VERORAB

verorab

CONTENTS

Inactivated rabies vaccine prepared on Vero cells.

PRESENTATION

Vial 1 dose + syringe (diluent) 0.5 mL x 1's, 5's.

DESCRIPTION

Each 0.5 mL-dose contains rabies virus*, Wistar Rabies PM/WI38 1503-3M strain (inactivated) ³2.5 iu**.

*Produced on VERO cells.

**Quantity measured according to the international standard and the NIH test.

It also contains the following ingredients: Powder: Maltose and human albumin. Solvent: Sodium chloride and water for injections.

ACTIONS: Pharmacology: Inactivated vaccine used for the prevention of rabies in individuals at a risk of infection and for treatment after confirmed or possible infection with rabies virus.

A serum antibody titre ³0.5 iu/mL, considered by WHO to confer protection, is reached after the injection of 3 doses on D0, D7 and D28 (or D21). This immunity must be maintained with an initial booster injection 1 year later, followed by booster injections every 5 years.

INDICATIONS

Pre-exposure Prevention of Rabies (Pre-exposure Vaccination): Pre-exposure vaccination should be offered to subjects at high risk of contamination by the rabies virus. All persons at a permanent risk eg, diagnostic, research or production laboratory staff working with rabies virus, should be vaccinated. A serological test is recommended every 6 months.

Pre-exposure vaccination should also be considered for subjects at frequent risk of exposure to the rabies virus eg, veterinarians and their assistants, animal handlers; those who are in contact with species likely to have rabies (dogs, cats, skunks, raccoons, bats) eg, gamekeepers, hunters, forestry workers, speleologists and taxidermists.

Individuals living or travelling in enzootic areas.

In areas where the enzootic level of rabies is low, veterinarians and assistants (including students), animal handlers and wildlife officers (gamekeepers) are considered to be at occasional risk of exposure and should receive a primary vaccination against rabies.

Serological tests for rabies antibodies should be performed at regular intervals in accordance with the subject's risk exposure. Systematic booster injections should be administered in accordance with the subject's risk exposure.

Post-Exposure Prevention of Rabies (Post-Exposure Vaccination): At the slightest risk of contamination, post-exposure vaccination should be performed as soon as possible.

In some countries, vaccination must be performed in a specialized rabies treatment centre.

Post-exposure treatment includes local, nonspecific treatment of the injury, passive immunization with rabies immunoglobulins (RIGs) and vaccination, depending on the type injury and the status of the animal (see Tables 1 and 2).

Table 1. Course of Action Depending on the Status of the Animal.
Circumstances	Course of Action Regarding		Remarks
Circumstances	The Animal	The Patient	Remarks
Animal Unavailable: Suspect or nonsuspect circumstances		To be taken to a rabies treatment centre for treatment	Treatmentb is always completed
Dead Animal: Suspect or nonsuspect circumstances	Send the brain to an approved laboratory for analysis	To be taken to a rabies treatment centre for treatment	Treatmentb is discontinued if the analyses are negative or, otherwise, continued
Live Animal: Nonsuspect circumstances Suspect circumstances	Place under veterinary supervisiona Place under veterinary supervisiona	Decision to delay rabies treatment To be taken to a rabies treatment centre for treatment	Treatmentb is adapted according to the results of veterinary supervision of the animal Treatmentb is discontinued if the supervision invalidates the initial doubts, otherwise, continued
aIn France, veterinary supervision includes 3 certificates drawn up on D0, D7 and D14 declaring the absence of signs of rabies. According to WHO recommendations, the minimum observation period under veterinary supervision for dogs and cats is 10 days. bTreatment is recommended depending on the severity of the wound: See Table 2.

Table 2. WHO Guidelines on Post-Exposure Treatment Depending on Wound Severity.
Category of Severity	Type of Contact with a Wilda or Domestic Animal Presumed or Confirmed Rabid or an Animal That Cannot be Placed Under Supervision	Recommended Treatment
	Touching or feeding of animals Licks on intact skin	None, if reliable case history can be obtained
	Nibbling of uncovered skin Minor scratches or abrasions without bleeding Licks on broken skin	Administer vaccine immediatelyb
	Single or multiple transdermal bites or scratches Contamination of mucous membrane with saliva (ie, licks)	Administer rabies immunoglobulins and vaccine immediatelyb
aContact with rodents, rabbits or hares does not normally necessitate specific rabies treatment. bDiscontinue treatment if the animal is in good health after 10 days of observation (for cats and dogs) or if after the animal has been euthanized, the results of the search for rabies by the appropriate laboratory techniques are negative.

DOSAGE & ADMINISTRATION

The vaccination schedule should be adapted in accordance with the circumstances of the vaccination and the patient's rabies immune status.

Pre-exposure Vaccination: Three doses of Verorab (0.5 mL) should be administered on D0, D7 and D28 or D21.

