL) for the BCG Vaccine SSI (Appendix 2).

4. A copy of the approved text of the information for medical and

healthcare professionals (an abbreviated version of the SPC that is included as a detachable section of the PIL) (Appendix 3)

The box of 10 x 1ml BCG vaccine from SSI will include only (3) and (4) above, i.e. a Patient Information Leaflet with the abbreviated information for medical or healthcare professionals attached. The comparison table provides information from the most recent approved Summary of Product Characteristics (SPC) for both the Statens Serum Institut (SSI) 1.0ml and Evans 10 dose Intradermal BCG Vaccines. The section numbers quoted refer to those in the SSI SPC (Appendix 1). It should be noted that certain details are given in different sections of the Evans Vaccine SPC. The table contains details of those SPC sections where the information or guidance for either the SSI or the Evans BCG are different. Those areas of the SPCs not listed are those where the information given is either identical or essentially similar. The references to the “Green Book” in the recommendation/note column relate to the handbook “Immunisation against Infectious Disease 1996”. It should be noted that SSI do not manufacture a Percutaneous BCG vaccine. Bold text has been used in the table to highlight significant areas. The initial deliveries of vaccine from SSI will have a supplementary label on the box which clarifies the dosage recommendations. Subsequent vaccine supplies will be supplied with this revised instructions included on the main box label.

Characteristics

SSI Evans Recommendations/ Notes

Qualitative and Quantitative Composition – SPC section 2.0

Mycobacterium bovis, BCG Danish Strain 1331

2-8 x 106 cfu per 1ml, equivalent to 0.2 –0.8 x 106 cfu per 0.1ml dose

BCG (Mycobacterium bovis not mentioned in the SPC) Copenhagen sub strain 1077. Dose given as viable units in 0.1ml dose 1 – 2.6 x 106

Differences reflect the different strains.

Pharmaceutical Form – SPC section 3.0

Powder for suspension. Separate solvent for suspension of the injection (Diluted Sauton “SSI”)

Freeze dried standardised preparation to be re-constituted with Water for Injections BP or Sodium Chloride Injection BP

Both BCG vaccines are freeze dried powders. BCGVaccine SSI must be suspended with the Diluted Sauton SSI solvent only.

Clinical Particulars SPC section 4.0

4.1. Therapeutic indications

For active immunisation against tuberculosis

Same as SSI plus a statement on vaccination and positive Mantoux test. This advice is given in section 5.1. of the SSI SPC.

Please cross refer to section 5.1. below. Tuberculin status should be assessed before vaccination using the Heaf or Mantoux test. Please refer to the “Green Book” for further details.

cfu = colony forming units

Characteristics SSI Evans Recommendations/

Notes 4.2. Posology Children 12

months and older: adults and the elderly 0.1 ml dose by intradermal injection. Children under 12 months: 0.05ml dose by intradermal injection.

Children 3 months and older: adults and the elderly 0.1 ml dose by intradermal injection. Children under 3 months: 0.05ml dose by intradermal injection. Subcutaneous injection must be avoided.

The recommended dose of BCG vaccine in children must follow the revised instructions given in the SSI SPC. Medical, Nursing and Pharmacy staff must be vigilant, as this will represent a change to clinical practice and guidance given in the “Green Book”.

Method of administration

Avoid contamination of the vaccination site with antiseptics.

Avoid contamination of the vaccination site with bactericides.

In the context of the use in the SPC – antiseptics and bactericides are one and the same.

The administration details are broadly similar. Precise details on the angle of the arm prior to administration is not included.

“The upper arm must be 45o to the body”.

Standard practice should continue as per the Evans Vaccine and the “Green Book”

Absent Good practice to record batch and expiry dates and date of administration.

Continue to maintain batch and expiry date records and date of administration.

No warning given. Administration of the vaccine into the leg in neonates has been associated with more severe reactions and should be avoided.

Neonatal administrations must be given into the upper arm only.

Jet injectors or multiple puncture devices should not be used.

Given in section 4.3 contra- indications section – multiple puncture technique should not be used.

The overall advice on administration is identical for both vaccines.

Characteristics SSI Evans Recommendations/ Notes

Contra-indications. SPC section 4.3

In areas where the risk of contracting tuberculosis and HIV is high, it may be appropriate to vaccinate asymptomatic HIV- positives with BCG according to WHO recommendations

Advice not included. The Joint Committee on Vaccination and Immunisation advise that BCG should not be administered to HIV infected individuals in the UK.

