Human Hepatitis B Immunoglobulin solution for injection

4.1 Therapeutic indications Immunoprophylaxis of hepatitis B

• In case of accidental exposure in non-immunised subjects (including persons whose vaccination is incomplete or status unknown).
• In haemodialysed patients, until vaccination has become effective.
• In the newborn of a hepatitis B virus carrier-mother.
• In subjects who did not show an immune response (no measurable hepatitis B antibodies) after vaccination and for whom a continuous prevention is necessary due to the continuous risk of being infected with hepatitis B.4.2 Posology and method of administration **Posology**
• Prevention of hepatitis B in case of accidental exposure in non-immunised subjects: At least 500 IU, depending on the intensity of exposure, as soon as possible after exposure, and preferably within 24 – 72 hours.
• Prevention of hepatitis B in case of accidental exposure in subjects or in subjects who have had not responded to a prior, full course of vaccination: At least 500 IU (age 10 years or older), depending on the intensity of exposure, as soon as possible after exposure, and preferably within 24 – 72 hours, although it should still be considered up to a week after exposure. The dose for children is as follows: 300 IU aged 5 – 9 years (inclusive); 200 IU aged 0-4 years (inclusive). Irrespective of whether the source of the exposure is known or unknown to be HBsAg positive, a second injection of Human Hepatitis B Immunoglobulin should be given one month later.
• Immunoprophylaxis of hepatitis B in haemodialysed patients: 8 – 12 IU/kg with a maximum of 500 IU, every 2 months until seroconversion following vaccination.
• Prevention of hepatitis B in the newborn, of a hepatitis B virus carrier-mother, at birth or as soon as possible after birth: 30 – 100 IU/kg. The hepatitis B immunoglobulin administration may be repeated until seroconversion following vaccination. In all these situations, vaccination against hepatitis B virus is highly recommended. The first vaccine dose can be injected the same day as human hepatitis B immunoglobulin, however in different sites. In subjects who did not show an immune response (no measurable hepatitis B antibodies) after vaccination, and for whom continuous prevention is necessary, administration of 500 IU to adults and 8 IU/kg to children every 2 months can be considered; a minimum protective antibody titre is considered to be 10 IU/ml. **Method of administration** Intramuscular use. 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. If intramuscular administration is contraindicated (bleeding disorders), the injection can be administered subcutaneously if no intravenous product is available. However, it should be noted that there are no clinical efficacy data to support administration by the subcutaneous route.4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hypersensitivity to human immunoglobulins, especially in patients with antibodies against IgA.4.4 Special warnings and precautions for use Ensure that Human Hepatitis B Immunoglobulin is not administered into a blood vessel, because of the risk of shock. If the recipient is a carrier of HBsAg, there is no benefit in administering this product. *Hypersensitivity* True hypersensitivity reactions are rare but allergic type responses to Human Hepatitis B Immunoglobulin may occur. Human Hepatitis B 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 Hepatitis B Immunoglobulin against the potential risk of hypersensitivity reactions. Rarely, human hepatitis B 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 hepatitis B 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 (HAV) 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 Hepatitis B 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. **Sodium** *500 IU vial* This medicinal product contains approximately 1 mmol (23 mg) sodium per vial, equivalent to 1% of the WHO recommended maximum daily intake of 2 g sodium for an adult.4.5 Interaction with other medicinal products and other forms of interaction **Live attenuated virus vaccines** Active immunisation with live virus vaccines (e.g. measles, mumps or rubella) should be postponed for 3 months after the last administration of Human Hepatitis B Immunoglobulin, as the efficacy of the live virus vaccine may be impaired. If Human Hepatitis B Immunoglobulin needs to be administered within 3-4 weeks of a live virus vaccination, then the efficacy of such a vaccination may be impaired.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 and therefore should only be given with caution to pregnant women and breast-feeding mothers. Immunoglobulin products have been shown to cross the placenta, increasingly during the third trimester. 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 hepatitis B immunoglobulin. Clinical experience with immunoglobulin 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 Human Hepatitis B Immunoglobulin has no influence on ability to drive and use machines.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. **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. The following undesirable effects 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 | Not known | | **Cardiac disorders** | Tachycardia | Not known | | **Vascular disorders** | Hypotension | Not known | | **Gastrointestinal disorders** | Nausea, vomiting | Not known | | **Skin and subcutaneous tissue disorders** | Skin reaction, erythema, itching, pruritus | Not known | | **Musculoskeletal and connective tissue disorders** | Arthralgia | Not known | | **General disorders and administration site conditions** | Fever, malaise, chills At injection site: swelling, pain, erythema, warmth, pruritus, rash, itching | Not known | | At injection site: induration | Not known | 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.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: immune sera and immunoglobulins: Hepatitis B Immunoglobulin, ATC code: J06BB04. Human Hepatitis B Immunoglobulin contains mainly immunoglobulin G (IgG) with a specifically high content of antibodies against hepatitis B virus surface antigen (HBs).5.2 Pharmacokinetic properties **Absorption and distribution** Human hepatitis B immunoglobulin for intramuscular use is bioavailable in the recipient's circulation after a delay of 2-3 days. Human hepatitis B 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 the reticuloendothelial system.5.3 Preclinical safety data Human Hepatitis B 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 bore no relevance to administration in humans. Repeated dose toxicity testing and embryofoetal toxicity studies are impracticable due to induction of, and interference with antibodies to human protein. Clinical experience provides no evidence of tumorigenic and mutagenic effects of immunoglobulins.

6.1 List of excipients Sodium chloride Glycine Sodium acetate trihydrate Hydrochloric acid (for pH adjustment) 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 3 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. **200 IU**

• 200 IU solution in a 5 ml glass vial (Type I) with stopper (halobutyl rubber), with an overseal (aluminium) and tamper-evident cap (polypropylene). **500 IU**
• 500 IU solution in a 10 ml glass vial (Type I) 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.