Booster Injection After Pre-exposure Vaccination: A booster injection of Verorab (0.5 mL) will be administered 1 year after primary vaccination, followed by a booster injection every 5 years. See Table 3.

Table 3. Recommendations for Primary Vaccination and Booster Injection.
Primary vaccination (3 injections) First booster Later booster	D0, D7, D28 and D21* 1 year later every 5 years
*The D28 injection can be administered on D21.

Verorab can be administered as a booster injection after primary vaccination with a rabies vaccine prepared on diploid or Vero cells.

Post-Exposure Vaccination: First-Aid: Local Treatment of the Wound: All bites and scratches should be immediately flushed out and washed with soap or detergent. Doing so can enable efficient elimination of the rabies virus at the infection site.

A 70% alcohol solution, a tincture (or solution) of iodine or a 0.1% quaternary ammonium solution can then be applied (provided that there are no remaining traces of soap, because these products neutralize each other).

Depending on the severity of the injuries, rabies immunoglobulins (RIGs) may need to be administered in association with the vaccine. In this case, refer to the Instructions for Use in the RIG package leaflet.

If necessary, treatment can be supplemented by the administration of a tetanus prophylactic and/or course of antibiotics.

Fully Immunized Subjects: Two booster doses of Verorab (0.5 mL) should be administered on D0 and D3.

Administration of rabies immunoglobulins (RIGs) is not necessary and should not be done in this case, since booster injection is always followed by an anamnestic response.

Previously immunized subjects should be able to document the following: Full pre- or post-exposure rabies vaccination, by a cell culture vaccine; a documented rabies antibody titre 0.5 iu/mL.

In case of doubt, if the booster injection was administered >5 years ago or in the case of incomplete vaccination, the patient should not be considered to be completely immunized and complete post-exposure treatment should be initiated. See Table 4.

Table 4. Recommendation for Post-Exposure Rabies Vaccination Depending on Previous Vaccinations.
Vaccination Status	Course of Action
Vaccination within the last 5 years (with a cell culture rabies vaccine)	2 injections: D0 and D3
Vaccination >5 years ago or incomplete vaccination	5 injections: D0, D3, D7, D14 and D28 with RIG administration if necessary

Non-Immunized Subjects: Five doses of Verorab (0.5 mL) should be administered on D0, D3, D7, D14 and D28. Rabies immunoglobulins (RIGs) should be administered at the same time as the 1st injection in the case of a severe injury (category III according to the WHO rabies risk classification). Equine and human immunoglobulins can be used with Verorab.

Internationally recognized RIG dosage is as follows: Human rabies immunoglobulins: 20 iu/kg body weight; equine rabies immunoglobulins: 40 iu/kg body weight.

Because RIGs may partially inhibit active antibody production, no more than the recommended dose should be administered.

The vaccine should be injected contralaterally to the RIG administration sites.

In enzootic rabies areas, the administration of 2 injections on D0 may be justified eg, in the case of lesions that are extremely severe or located near the nervous system or when the subject is immunodeficient or did not come in for a medical consultation immediately after exposure.

Vaccination Via Intradermal Route: Pre-exposure Vaccination: Primary Vaccination: As according to WHO, Verorab may be given intradermally (0.1 mL dose on D0, D7 and D28 or D21).

However, IM injections are preferable if antimalarial chemoprophylaxis (eg, chloroquine) is being used concurrently or there is a possibility of an immunocompromised state (antibody response may be impaired if the intradermal method is used).

Booster Injections: A booster injection of Verorab (0.5 mL) will be administered 1 year after primary vaccination, followed by a booster injection every 5 years.

Post-Exposure Vaccination: Intradermal Schedule: Verorab is of sufficient potency to allow its safe use in the WHO recommended intradermal post-exposure regimen in countries where relevant national authorities have approved the intradermal route for rabies post-exposure treatment.

If Verorab is administered by the intradermal route, the following instructions and warnings must be strictly adhered to.

Dosage: One intradermal dose comprises 0.1 mL of reconstituted vaccine ie, 1/5 of the IM dose. For Verorab, the administration schedule recommended by WHO is:

Non-Immunized Individuals: The 2-site intradermal regimen "2-2-2-0-1-1" includes: 2 injections of 0.1 mL at 2 sites on days D0, D3, D7; 1 injection of 0.1 mL at 1 site on days D28 (or D30) and D90.

The 2-site intradermal regimen "2-2-2-0-2" (known as updated Thai Red Cross regimen, also recommended by WHO) prescribes 2 injection of 0.1 mL at 2 sites on days D0, D3, D7 and D28 can be applied too.

Fully Immunized Individuals: 2 injections of 0.1 mL on D0, D3. This schedule should not apply to immunocompromised patients.