Special warnings and precautions in use. SPC section 4.4.

Tuberculin positive persons (consult national recommendations for the definition of a positive tuberculin reaction) do not require the vaccine. Administration of the vaccine to such persons may result in a severe local reaction.

Similar guidance given under section 4.3 with definition of positive tuberculin reaction.

Do not administer the BCG vaccine to individuals who are tuberculin positive. Such individuals will have either an induration of 5mm or greater in diameter in the Mantoux test or a Heaf grade 2 to 4. See the “Green Book” for more details.

Injections made too deeply increase the risk of lymphadenitis and abscess formation.

The SSI guidance is compatible with the advice given in the “Green Book”. The technique for intradermal injection is important.

Characteristics SSI Evans Recommendations/

Notes Interactions with other medicaments and other forms of injection. SPC section 4.5. (Refers to the SSI SPC section but this guidance should be given in 4.4 Special warnings and special precautions in use.)

Intradermal BCG vaccination may be given concurrently with inactivated or live vaccines, including combined MMR.

Similar guidance given in section 4.4 as follows: Intradermal BCG vaccination may be given concurrently with another live vaccine, including Oral Poliomyelitis Vaccine BP.

The SSI guidance is compatible with the advice given in the “Green Book”.

Other vaccines if not given at the same time as BCG an interval of not less than four weeks should normally be allowed to lapse between the administrations of any two live vaccines

Other vaccines if not given at the same time as BCG an interval of not less than three weeks should normally be allowed to lapse between the administrations of any two live vaccines

Allow 4 weeks interval between BCG vaccination and any other live vaccine.

Other vaccines given at the same time as BCG vaccine should not be given into the same arm.

Not given but both Evans and SSI recommend that no further vaccination should be given for at least three months in the arm used for BCG, because of the risks of lymphadenitis.

Follow the SSI SPC recommendations.

Absent. When Intradermal BCG is given to infants there is no need to delay the primary childhood immunisations.

Continue to follow the advice given in the “Green Book”.

Characteristics SSI Evans Recommendations/

Notes Undesirable effects SPC section 4.8.

No advice on the dressing of ulcers formed as the result of an excessive vaccination response.

Waterproof dressings should not be used on ulcers formed as the result of an excessive vaccination response.

Waterproof dressings should not be applied on ulcers formed as a result of an excessive vaccination response

The SPC carries a Black Triangle.

Any untoward reactions should be reported to the Regulatory Authorities and Marketing Authorisation Holder.

All suspected adverse events must be reported to the CSM using the Yellow Card Reporting System. From 31 October reporting of suspected adverse reactions to all medicines was extended to include nurses, midwives and health visitors as recognised reporters.

Pharmacological Properties – SPC Section 5

Pharmacodynamic properties – SPC Section 5.1

Vaccination confers a variable degree of protection to infection with M. tuberculosis

In British schoolchildren efficacy (protection against tuberculosis) is 70 to 80%.

The SSI statement reflects the current expert opinion on BCG vaccination.

The duration of immunity after BCG vaccination is not known, but there are some indications of waning immunity after 10 years.

The above sentence concludes with “with protection lasting at least 15 years.”

The duration of immunity is not known. Revaccination is not recommended.

Vaccinated persons normally become tuberculin positive after 6 weeks.

Evans gives a normal response after 8 weeks, but sometimes up to 14 weeks are needed.

Continue to monitor vaccination response as per current clinical practice.

Characteristics SSI Evans Recommendations/

Notes Pharmacodynamic properties – SPC Section 5.1

A positive tuberculin skin test does indicate a response of the immune system to the BCG vaccination or to a mycobacterial infection, however the relationship between post vaccination tuberculin skin test reaction and the degree of protection afforded by BCG remains unclear.

No similar statement in the Evans vaccine SPC.

The SSI statement reflects the current expert opinion on BCG vaccination.

Pharmaceutical Particulars – SPC section 6.0

List of excipients –SPC section 6.1.

BCG Vaccine Sodium glutamate Diluted Sauton SSI Magnesium sulphate Dipotassium phosphate Citric acid, monohydrate L-asparagine monohydrate Ferric ammonium citrate Glycerol 85% Water for Injections

Before freeze drying, each vial contains 0.5 to 1.0 ml (plus or minus 10%) of freeze drying medium of the following composition: Dextran Glucose Triton WR 1339 Water for Injections Diluent is either Water for Injections BP or Sodium Chloride Injection BP.

