This information is intended for use by health professionals

1. Name of the medicinal product

Human Varicella-Zoster Immunoglobulin 100 IU/ml solution for injection

2. Qualitative and quantitative composition

Human varicella-zoster immunoglobulin

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

Each vial contains 250mg human varicella-zoster immunoglobulin.

One ml contains 100 IU/ml human varicella immunoglobulin

The maximum IgA content is 540 micrograms/ml

Distribution of the IgG subclasses (approximate values):

IgG1……….64.3%

IgG2……….29.0%

IgG3……….6.2%

IgG4……….0.5%

Produced from the plasma of human donors.

Excipient with known effect:

Sodium content:

This medicinal product contains not more than 10 mg (0.5 mmol) sodium per 250 mg therefore it is essentially 'sodium-free'.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection.

The colour can vary from a colourless to pale yellow sterile solution (see section 6.6).

4. Clinical particulars
4.1 Therapeutic indications

Prophylaxis against varicella zoster virus (VZV) infection in at risk patients exposed to varicella (chickenpox) or herpes zoster:

1. pregnant women with negative VZV immune status especially up to early in the third trimester

2. neonates whose mothers develop varicella infection within 7 days before and 7 days after delivery

3. neonates whose mothers have no history of varicella and/or a negative immune status

4. premature infants <28 weeks of gestation or newborns with low birth weight

5. adults and children with no history of varicella and/or a negative immune status, receiving immunosuppressive therapy including steroids, cytostatic agents, radiotherapy, recent stem cell transplantation, or who have congenital or acquired immunodeficiency disorders and are not receiving replacement therapy with immunoglobulin.

Notes on use of Human Varicella-Zoster Immunoglobulin

Whenever possible, contacts without a definite history of chickenpox should be screened for antibody by a sensitive test (e.g. ELISA, radioimmunoassay or immunofluorescence). There is no need to test neonates for antibody.

If antibodies to VZV are detectable, Human Varicella-Zoster Immunoglobulin is generally NOT needed. The following infants will possess maternal antibody and do NOT require Human Varicella-Zoster Immunoglobulin.

(i) Infants born more than seven days after the onset of maternal chickenpox.

(ii) Infants whose mothers have a positive history of chickenpox and/or a positive antibody result.

(iii) Infants whose mothers develop zoster (shingles) before or after delivery.

4.2 Posology and method of administration

Posology

≥15 IU/kg body weight as soon as possible, ideally within 3 days but within 10 days maximum.

Alternative dose levels for treatment are as follows:

0 - 5 years

250 mg (1 vial)

6 - 10 years

500 mg (2 vials)

11 - 14 years

750 mg (3 vials)

15 years and older

1000 mg (4 vials)

If a second exposure to chickenpox occurs three weeks or more after the first dose of Human Varicella-Zoster Immunoglobulin, a second dose is required.

Method of administration

Human Varicella-Zoster 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.

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.

The safety and efficacy of Human Varicella-Zoster Immunoglobulin in children aged 0-18 years has not been established. No data are available.

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 Varicella-Zoster 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 varicella-zoster immunoglobulin may occur.

Human Varicella-Zoster 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 Varicella-Zoster Immunoglobulin against the potential risks of hypersensitivity reactions.

Rarely, Human Varicella-Zoster 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 direct antiglobulin test (DAT, direct 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 Varicella-Zoster 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 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.

No interaction studies have been performed.

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 into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry.

Fertility

No animal fertility studies have been conducted with Human Varicella-Zoster Immunoglobulin. Clinical experience with immunoglobulins suggests that no harmful effects on fertility 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

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 injection sites: swelling, soreness, redness, induration, local heat, itching, bruising and rash.

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

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

Anaphylactic shock, Hypersensitivity

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, chill

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

Not known

Not known

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

Reporting 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 reactions via the United Kingdom Yellow Card Scheme: 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 varicella immunoglobulin

ATC code: J06B B03.

Human Varicella-Zoster Immunoglobulin contains mainly immunoglobulin G (IgG) with a specifically high content of antibodies against varicella-zoster virus.

5.2 Pharmacokinetic properties

Absorption and Distribution

Human Varicella-Zoster Immunoglobulin for intramuscular administration is bioavailable in the recipient's circulation after a delay of 2-3 days.

Human Varicella-Zoster Immunoglobulin has a half-life of about 3-4 weeks. This half-life may vary from patient to patient.

Biotransformation and Elimination

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

5.3 Preclinical safety data

Human Varicella-Zoster 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 rats and mice with immunoglobulins 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 an induction of, and interference with antibodies to human protein.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium chloride

Glycine

Sodium acetate trihydrate

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

Once the vial has been opened, the solution should be used immediately.

6.4 Special precautions for storage

Store in a refrigerator (2°C - 8°C)

Do not freeze.

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

Storage for up to one week at 25°C in the original container is not detrimental.

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

6.5 Nature and contents of container

5 ml glass vial (Type I Ph.Eur.) closed with a halobutyl stopper and over-sealed with a tamper-evident cap.

Vials are for single use only.

Pack size

Human Varicella-Zoster Immunoglobulin 100 IU/ml solution for injection

1 x 250 mg vial

6.6 Special precautions for disposal and other handling

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

Do not use solutions which 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 Ltd.,

Elstree

WD6 3BX

United Kingdom.

8. Marketing authorisation number(s)

PL 08801/0013

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: November 1991

10. Date of revision of the text

January 2019

Version 11