4.1. Therapeutic indications

Post-exposure prophylaxis

Immediate prophylaxis after tetanus prone injuries in patients not adequately vaccinated, in patients whose immunisation status is not known with certainty, and in patients with severe deficiency in antibody production or vaccinated patients with high risk wounds.

4.2. Posology and method of administration

Posology

Prophylaxis of tetanus prone wounds

• 250 IU, unless the risk is thought to be extremely high

• the dose may be increased to 500 IU in:

- infected wounds, where surgically appropriate treatment cannot be achieved within 24 hours

- deep or contaminated wounds with tissue damage and reduced oxygen supply, as well as foreign body injury (e.g. bites, stings or shots)

Method of administration

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.

When simultaneous vaccination is necessary, the immunoglobulin and the vaccine should be administered at two different sites.

For prophylaxis, 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.

For acute therapy, if intramuscular administration is not clinically appropriate, an alternative intravenous product may be used if available.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4).

Hypersensitivity to human immunoglobulins, especially in patients with antibodies against IgA.

4.4. Special warnings and precautions for use

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

Hypersensitivity

True hypersensitivity reactions are rare but allergic-type responses to human tetanus immunoglobulin may occur.

Human Tetanus 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. The physician must therefore weigh the benefit of treatment with Human Tetanus Immunoglobulin against the potential risk of hypersensitivity reactions.

Rarely, human tetanus 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), especially when higher doses of human tetanus immunoglobulin are prescribed.

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 Tetanus 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 to both 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 5 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 Tetanus Immunoglobulin. Clinical experience with immunoglobulins suggest 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

Summary of the safety profile

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally.

Rarely human immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.

Local reactions at administration sites: swelling, soreness, redness, induration, local heat, itching, bruising and rash.

There are no robust data on the frequency of undesirable effects from clinical trials.

Tabulated summary 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 <1,1000); 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.

The following adverse reactions have been reported from post-marketing experience.

MedDRA Standard System Organ Class

Adverse reaction

Frequency

Immune system disorders

Hypersensitivity, anaphylactic shock

Not known

Nervous system disorders

Headache, dizziness, tremor

Not known

Cardiac disorders

Tachycardia

Not known

Vascular disorders

Hypotension

Not known

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Not known

Gastrointestinal disorders

Nausea, vomiting, glossitis, buccal ulceration

Not known

Skin and subcutaneous disorders

Skin reaction, erythema, itching, pruritus, facial oedema

Not known

Musculoskeletal and connective tissue disorders

Arthralgia

Not known

General disorders and administration site conditions

Fever, malaise, chills, chest pain

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

Not known

Description of selected adverse reactions

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 deep intramuscular injection.

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.