Both vaccines are freeze dried powders for re-constitution. The formulation differences reflect the differences in freeze drying methodology used by both manufacturers.

Incompatibilities – SPC section 6.2.

Only Diluted Sauton SSI may be used to reconstitute the BCG vaccine.

No incompatibilities are listed.

Do not use Water for Injections BP or Sodium Chloride Injection BP to reconstitute the SSI BCG vaccine.

Characteristics SSI Evans Recommendations/

Notes Shelf life – SPC section 6.3.

Vaccine – 18 months. Diluted Sauton SSI – 36 months.

10 dose Vaccine – 36 months. Water for Injections & Sodium Chloride Injection BP – 36 months.

Users are advised to review their ordering profile for SSI BCG vaccine to prevent wastage.

Reconstituted vaccine: From a microbiological point of view the product should be used immediately. In use stability in terms of viability has been demonstrated for 4 hours after reconstitution.

Reconstituted vaccine: After reconstitution, the vaccine should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

BCG Vaccine SSI must be used within 4 hours after reconstitution.

Special precautions for storage – SPC section 6.4.

Store protected from light.

Store in the original container.

Users are advised to store the SSI vaccine in the original container to protect the vaccine from light.

Characteristics SSI Evans Recommendations/

Notes Nature and contents of the container – SPC section 6.5.

Nature and contents: Details of the glass container type, seal and closure are absent. Details of vial size is also absent.

Full details given. BCG Vaccine SSI is presented in amber glass vials and the diluent “Diluted Sauton SSI” is presented in a clear/colourless glass vial.

Presentations: Four presentations listed.

Not given. At this stage SSI will be supplying the 10 x 1ml BCG and 10 x 1ml Diluted Sauton SSI in separate boxes to the NHS. There is no direct statement in the SSI SPC that a 1ml BCG vial contains 10 doses. Each vial contains a maximum of 10 doses and it is envisaged that in practice a maximum of 6 to 7 doses of BCG may be administered from each vial.

Characteristics SSI Evans Recommendations/

Notes Instructions for use and handling – SPC section 6.6.

Reconstitution: “transfer to the vial the volume of Diluted Sauton SSI given on label”

Reconstitution: 1ml of Water for injections BP or Sodium Chloride Injection BP for a 10-dose vial.

The advice on the volume of diluent to be used to reconstitute the BCG Vaccine SSI is given on the vaccine vial label

SSI recommend that the vial is gently inverted a few times to resuspend the vaccine.

Evans recommend that the reconstituted vaccine should be allowed to stand for one minute, then draw into the syringe twice to ensure homogeneity.

The instructions for reconstitution of the BCG Vaccine SSI must be followed. Do not shake the vaccine vial.

Gently swirl the vial of the resuspended vaccine in between doses.

Not applicable SSI vaccine is a suspension.

Appearance of the reconstituted vaccine.

Homogeneous, slightly opaque, colourless suspension

Clear liquid. The appearance of the BCG Vaccine SSI may appear slightly cloudy compared to the Evans vaccine.

Disposal instructions Not given. Any unused product or waste material should be disposed of in accordance with local requirements. Recommended disposal should be at a temperature not less than 1100oC.

Any unused product or waste material should be disposed of in accordance with local requirements. Recommended disposal should be at a temperature not less than 1100oC.

Section C - Page 1

Appendix (1).

SUMMARY OF PRODUCT CHARACTERISTICS BCG VACCINE SSI.

Product Summary 1. Trade Name of the Medicinal Product

BCG Vaccine “SSI”, powder for suspension for injection.

2. Qualitative and Quantitative Composition The reconstituted vaccine contains: Mycobacterium bovis BCG (Bacillus Calmette-Guerin), Danish strain 1331, 2-8 x 106 cfu/ml. For excipients, refer to section 6.1

3. Pharmaceutical Form Powder for suspension for injection (BCG Vaccine “SSI”). Solvent for suspension for injection (Diluted Sauton “SSI”).

Clinical Particulars 4.1. Therapeutic Indications

For active immunisation against tuberculosis.

