RABIES VACCINE BP > 2.5 IU/ML POWDER AND SOLVENT FOR SUSPENSION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Rabies Vaccine BP > 2.5 lU/ml, Powder and solvent for suspension for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

After reconstitution, 1 dose (1ml) contains:

Rabies virus* (inactivated, strain PM/WI 38 1503–3M)........>2.5 IU

*produced in human diploid MRC-5 cells

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Powder and solvent for suspension for injection The powder is pinkish beige to orangey yellow. The solvent is a clear, colourless solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Rabies Vaccine BP is indicated for pre-exposure prophylaxis and for post-exposure prophylaxis against rabies in all age groups (see Sections 4.2 and 5.1).

The use of Rabies Vaccine BP should be based on official recommendations.

4.2 Posology and method of administration

Posology

The recommended dose is 1mL of reconstituted vaccine.

Pre-exposure prophylaxis

The primary pre-exposure immunisation course consists of 3 injections at D0, D7 and either D21 or D28.

For individuals at continued risk, booster doses should be given in line with official recommendations.

The need for serology testing to detect the presence of rabies virus-neutralising antibodies (>0.5 IU/ml) should be assessed and conducted, if appropriate, in accordance with official recommendations.

Post-exposure prophylaxis

Post-exposure prophylaxis should be initiated as soon as possible after suspected rabies exposure. In all cases, proper wound care (thorough flushing and washing of all bite wounds and scratches with soap or detergent and copious amounts of water and/or virucidal agents) must be performed immediately or as soon as possible after exposure). It must be performed before administration of rabies vaccine or rabies immunoglobulin, when they are indicated.

The rabies vaccine administration must be performed strictly in accordance with the category of exposure, the patient immune status, and the animal status for rabies (according to local official recommendations, see Table 1 for WHO recommendations).

Table 1: WHO category of severity of exposure

a If an apparently healthy dog or cat in or from a low-risk area is placed under observation, treatment may be delayed.

b This observation period applies only to dogs and cats. Except for threatened or endangered species, other domestic and wild animals suspected of being rabid should be euthanized and their tissues examined for the presence of rabies antigen by appropriate laboratory techniques.

c Bites especially on the head, neck, face, hands and genitals are category III exposures because of the rich innervation of these areas.

Post-exposure prophylaxis of previously non-immunised individuals

Vaccine should be administered on D0, D3, D7, D14 and D28 (5 injections of 1mL).

For category III exposure (see Table 1), rabies immunoglobulin should be given in association with vaccine. In this case, the vaccine should be administered contra-laterally, if possible.

Vaccination should not be discontinued unless the animal is declared not rabid according to a veterinarian assessment (supervision of animal and/or laboratory analysis).

Post-exposure prophylaxis of previously immunised individuals

Previously immunised individuals should receive one dose of vaccine intramuscularly on both days 0 and 3. Rabies immunoglobulin is not indicated in such cases.

According to WHO recommendation, previously immunised individuals are patients who can document previous complete PrEP (pre-exposure prophylaxis) or PEP (postexposure prophylaxis) and people who discontinued a PEP series after at least two doses of a cell culture rabies vaccine.

Special population- immunocompromised individuals

Pre-exposure prophylaxis

For immunocompromised individuals, serology testing of neutralizing antibodies should be performed 2 to 4 weeks after the vaccination to assess the possible need for an additional dose of the vaccine.

Post-exposure prophylaxis

For immunocompromised individuals, only a full vaccination schedule should be administered. Rabies immunoglobulin should be given in association with the vaccine for both categories II & III exposures (see Table 1).

Paediatric population

Paediatric individuals should receive the same dose as adults (1mL).

Method of Administration

The vaccine is for intramuscular administration only. The vaccine should be administered into the deltoid muscle for adults and children or the anterolateral area of the thigh muscle in infants and toddlers. For instructions on the reconstitution of the vaccine before administration, see section 6.6.

4.3 Contraindications

Pre Exposure

Known systemic hypersensitivity reaction to any component of Rabies Vaccine BP or

after previous administration of the vaccine or a vaccine containing the same

components as Rabies Vaccine BP.

Vaccination must be postponed in case of febrile and/or acute disease.

Post Exposure

Since declared rabies infection generally results in death, there are no contraindications to post exposure vaccination.

4.4 Special warnings and precautions for use

As with any vaccine, vaccination with Rabies Vaccine BP may not protect 100% of vaccinated individuals.

