BPL (Bio Products Laboratory)

            Human Rabies Immunoglobulin, not less than 150 IU/mL solution for injection

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Human Rabies Immunoglobulin contains human protein, 40-180 g/L of which at least 95% is IgG. The concentration of specific IgG to Rabies virus is not less than 150 IU/mL in nominal 500 IU vials. The correct volume to give the stated potency is overprinted on the label.

This product is prepared from plasma from screened donors. Donors are selected from the USA.

For excipients, see section 6.1.

3.         PHARMACEUTICAL FORM

Solution for injection.

4.         CLINICAL PARTICULARS

4.1              Therapeutic indications

Post-exposure prophylaxis of rabies infection in persons after exposure to scratches, bites or other injuries including mucous membrane contamination with infectious tissue, such as saliva, caused by a suspected rabid animal.

Human Rabies Immunoglobulin must always be used in combination with a rabies vaccine.

4.2       Posology and method of administration

4.2.1    Posology

Post-exposure prophylaxis consists of a regimen of one dose of immunoglobulin and full courses of rabies vaccination. Rabies immunoglobulin and the first dose of rabies vaccine should be given as sooon soon as possible after exposure. Additional doses of rabies vaccine should be given according to official guidelines or the manufacturer’s instructions.

Rabies prophylaxis exclusively with simultaneous vaccination: recommended dose of rabies immunoglobulin is 20 IU/kg body weight.

If vaccine is given but treatment with human rabies immunoglobulin is delayed, human rabies immunoglobulin should still be given up to seven days after starting the course of vaccine.

Because of the risk of interference with antibody production related to vaccination, neither the dose should be increased nor repeat rabies immunoglobulin be given (even if the onset of the simultaneous prophylaxis is delayed).

The volume of solution that needs to be administered to give 500 IU is stated on the label.

            4.2.2 Method of administration

Human rabies immunoglobulin should be administered via the intramuscular route.

If a large volume (> 2mL for children or > 5 mL for adults) is required, it is recommended to administer this in divided doses at different sites.

The immunoglobulin and the vaccine should be administered at two different sites of the body.

The wound should be cleaned with soap and disinfectant.

Injections of the immunoglobulin should preferably be administered in the bitten site. The immunoglobulin should be carefully infiltrated in the depth of and around the wound. Any remainder should be injected intramuscularly at a site distant from that used for the rabies vaccine.

If intramuscular administration is contraindicated (bleeding disorders), the injection can be administered subcutaneously.  However, it should be noted that there are no clinical efficacy data to support administration by the subcutaneous route.

4.3       Contraindications

Because of the life-threatening risk due to rabies, there are no contraindications to the administration of rabies immunoglobulin.

4.4       Special warnings and special precautions for use

Ensure that Human Rabies Immunoglobulin is not administered into a blood vessel, because of the risk of shock.

True allergic hypersensitivity reactions are rare.

Human Rabies rabies Iimmunoglobulin contains a small quantity of IgA. Individuals who are deficient in IgA have the potential for developing IgA antibodies and may have anaphylactic reactions after administration of blood components containing IgA.

Rarely, Hhuman Rabies rabies Iimmunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who have tolerated previous treatment with human immunoglobulin.

Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the injection. In case of shock, standard medical treatment for shock should be implemented.

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV. The measures taken may be of limited value against non-enveloped viruses such as HAV and parvovirus B19.

There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety.

It is strongly recommended that every time that Human Rabies Immunoglobulin is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

4.5       Interactions with other medicamentsinal products and other forms of interactions

            Live attenuated virus vaccines

Immunoglobulin administration may interfere with the development of an immune response to live attenuated virus vaccines, such as rubella, mumps, and varicella, for a period of up to 3 months.  After administration of this product, an interval of at least 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 4 months.

Interference with serological testing

After injection of immunoglobulin, the transitory rise of the various passively transferred antibodies in the patient’s blood may result in misleading positive results in serological testing.

Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D, may interfere with some serological tests for red cell antibodies, for example the antiglobulin test (Coombs’ test).

4.6       Pregnancy and lactation

The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected.

4.7              Effects on ability to drive and use machines

No effects on ability to drive and use machines have been observed.

4.8       Undesirable effects

There are no robust data on the frequency of undesirable effects from clinical trials. The following undesirable effects have been reported with intramuscular immunoglobulins:

chest pain, dyspnoea, tremor, dizziness, facial oedema, glossitis, buccal ulceration and arthralgia. Anaphylactic reactions occur rarely and are more likely in patients who have antibodies to IgA, or who have had an allergic reaction after blood transfusion or treatment with plasma derivatives.

As with all intramuscular injections, some short term discomfort can be expected at the injection site and in rare instances local induration, which can be minimised by d

Deep intramuscular injection may reduce the risk of local induration.

For safety with respect to risk of transmissionble agents of virus infectctions, see Section 4.4.

4.9       Overdose
            Consequences of an overdose are not known.

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: immune sera and immunoglobulins: Human rabies immunoglobulin.  ATC code: J06BB05.

Human rabies immunoglobulin contains mainly immunoglobulin G (IgG) with a specifically high content of antibodies against rabies virus.

5.2       Pharmacokinetic properties

Human rabies immunoglobulin for intramuscular use is bioavailable in the recipient’s circulation after a delay of 2-3 days. Human rabies immunoglobulin has a half-life of about 3 – 4 weeks. This half-life may vary from patient to patient.

IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.

5.3       Preclinical safety data

Human rabies immunoglobulin is a preparation of human plasma proteins, so safety testing in animals is not particularly relevant to the safety of use in man.  Acute toxicity studies in rat and mouse showed species specific reactions which bear no relevance to administration in humans.  Repeated dose toxicity testing and embryo-foetal toxicity studies are impracticable due to the induction of, and interference with, antibodies to human protein.  Clinical experience provides no sign of tumourigenic and mutagenic effects of immunoglobulins.

6.         PHARMACEUTICAL PARTICULARS

6.1       List of excipients

Sodium chloride

Glycine

Sodium acetate

Sodium hydroxide

6.2       Incompatibilities

This medicinal product must not be mixed with other medicinal products.

6.3              Shelf-life

6.4       Special precautions for storage

Human Rabies Immunoglobulin should be stored in the original container at 2°C to 8°C.  Storage for up to one week at ambient temperatures (25°C) in the original container is not detrimental.  DO NOT FREEZE.

Store in the original vial. Keep vial in the outer carton in order to protect from light.

6.5       Nature and contents of container

Neutral borosilicate glass vial (type I Ph.Eur.) with overseal consisting of a halobutyl rubber wad (type I Ph.Eur.), clear lacquered aluminium skirt and flip-off polypropylene cap.

6.6       Instruction for use and handling and disposal

The product should be brought to room or body temperature before use.

The colour can vary from colourless to pale-yellow and is either clear or slightly opalescent. Do not use solutions that are cloudy or have deposits.

Any used product or waste material should be disposed of in accordance with local requirements.

7.         MARKETING AUTHORISATION HOLDER

Bio Products Laboratory

Dagger Lane

Elstree

Hertfordshire

WD6 3BX

United Kingdom.

            Tel: +44 (0)20 8258 2200

            Fax: +44 (0)20 8258 2608

            Email: info@bpl.co.uk

8.         MARKETING AUTHORISATION NUMBER

PL 08801/0014

            9.         DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

February 1992

10.       DATE OF (PARTIAL) REVISION OF THE TEXT