4.2. Posology and Method of Administration Posology: Children aged 12 months and over, adults and elderly: 0.1 ml of the reconstituted vaccine strictly by intradermal injection. National recommendations should be consulted regarding the need for tuberculin testing prior to administration of BCG Vaccine SSI. Infants under 12 months of age: 0.05 ml of the reconstituted vaccine strictly by intradermal injection. Method of Administration : When drawn up into the syringe the vaccine suspension should appear homogeneous, slightly opaque and colourless. BCG Vaccine “SSI” should be administered with a syringe fitted with a short bevel needle (gauge 25 or 26 G). Jet injectors or multiple puncture devices should not be used to administer the vaccine. The injection site should be clean and dry and not contaminated with antiseptics. If alcohol is used to swab the skin, it must be allowed to evaporate before the vaccine is injected. The vaccine should be injected strictly intradermally in the arm, over the distal insertion of the deltoid muscle onto the humerus (approx. one third down the upper arm), as follows: - The skin is stretched between thumb and forefinger. - The needle should be almost parallel with the skin surface and slowly inserted

(bevel upwards), approximately 2 mm into the superficial layers of the dermis.- - The needle should be visible through the epidermis during insertion. - The injection is given slowly. - A raised, blanched bleb is a sign of correct injection. - The injection site is best left uncovered to facilitate healing.

Section C - Page 2

4.3. Contra-indications BCG Vaccine “SSI” should not be administered to persons known to be hypersensitive to any component of the vaccine. Normally, the vaccination should be postponed in persons with pyrexia or generalised infected skin conditions. Eczema is not a contraindication, but the vaccine site should be lesion free. BCG Vaccine “SSI” should not be given to persons receiving systemic corticosteroids or immunosuppressive treatment including radiotherapy, to those suffering from malignant conditions (e.g. lymphoma, leukaemia, Hodgkin’s disease or other tumours of the reticulo-endothelial system), those with primary or secondary immunodeficiencies, those with HIV-infection, including infants born to HIV-positive mothers. The effect of BCG vaccination may be exaggerated in these patients, and a generalised BCG-infection is possible. In areas where the risk of contracting tuberculosis and HIV is high, it may be appropriate to vaccinate asymptomatic HIV-positives with BCG according to WHO recommendations. BCG Vaccine “SSI” should not be given to patients who are receiving prophylactic doses of anti-tuberculous drugs.

4.4. Special Warnings and Precautions for Use Although anaphylaxis is rare, facilities for its management should always be available during vaccination. Tuberculin positive persons (consult national recommendations for the definition of a positive tuberculin reaction) do not require the vaccine. Administration of the vaccine to such persons may result in a severe local reaction. Injections made too deeply increase the risk of lymphadenitis and abscess formation.

4.5. Interactions with other Medicaments and other forms of Interaction Intradermal BCG vaccination may be given concurrently with inactivated or live vaccines, including combined measles, mumps and rubella vaccines. Other vaccines to be given at the same time as BCG Vaccine “SSI” should not be given into the same arm. If not given at the same time an interval of not less than four weeks should normally be allowed to lapse between the administrations of any two live vaccines. No further vaccination should be given for at least three months in the arm used for BCG vaccination, because of the risk of regional lymphadenitis.

4.6. Pregnancy and Lactation Although no harmful effects to the foetus have been associated with BCG SSI vaccine, vaccination is not recommended during pregnancy or lactation. However, in areas with high risk of tuberculosis infection, BCG SSI vaccine may be given during pregnancy or lactation if the benefit of vaccination outweighs the risk.

4.7. Effects on Ability to Drive and Use Machines No effect on ability to drive and use machines has been observed.

Section C - Page 3

4.8. Undesirable Effects The expected reaction to successful vaccination with BCG vaccine “SSI” includes induration at the injection site followed by a local lesion that may ulcerate some weeks later and heal over some months leaving a small, flat scar. It also may include enlargement of a regional lymph node to < 1 cm. Undesirable effects of the vaccine include the following:

Uncommon Systemic: Headache, fever. Local: Enlargement of regional lymph node > 1 cm. Ulceration with a discharging ulcer at the site of

injection. Rare (<1/1000) Systemic: Disseminated BCG complications as osteitis or

osteomyelitis. Allergic reactions, including anaphylactic reactions.

Local: Suppurative lymphadenitis, abscess formation. An excessive response to the BCG Vaccine “SSI” may result in a discharging ulcer. This may be attributable to inadvertent subcutaneous injection or to excessive dosage. The ulcer should be encouraged to dry and abrasion (by tight clothes, for example) avoided. If the ulcer persists, seek expert medical advice. If a disseminated infection with BCG occurs, systemic anti-tubercular treatment should be considered. Expert medical advice should be obtained on management and treatment. In-vitro testing has shown that BCG SSI (Danish strain 1331) is susceptible to isoniazid and rifampicin.

