This information is intended for use by health professionals

1. Name of the medicinal product

Human Rabies Immunoglobulin 150 IU/ml solution for injection

2. Qualitative and quantitative composition

Human rabies immunoglobulin.

Human protein content: 40-180 g/l of which at least 95% is IgG.

Each vial contains nominally 500 IU of human rabies immunoglobulin.

One ml contains a minimum of 150 IU human rabies immunoglobulin.

Distribution of the IgG subclasses (approximate values):

IgG1 64%

IgG2 29%

IgG3 6%

IgG4 1%

The maximum IgA content is 540 micrograms/ml.

Produced from the plasma of human donors.

Excipient with known effect:

This medicinal product contains maximum 0.2 mmol (4.6 mg) sodium per ml.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection.

Clear or slightly opalescent, colourless or pale yellow sterile solution.

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

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 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.

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).

Method of administration

Human rabies immunoglobulin should be administered via the intramuscular route.

If a large volume (>2 ml 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 precautions for use

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

Hypersensitivity

True hypersensitivity reactions are rare.

Human Rabies Immunoglobulin 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, human rabies immunoglobulin 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.

Thromboembolism

Arterial and venous thromboembolic events including myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism have been associated with the use of immunoglobulins. Patients should be sufficiently hydrated before use of immunoglobulins. Caution should be exercised in patients with pre-existing risk factors for thrombotic events (such as hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolemic patients, patients with diseases which increase blood viscosity).

Patients should be informed about first symptoms of thromboembolic events including shortness of breath, pain and swelling of a limb, focal neurological deficits and chest pain and should be advised to contact their physician immediately upon onset of symptoms.

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).

Transmissible agents

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 human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) and for the non-enveloped hepatitis A and parvovirus B19 viruses.

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.

Paediatric population

The listed warnings and precautions apply both to adults and children.

4.5 Interaction with other medicinal products and other forms of interaction

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

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.

Breast-feeding

Immunoglobulins are excreted in human milk and may contribute to protecting the neonate from pathogens which have a mucosal port of entry.

Fertility

No animal fertility studies have been conducted with human rabies immunoglobulin. Clinical experience with immunoglobulin suggests that no harmful effects on fertility are to be expected (see section 5.3).

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

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).

Frequencies have been evaluated according to the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA Standard System Organ Class

Adverse reaction

Frequency

Immune system disorders

Hypersensitivity, anaphylactic shock

Rare

Nervous system disorders

Headache

Rare

Cardiac disorders

Tachycardia

Rare

Vascular disorders

Hypotension

Rare

Gastrointestinal disorders

Nausea, vomiting

Rare

Skin and subcutaneous tissue disorders

Skin reaction, erythema, pruritus

Rare

Musculoskeletal and connective tissue disorders

Arthralgia

Rare

General disorders and administration site conditions

Fever (pyrexia), malaise, chills

At injection site: swelling, pain, erythema, induration, warmth, rash

Rare

For safety information with respect to transmissible agents, see section 4.4.

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. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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

Absorption and distribution

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.

Elimination

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 (for pH adjustment)

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

2 years.

From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Storage for up to one week at room temperature (up to 25°C) in the original unopened container is not detrimental.

Do not freeze.

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

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Vials are for single use only.

500 IU solution in a 5 ml glass (Type I) vial with stopper (halobutyl rubber), with an overseal (aluminium) and tamper-evident cap (polypropylene).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

Do not use solutions that are cloudy or have deposits.

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

7. Marketing authorisation holder

Bio Products Laboratory Limited

Dagger Lane

Elstree

Hertfordshire

WD6 3BX

United Kingdom.

8. Marketing authorisation number(s)

PL 08801/0014

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 6 June 1991

10. Date of revision of the text

September 2020