1.         Name of Medicinal Product:

            Human Varicella-Zoster Immunoglobulin 250 mg solution for injection

2.         Qualitative and Quantitative Composition:

            Human Varicella-Zoster Immunoglobulin Ph.Eur.*

            Each vial contains 250 mg human protein (, 40-180 mg/ml)g/L of which at least 95% are gammaglobulins (is IgG). This product is prepared from plasma from screened donors. Donors are selected from the USA.

            *One millilitre contains not less than 100 iu. The concentration of specific IgG to Varicella- Zoster antibodyis at least 100 IU/mL in nominal 250 mg vials. The correct volume to give 250 mg 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

            Human Varicella-Zoster Immunoglobulin is indicated for:

1.         Leukaemic and other immunosuppressed contacts of chickenpox or zoster, without a definite history of chickenpox (see notes 1, 2 and 3).

2.         Contacts of chickenpox or zoster with severe debilitating disease, without a definite history of chickenpox (see notes 1 and 2).

3.         Neonates whose mothers develop chickenpox (not zoster) in the period 7 days before, to one month after, delivery (see note 4a).

4.         Neonates in contact with chickenpox or zoster whose mothers have no history of chickenpox or who have no antibody (for pre-term or small babies see note 4b).

5.         Pregnant contacts who have no antibody (see note 5).

            Notes on use of human Varicella-Zoster immunoglobulin

1.         Human Varicella-Zoster Immunoglobulin does not prevent infection even if given within 72 hours of exposure, but may attenuate an attack if given within 10 days after exposure.  Both sub-clinical and clinical attacks occur.  The latter are occasionally severe despite use of Human Varicella-Zoster Immunoglobulin.

2.         Measurement of antibody

   Whenever possible, contacts without a definite history of chickenpox should be screened for antibody by a sensitive test (e.g. ELISA, radioimmunoassay or immunofluorescence).

3.         Immunosuppressed patients

a)         Bone marrow transplant:  These patients should be given Human Varicella-Zoster Immunoglobulin following contact regardless of any history of chickenpox or the result of any antibody tests.  (Patients receiving other organ transplants should be screened for antibody as in 2 above).

b)         Steroid therapy:  Only patients who have been on high dose steroids (e.g. 2 mg/kg/day prednisolone for more than 1 week) within the last 3 months require Human Varicella-Zoster Immunoglobulin.

c)         HIV positive individuals:  HIV positive contacts with symptoms and without a history of chickenpox or shingles should be given Human Varicella-Zoster Immunoglobulin without antibody testing.  There is as yet no evidence of increased risk of serious illness in asymptomatic HIV positive individuals.

4.         Neonates

a)         About two-thirds of infants whose mothers have chickenpox around the time of delivery will develop varicella despite Human Varicella-Zoster Immunoglobulin prophylaxis.  Infection is usually mild, but fatal cases have occurred.

b)         Premature infants:  Those born before 30 weeks of gestation or with a birth weight less than 1 kg may not possess maternal antibody despite a positive history in the mother.

c)         The following will possess maternal antibody and do NOT require Human Varicella-Zoster Immunoglobulin.

            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 before or after delivery.

5.         Pregnant contacts

a)       Pregnant contacts should be tested for antibody before Human Varicella-Zoster Immunoglobulin is given as about two-thirds will have antibody despite a negative history.

b)      The aim of Human Varicella-Zoster Immunoglobulin prophylaxis, in pregnant contacts is attenuation of maternal disease.  Fetal damage following maternal varicella is rare.

c)       Despite Human Varicella-Zoster Immunoglobulin prophylaxis, about two-thirds of antibody negative pregnant contacts become infected; infections are usually mild or asymptomatic but severe cases have occurred.  The incidence and severity of infection are not affected by the interval between contact and Human Varicella-Zoster Immunoglobulin administration.

6.         Treatment of chickenpox

There is no evidence that Human Varicella-Zoster Immunoglobulin is effective in the treatment of severe disease.  However, since antibody production can be delayed in immunosuppressed individuals, intravenous preparations of normal human immunoglobulin may be used to provide an immediate source of antibody.