4.9. Overdose Overdose in infants increases the risk of suppurative lymphadenitis and may lead to excessive scar formation. Gross overdosage increases the risk of undesirable BCG complications. For treatment of disseminated infections with BCG, refer to section 4.8.

Pharmacological Properties 5.1. Pharmacodynamic Properties

Pharmacotherapeutic group (ATC code): J 07 AN 01. The vaccine contains Mycobacterium bovis BCG (Bacillus Calmette-Guerin) of the Danish strain 1331. BCG is an attenuated strain of Mycobacterium bovis. Vaccination with BCG Vaccine SSI elicits a cell-mediated immune response that confers a variable degree of protection to infection with M. tuberculosis. Vaccinated persons normally become tuberculin positive after 6 weeks. A positive tuberculin skin test does indicate a response of the immune system to the BCG vaccination or to a mycobacterial infection, however the relationship between post vaccination tuberculin skin test reaction and the degree of protection afforded by BCG remains unclear. The duration of immunity after BCG vaccination is not known, but there are some indications of a waning immunity after 10 years.

5.2. Pharmacokinetic Properties Not relevant for vaccines.

Section C - Page 4

5.3. Preclinical Safety Data Not available.

Pharmaceutical Particulars 6.1. List of Excipients

BCG Vaccine “SSI”: Sodium glutamate. Diluted Sauton SSI: Magnesium sulphate Dipotassium phosphate Citric acid, monohydrate L-asparagine monohydrate Ferric ammonium citrate Glycerol 85% Water for injections.

6.2. Incompatibilities Only Diluted Sauton “SSI” may be used for reconstitution of BCG Vaccine “SSI”.

6.3. Shelf Life BCG Vaccine “SSI”: 18 months. Diluted Sauton “SSI”: 36 months. Reconstituted vaccine: From a microbiological point of view the product should be used immediately. In use stability in terms of viability has been demonstrated for 4 hours after reconstitution.

6.4. Special Precautions for Storage BCG Vaccine “SSI”: Store at 2° C - 8° C. Store protected from light. Diluted Sauton “SSI”: Do not freeze.

6.5. Nature and Contents of Container Nature and content: BCG Vaccine “SSI”, amber Type I glass (Ph.Eur.). Diluted Sauton “SSI”, colourless Type I glass (Ph.Eur.). Presentations: 1 vial BCG Vaccine “SSI” (for 1 ml vaccine) + 1 vial Diluted Sauton “SSI” (1 ml). The two vials are packed in the same box. 10 vials BCG Vaccine “SSI” (for 1 ml vaccine) + 10 vials Diluted Sauton “SSI” (1 ml). The BCG Vaccine “SSI” and the Diluted Sauton “SSI” are packed in two separate boxes. 1 vial BCG Vaccine “SSI” (for 2 ml vaccine) + 1 vial Diluted Sauton “SSI” (2 ml). The two vials are packed in the same box. 10 vials BCG Vaccine “SSI” (for 2 ml vaccine) + 10 vials Diluted Sauton “SSI” (2 ml). The BCG Vaccine “SSI” and the Diluted Sauton “SSI” are packed in two separate boxes. Not all package sizes may be marketed.

Section C - Page 5

6.6. Instruction for Use/Handling

Reconstitution: The rubber stopper must not be contaminated with any antiseptic or detergent. If alcohol is used to swab the rubber stopper of the vial, it must be allowed to evaporate before the stopper is penetrated with the syringe needle. Using a syringe fitted with a long needle, transfer to the vial the volume of Diluted Sauton “SSI” given on the label. Carefully invert the vial a few times to resuspend the lyophilised BCG completely. DO NOT SHAKE. Gently swirl the vial of resuspended vaccine before drawing up each subsequent dose. When drawn up into the syringe the vaccine suspension should appear homogeneous, slightly opaque and colourless. From a microbiological point of view the product should be used immediately. In use stability in terms of viability has been demonstrated for 4 hours after reconstitution.

Administrative Data 7. Marketing Authorisation Holder

Statens Serum Institut 5, Artillerivej DK-2300 Copenhagen S Denmark

8. Marketing Authorisation Number PL 17282/0001

9. Date of First Authorisation/Renewal of Authorisation 9 September 2002

10. Date of (Partial) Revision of the Text

Appendix (2).