In subjects with a history of allergy there may be an increased risk of side-effects and this possibility should be taken into account.

As with all vaccines, appropriate facilities and medication such as epinephrine (adrenaline) should be readily available for immediate use in case of anaphylaxis or hypersensitivity following injection.

The vaccine may contain traces of neomycin and betapropiolactone which are used during the manufacturing process. Caution must be exercised when the vaccine is administered to subjects with hypersensitivity to betapropiolactone, neomycin, and other antibiotics of the same class.

If Rabies Immunoglobulin is indicated in addition to Rabies Vaccine BP, then it must be administered at a different anatomical site to the vaccination site.

Rabies Vaccine BP should not be administered to patients with bleeding disorders such as haemophilia or thrombocytopenia, or to persons on anticoagulant therapy unless the potential benefit clearly outweighs the risk of administration. If the decision is taken to administer Rabies Vaccine BP in such persons, it should be given with caution with steps taken to avoid the risk of haematoma formation following injection.

The tip caps of the pre-filled syringes contain a natural rubber latex derivative, which may cause severe allergic reactions in latex sensitive individuals.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded

Paediatric population

The potential risk of apnoea and the need for respiratory monitoring for 48–72 h should be considered when administering the primary immunisation series to very premature infants (born < 28 weeks of gestation) and particularly for those with a previous history of respiratory immaturity.

4.5 Interaction with other medicinal products and other forms of interaction Immunosuppressive treatments, including long-term systemic corticosteroid therapy, may interfere with antibody production and cause the failure of the vaccination. It is therefore advisable to perform a serological test 2 to 4 weeks after the last injection (see also Section 4.2).

There are no clinical data available on the concurrent administration of Rabies Vaccine BP with other vaccines. Official recommendations should be followed with regard to co-administration with other vaccines or drugs.

Separate injection sites and separate syringes must be used in case of concomitant administration with any other medicinal product, including rabies immunoglobulins.

As rabies immunoglobulin interferes with development of immune response to the vaccine, the recommendation of administration of rabies immunoglobulin must be strictly followed.

4.6 Fertility, pregnancy and lactation

Pregnancy

Data on limited number of exposed pregnancies do not allow a conclusion on the potential risk of Rabies HDCV for pregnancy or for the health of the foetus/newborn child. Due to the severity of disease, pregnancy is not considered a contraindication to post exposure prophylaxis. If there is substantial risk of exposure to rabies, preexposure prophylaxis may also be indicated during pregnancy.

Breastfeeding

Due to the severity of the disease, breast feeding is not considered a contraindication and treatment must not be discontinued. It is not known whether this vaccine is excreted in human breast milk, thus no recommendation on continuation/dis­continuation of breastfeeding can be made.

Fertility

Rabies Vaccine BP has not been evaluated for impairment of male or female fertility.

4.7 Effects on ability to drive and use machines No adverse effects reported.

4.8 Undesirable effects

Summary of the safety profile

In clinical studies, more than 1,600 subjects, including approximately 600 children and adolescents, received at least one dose of Rabies Vaccine BP.

The adverse reactions were generally of mild intensity and appeared within 3 days after vaccination. Most reactions resolved spontaneously within 1 to 3 days after onset.

Most frequent adverse reactions in all age groups were injection site pain, headache, malaise and myalgia.

Tabulated list of adverse reactions

Adverse event information is derived from clinical studies and worldwide postmarketing experience. Within each system organ class the adverse events are ranked under headings of frequency, using the following CIOMS frequency rating:

Very common >10%;

Common > 1 and <10%;

Uncommon >0.1 and <1%;

Rare >0.01 and < 0.1%;

Very rare < 0.01%;

Not known (cannot be estimated from available data).

Serum sickness type reactions might be associated with the presence of betapropiolactone-altered human albumin in the HDCV.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Not applicable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Rabies vaccines, ATC Code: J07BG01.

Mechanism of action

Protection after vaccination is provided by the induction of rabies neutralizing antibodies (RNA).

Clinical studies were conducted to assess the immunogenicity of the vaccine in both pre-exposure and post-exposure situations. A rabies neutralizing antibody titer > 0.5 IU/ml, is considered to confer protection.