Administration: Verorab is administered by the IM route, into the deltoid area in adults or the anterolateral area of the thigh in infants and toddlers. Do not inject in the gluteal area. The intradermal (ID) injection may be used as an alternative, on upper or forearm.

Do not inject by the intravascular route. Ensure that the needle does not penetrate a blood vessel before vaccine injection. Do not administer by the SC route.

CONTRAINDICATIONS

Pre-Exposure: Vaccination should be postponed in case of fever or acute illness.

Hypersensitivity to any of the components Verorab, polymyxin B, streptomycin or neomycin.

Post-Exposure: Because rabies is always fatal, there is no contraindication to post-exposure vaccination.

Intradermal Route: The intradermal route must not be used in individuals receiving long-term corticosteroid or other immunosuppressive therapy or chloroquine; immunocompromised individuals; with severe wounds, especially to the head and neck or presenting late for consultation particularly children.

PRECAUTIONS

As is the case with all injectable vaccines, it is recommended to have appropriate medical treatment readily available in case of anaphylactic reaction immediately after vaccination, particularly a post-exposure vaccination in subjects with a known hypersensitivity to polymyxin B, streptomycin or neomycin.

Do not inject the vaccine into the gluteal area, because weaker levels of neutralising antibodies have been observed when this area is used.

Regular serological tests are necessary. These serological tests are performed by verifying the complete neutralisation of a reference virus, by the Rapid Fluorescent Focus Inhibition Test (RFFIT) method. This test should be done every 6 months in people at permanent risk of exposure and every 2-3 years after each booster dose injection in subjects at discontinuous risk of exposure. If the antibody level is under that considered to be protective ie, 0.5 iu/mL (RFFIT), a booster injection should be administered.

When the vaccine is administered to subjects with a known immunodeficiency due to an immunosuppressive illness or a concomitant immunosuppressive treatment (eg, corticosteroids), a serological test of their antibody level should be done 2-4 weeks after vaccination. If the antibody level is lower than that considered to be protective ie, 0.5 iu/mL (RFFIT), an additional injection should be administered.

Effects on the Ability to Drive or Operate Machinery: Post-vaccination dizziness has been frequently reported. This can temporarily affect ability to drive and use machines.

Use in pregnancy & lactation: Because of the severity of the disease, the vaccination schedule must not be modified as a result of pregnancy. Consult the physician immediately if pregnancy is discovered during a vaccination series.

Verorab may be used during lactation.

ADVERSE REACTIONS

Minor Local Reactions: Pain, erythema, edema, pruritus and induration at the injection site.

General Reactions: Moderate fever, shivering, malaise, asthenia, headaches, dizziness, arthralgia, myalgia, GI disorders (nausea, abdominal pain).

Exceptional cases of anaphylactoid reactions, urticaria, rash.

INTERACTIONS

Corticosteroids and other immunosuppressive treatments may interfere with antibody production and cause the failure of the vaccination.

Immunoglobulins must be administered at a different site from that of the vaccine (the contralateral side).

CAUTIONS FOR USAGE

Instructions for Use/Handling and Disposal: Reconstitution: Take the cap off the vaccine vial.

Inject the solvent from the ampoule into the vial of powder.

Shake gently to obtain a homogenous suspension of the vaccine. The reconstituted vaccine appears as a limpid liquid.

Immediately withdraw 0.5 mL of suspension for IM administration.

The vaccine may be used up to 8 hrs after reconstitution, provided it is maintained at 2-8°C. Unused vaccine must be discarded after 8 hrs.

Any unused product or waste should be disposed of in accordance with the regulations in effect.

Special Precautions for the Intradermal Route: It is essential that intradermal administration of Verorab be carried out only by medical staff trained in this technique in order to ensure that the vaccine is delivered intradermally and not SC.

For the intradermal route, a sterile syringe with fixed needle (insulin type) is preferred. Correct intradermal injection should result in a raised papule with an "orange peel" appearance. If the vaccine is injected too deeply into the skin and a papule is not seen, the needle should be withdrawn and reinserted nearby. If there is a complete failure to inject intradermally at more than half of the multiple injection sites, an extra intradermal dose should be given in the opposite site.

Special Storage Conditions for Intradermal Route: Verorab does not contain a preservative; therefore, great care must be taken to avoid contamination of reconstituted vaccine.

The vaccine may be used up to 8 hrs after reconstitution provided it is maintained at 2-8°C. Unused vaccine must be discarded after 8 hrs. Using aseptic technique, a dose of vaccine may be withdrawn from a vial and the remainder used for another patient provided that the vial is stored in a refrigerator between 2-8°C. A new sterile needle and syringe must be used to withdraw and administer each dose of vaccine for each patient to avoid cross infection.

STORAGE

Store in the refrigerator (2-8°C). Do not freeze.

The reconstituted vaccine should be administered immediately.

Shelf-Life: 36 months.