Patient Information Leaflet text BCG Vaccine SSI. BCG Vaccine SSI Powder and solvent for suspension for injection Read the entire leaflet carefully before you are given this vaccine. Keep this leaflet. You may need to read it again. If you have further questions, please ask your doctor or nurse. This leaflet tells you: 1. What BCG Vaccine SSI is and what it is used for 2. Before you or your child receive BCG Vaccine SSI 3. How BCG Vaccine SSI is given 4. Possible side effects 5 How to store BCG Vaccine SSI

The full name of your vaccine is: BCG Vaccine SSI Bacillus Calmette -Guerin (BCG) vaccine Vaccine against tuberculosis Powder and solvent for suspension for injection BCG Vaccine SSI is a freeze-dried powder containing the bacteria Mycobacterium bovis BCG (Bacillus Calmette-Guerin), Danish strain 1331 as the active substance. The vaccine powder is mixed with the solvent, Diluted Sauton SSI, before use. 1 ml of the ready-to-use vaccine contains between 2 and 8 million live units of Mycobacterium bovis BCG. The other ingredients are sodium glutamate, magnesium sulphate, dipotassium phosphate, L-asparagine monohydrate, ferric ammonium citrate, glycerol, citric acid monohydrate and water for injections. Manufacturer and marketing authorisation holder Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen S. 1. What BCG Vaccine SSI is and what it is used for BCG Vaccine SSI is a vaccine used for protection against tuberculosis. The vaccine contains live bacteria of the type called Mycobacterium bovis. These bacteria belong to the same family of bacteria that causes tuberculosis (TB). Mycobacterium bovis bacteria can cause infections in cattle. They very rarely cause infections in humans. The Mycobacterium bovis bacteria in the vaccine have been weakened so that they do not cause disease when they are injected into the skin of healthy people. After vaccination, the live but weakened bacteria in this BCG vaccine react with the body’s natural defences (called the immune system). The immune system is then able to protect you/your child against infection with the bacteria that cause tuberculosis (TB) in humans. TB is spread between humans mainly by breathing in bacteria that are breathed out or spat out by people who have an active infection with the bacteria in their lungs. Most infections start in the lungs but can spread to all other parts of the body if the infection is not treated properly. Like all vaccines, BCG Vaccine SSI cannot completely prevent infections with the bacteria that cause tuberculosis (TB). Also, if BCG Vaccine SSI is given to someone who is already infected with the bacteria that cause tuberculosis (TB) but does not have any symptoms yet, the vaccine cannot prevent the infection from spreading. 2. Before you or your child receive BCG Vaccine SSI If the answer to any of the questions below is “YES” for the person who is to be vaccinated, BCG Vaccine SSI should not be given. If you are not sure about anything, ask your doctor or nurse.

- Are you/is your child allergic to any of the active or other ingredients of the vaccine? - Do you/does your child have a fever or generalised skin

infection? If so, vaccination should be postponed until the fever or infection has cleared.

- Do you/does your child have poor resistance to infections or been told that your immune system is not working properly for any reason? For example, are you/is your child taking steroids or receiving medication or treatment that weakens the immune system (including radiotherapy), or suffering from any malignant conditions (e.g., lymphoma, leukaemia or Hodgkin’s disease) ?

- Are you/is your child infected with the HIV virus that causes AIDS? People who are infected with the virus but are well may sometimes be vaccinated with BCG if there is a high risk of catching TB.

- Are you/is your child taking medicines that are active against the bacteria that cause TB?

Take special care with BCG Vaccine SSI: BCG Vaccine SSI is not suitable for everyone. Tell your doctor or nurse if the answer to any of the following questions is “YES” for the person who is to be vaccinated. Your doctor or nurse will advise you if BCG Vaccine SSI is right for you.

- Do you/does your child have eczema? BCG Vaccine SSI can still be given into an area of normal skin if the eczema in other areas is not infected. - Have you/has your child had a skin test for TB infection that has come up positive? BCG Vaccine SSI is not helpful in such people and there can be

problems at the injection site if it is given. Pregnancy and breast-feeding: Tell your doctor if you are pregnant, think you may be pregnant or are breast-feeding. BCG Vaccine SSI is not usually given to women who are pregnant or who are breast-feeding unless it is thought that they are at high risk of catching TB. Driving and using machines: Having BCG Vaccine SSI should not affect you when driving or using machinery.