Pre-exposure prophylaxis

In clinical trials assessing a 3-dose regimen (D0, D7, D28 (or D21))in both adults and children, almost all subjects achieved an adequate immune response with rabies neutralizing antibody titers > 0.5 lU/mL by 2 weeks after the end of the primary series.

A ten-year follow-up in 17 subjects who received a 3-dose regimen (D0, D7, D28) followed by a booster dose 1 year later has shown persistence of immune response with rabies neutralizing antibody titers > 0.5 lU/mL up to 10 years in 96.2% (CI95% 88.8; 100) of subjects.

Post exposure prophylaxis

In clinical trials assessing the 5-dose Essen regimen (D0, D3, D7, D14, D28) in both children and adults, with or without immunoglobulin, Rabies Vaccine BP elicited adequate rabies neutralizing antibody titers (> 0.5 lU/mL) in almost all subjects by D14 and in all of them by D42.

In a phase 2 trial, 124 healthy seronegative adults received the 5-dose Essen regimen (D0, D3, D7, D14, D28) IM and human rabies immunoglobulin at D0. All vaccinees reached a rabies neutralizing antibody titer > 0.5 lU/mL by D14 with a maximum level on D42. One year later, protective level of rabies neutralizing antibodies was maintained in 98.3% (CI95% 93.9; 99.8) of subjects.

In a clinical trial simulating post-exposure prophylaxis, 47 previously immunised adult subjects received 2 doses of Rabies Vaccine BP 3 days apart (D0 and D3), 1 year after primary immunisation. Protective rabies neutralizing antibody titer (> 0.5 IU/mL) was reached by D7 in all subjects.

Paediatric population

Immunogenicity of the pre-exposure schedule (3 doses on D0, D7 and D28 by IM route) has been assessed at D42 in 112 subjects from 2 to 17 years of age included in VRV06 study, and in 190 subjects from 5 to 13 years of age included in RAC03396 study. All vaccinees reached a rabies neutralizing antibody titer > 0.5 lU/ml at D42.

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data None stated.

6.1

Human albumin solution.

Solvent: Water for Injections (1 millilitre).

6.2 Incompatibilities

In the absence of compatibility studies, this vaccine must not be mixed with other

medicinal products.

6.3 Shelf life

3 years

Once reconstituted, the vaccine must be used immediately.

6.4 Special precautions for storage

Store between +2°C and +8°C in a refrigerator. Do not freeze.

6.5 Nature and contents of container

Powder:

Single dose (Ph Eur type 1 glass) vial with elastomeric stopper (chlorobutyl) and aluminium overcap.

Solvent:

1.0 ml disposable Needleless (Luer-lok™) prefilled syringe (type 1 glass) with rigid adapter (polycarbonate) and Plastic Rigid Tip Cap (PRTC) (polypropylene and isoprene-bromobutyl rubber), with a plunger-stopper (bromobutyl rubber). Up to two separate needles (for each syringe) may be included in the pack.

Pack of 1 vial and 1 prefilled syringe.

Not all pack presentations may be marketed.

6.6 Special precautions for disposal

Specific instructions for Luer-lok™ syringe:

1. Holding the syringe cap in one hand (avoid holding the syringe plunger or barrel), unscrew the tip cap by twisting it counterclockwise.

2. To attach the needle to the syringe, gently twist the needle clockwise into the syringe until slight resistance is felt.

Picture A: Luer-Lok™ syringe

syringe cap

syringe         syringe                tip cap

plunger         barrel

Picture B: Step 1

Picture C: Step 2

Reconstitution of the vaccine: introduce the solvent into the vial of powder and. gently swirl until complete suspension of the powder is obtained. The suspension should be clear or slightly opalescent, red to purple-red in colour. Without removing the needle from the vial, unscrew the syringe to eliminate negative pressure (as the vial is sealed under vacuum). Reattach the needle remaining in the vial to the syringe (as per step 2).

Withdraw the total contents of the vial into the syringe.

Unscrew the reconstitution needle and replace it with a sterile needle (as per step 2) of a proper length for intramuscular injection of your patient. Inject immediately.

The vaccine must be visually inspected before any administration in order to make sure there are no foreign particles in the vaccine.

Any unused medicinal product or waste material should be disposed of, in accordance with local requirements.

Sanofi Pasteur Europe

14 Espace Henry Vallée

69007 Lyon

FRANCE

Distributed in the UK by:

Sanofi

410 Thames Valley Park Drive

Reading

RG6 1PT

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 46602/0004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

7 November 1994