Taking other medicines: Please inform your doctor if you are taking or have recently taken any other medicines, whether these have been prescribed or bought without a prescription. Having other vaccines: BCG Vaccine SSI can be given at the same time as other vaccines but will be given into a different area of your body. If other live vaccines are not given at the same visit, they are normally not given until one month after BCG Vaccine SSI was injected. No other vaccines should be injected into the arm or leg where BCG Vaccine SSI was given for three months afterwards. Ask your doctor or nurse if you have any questions about whether you should have and when you should have other vaccines. 3. How BCG Vaccine SSI is given The dose of BCG Vaccine SSI for adults and for children who are at least 12 months old is a single injection of 0.1 ml (a very small amount of liquid). Children who are under 12 months old are given half of this dose (0.05 ml). The vaccine is usually injected into the upper arm. A small scar usually remains after a successful vaccination. BCG Vaccine SSI will be given to you by a doctor or a nurse who will take care that the vaccine is injected correctly into the skin and not into the muscle or into a blood vessel. After having the injection, the site can be left uncovered. Your doctor or nurse will give you advice about bathing. If you notice any problems in or around the site that worry you or persist, or if you feel generally unwell or if you notice any swelling of the glands in your armpit or anywhere else, you should contact your doctor or nurse for advice. See also Possible Side Effects below. Since BCG Vaccine SSI will be given by a doctor or nurse, it is very unlikely that you may receive too much or too little of the vaccine. If you think you may not have had the right dose, ask your doctor or nurse about this. Having more vaccine than is necessary can increase the risk of problems at the injection site. Having less vaccine than is necessary may mean that you are not protected against TB. 4. Possible side effects Like all medicines, BCG Vaccine SSI can have side effects. It is quite normal to have a small amount of swelling at the injection site that can form a small ulcer. This usually heals eventually and leaves a small flat scar. It is also possible that you may have some swelling of glands in the armpit but less than one centimetre across. These are natural reactions to the vaccine. If you have swelling at the injection site that does not settle or seems to be getting bigger, or an ulcer that gets bigger and seems very slow to heal, or if you notice swellings in your armpit that are larger than one centimetre across, you should tell your doctor or nurse. These are not normal reactions to the vaccine. Other side effects In less than one in a thousand people, severe allergic reactions (such as redness of the face and neck, swelling of the face, throat or neck, skin rash, breathing difficulties and collapse) can occur. These often start very soon after the injection, and may happen while you are still in the clinic. If the symptoms start after leaving the clinic, it is very important that you contact a doctor urgently or visit the nearest hospital emergency department.

Uncommon side effects (happens to more than one in a thousand pe ople but less than one in one hundred people) - Headache - Fever - Swelling of glands in the armpit to more than 1 cm across - An ulcer that lets out fluid at the injection site. If this happens, the ulcer should be allowed to dry and tight clothes should be avoided. If the ulcer seems

very slow to heal, contact your doctor or nurse for advice. Rare side effects (happens to less than one in a thousand people but more than one in ten thousand people) - Inflammation of glands, sometime with abscesses and release of fluid from the swellings - Infection with the bacteria in the vaccine (Mycobacterium bovis BCG) can occur, that can spread through the body, including to the bones. This does not

usually happen in people who are otherwise healthy but it has been reported. These infections need to be treated in a similar way to the treatment of TB.

If you notice any side effects not mentioned in this leaflet, please inform your doctor. 5. How to store BCG Vaccine SSI Your doctor or nurse will make sure that BCG Vaccine SSI is stored in a refrigerator at 2°C−8°C, that it is protected from light, and that the diluent is not f rozen. Once the diluent has been mixed with vaccine, your doctor or nurse should make sure that the vaccine is then given immediately and not left lying around. Your doctor or nurse will check that the expiry date specified on the label has not been passed. Your doctor or nurse will make sure that the vaccine is kept out of the reach and sight of children. This leaflet was last approved on 30.08.2002

Appendix (3).

Abbreviated instructions to medical and healthcare professionals included in the SSI BCG Vaccine Patient Information Leaflet.

The following information is intended for medical or healthcare professionals only: BCG Vaccine SSI is used f or active immunisation against tuberculosis. Reconstitution The rubber stopper must not be contaminated with any antiseptic or detergent. If alcohol is used to swab the rubber stopper of the vial, it must be allowed to evaporate before the stopper is penetrated with the syringe needle. Using a syringe fitted with a long needle, transfer to the vial the volume of Diluted Sauton SSI given on the label (do not use any other diluent than Diluted Sauton SSI for reconstitution). Carefully invert the vial a few times to resuspend the lyophilised BCG completely. DO NOT SHAKE. Gently swirl the vial of resuspended vaccine before drawing up each subsequent dose. From a microbiological point of view the product should be used immediately. In use stability in terms of viability has been demonstrated for 4 hours after reconstitution. Method of administration When drawn up into the syringe the vaccine suspension should appear homogeneous, slightly opaque and colourless. BCG Vaccine SSI should be administered with a syringe fitted with a short bevel needle (gauge 25 or 26 G). Jet injectors or multiple puncture devices should not be used to administer the vaccine. The injection site should be clean and dry and not contaminated with antiseptics. If alcohol is used to swab the skin, it must be allowed to evaporate before the vaccine is injected. The vaccine should be injected strictly intradermally in the arm, over the distal insertion of the deltoid muscle onto the humerus (approximately one third down the upper arm), as follows:

- The skin is stretched between thumb and forefinger. - The needle should be almost parallel with the skin surface and slowly inserted with the bevel upwards ,

approximately 2 mm into the superficial layers of the dermis; the needle should be visible through the epidermis during insertion.

- The injection should be given slowly. - A raised, blanched bleb is a sign of correct injection. - The injection site is best left uncovered to facilitate healing.

Dosage Children aged 12 months and over, adults and elderly : 0.1 ml of the reconstituted vaccine strictly by intradermal injection. National recommendations should be consulted regarding the need for tuberculin testing prior to administration of BCG Vaccine SSI. Infants under 12 months of age: 0.05 ml of the reconstituted vaccine strictly by intradermal injection. Interactions Intradermal BCG vaccination may be given concurrently with inactivated or live vaccines, including combined measles, mumps and rubella vaccines. Other vaccines to be given at the same time as BCG Vaccine SSI should not be given into the same arm. If not given at the same time, an interval of not less than four weeks should normally be allowed to lapse between the administrations of any two live vaccines. No further vaccination should be given for at least three months in the arm used for BCG vaccination, because of the risk of regional lymphadenitis. Contra-indications BCG Vaccine SSI should not be administered to persons known to be hypersensitive to any component of the vaccine. Normally, the vaccination should be postponed in persons with pyrexia or generalised infected skin conditions. Eczema is not a contraindication, but the vaccine site should be lesion free. BCG Vaccine SSI should not be given to persons receiving systemic corticosteroids or immunosuppressive treatment including radiotherapy, to those suffering from malignant conditions (e.g., lymphoma, leukaemia, Hodgkin’s disease or other tumours of the reticulo-endothelial system), those with primary or secondary immunodeficiencies, those with HIV-infection, including infants born to HIV -positive mothers. The effect of BCG vaccination may be exaggerated in these patients, and a generalised BCG-infection is possible. In areas where the risk of contracting tuberculosis and HIV is high, it may be appropriate to vaccinate asymptomatic HIV -positives with BCG according to WHO recommendations. BCG Vaccine SSI should not be given to patients who are receiving prophylactic doses of anti-tuberculous drugs. Special warnings and precautions for use Although anaphylaxis is very rare, facilities for its management should always be available during vaccination.

Tuberculin positive persons do not require the vaccine. Administration of the vaccine to such persons may result in a severe local reaction. An excessive response to the BCG Vaccine SSI may result in a discharging ulcer. This may be attributed to inadvertent subcutaneous injection or to excessive dosage. Injections made too deeply may also increase the risk of lymphadenitis and abscess formation. Precautions in case of overdose Overdosage in infants increases the risk of suppurative lymphadenitis and may lead to excessive scar formation. If a disseminated infection with BCG occurs, systemic treatment with a suitable antituberculous drug should be considered. In-vitro testing has shown that BCG SSI (Danish Strain 1331) is susceptible to isoniazid and rifampicin. Storage BCG Vaccine SSI must always be stored at 2°C−8°C and protected from light. The expiry date specified on the label must not be exceeded. From a microbiological point of view the reconstituted vaccine should be used immediately. In use stability in terms of viability has been demonstrated for 4 hours after reconstitution. Do not freeze Diluted Sauton SSI.