4.2       Posology and method of administration

4.2.1    Posology

            Dose levels for treatment are as follows:

0 - 5 years                    250 mg

6 - 10 years                  500 mg

11 - 14 years                750 mg

15 years and older        1000 mg

If a second exposure of chickenpox occurs three weeks or more after the first dose of Human Varicella-Zoster Immunoglobulin, a second dose must be given.

4.2.2    Method of administration

Human Varicella-Zoster Immunoglobulin should be administered by slow injection via the intramuscular route only.  If large total doses (³5 ml) are required, it is advisable to administer them in divided doses, at different sites.

In the case of clotting disorders where intramuscular injections are contra-indicated, Human Varicella-Zoster Immunoglobulin may be administered subcutaneously.  Careful manual pressure with a compress should be applied to the site after the injection.

Human Varicella-Zoster Immunoglobulin is for single injection only; any used materials and unused solution should be discarded by approved means.

4.3       Contra-indications

Human Varicella-Zoster Immunoglobulin should not be administered to patients suffering from severe thrombocytopenia or any coagulation disorder that would contra-indicate intramuscular injection, unless the patient is having appropriate treatment for these disorders.

(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)

The correct volume of solution to give a dose of 250 mg is overprinted on the label.

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.  The usually recommended sites for adults are the buttock, thigh or deltoid; for infants the lateral aspect of the thigh is preferable. 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.

4.3       Contraindications

       Hypersensitivity to any of the components.

       Hypersensitivity to human immunoglobulins.

4.4       Special warnings and special precautions for use

Human Varicella-Zoster Immunoglobulin must not be administered intravenously, because the preparation may cause severe reactions if given by this route.

Injections must be made intramuscularly and care should be taken to draw back the plunger of the syringe before injection in order to be certain that the needle is not in a blood vessel.

Neonatal varicella-zoster infection can still develop in infants although they have received Human Varicella-Zoster Immunoglobulin. In these affected infants, the infection is mild in up to two-thirds of the cases. In the remaining affected infants varicella-zoster infection may still be severe and rare fatal cases have occurred.

True allergic reactions to Human Varicella-Zoster Immunoglobulin are rare, when administered by the prescribed intramuscular method.  In the case of shock, treatment should follow the guidelines for therapy of shock.

Suspicion of allergic or anaphylactic type reaction requires the injection be discontinued immediately.

Patients should be observed for at least twenty minutes after administration.

In the case of clotting disorders where intramuscular injections are normally contra-indicated, the patient should receive the appropriate medication for the disorder or the injection given subcutaneously. Careful manual pressure with a compress should be applied to the site after the injection.

4.5       Interactions with other medicaments and other forms of interactions

4.5.1    Live attenuated virus vaccines

            Human Varicella-Zoster Immunoglobulin administration may interfere with response to live virus vaccines, such as measles, rubella, mumps and varicella, for a period of at least five weeks and up to three months.  Such vaccinations should only be given after an interval of three months after administration of Human Varicella-Zoster Immunoglobulin.

4.5.2    Interference with serological testing

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

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

True hypersensitivity reactions are rare.

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.

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 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       Interactions with other medicaments 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 5 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 tests.

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 (Coomb’s test).

4.6       Pregnancy and lactation

There is inadequate evidence of safety in human pregnancy, but intramuscular immunoglobulins, especially Anti-D Immunoglobulin, have been widely used during pregnancy for many years without apparent ill consequence. No animal studies have been carried out.  Human Varicella-Zoster Immunoglobulin should be administered to a pregnant woman or breast-feeding mother only if clearly needed.

The aim of Human Varicella-Zoster Immunoglobulin prophylaxis in pregnant contacts is attenuation of maternal disease. Fetal damage following maternal varicella is rare.  Pregnant contacts should be tested for antibody before administration, as about two-thirds will have antibody despite a negative history.  Despite varicella-zoster prophylaxis, about two thirds of antibody negative pregnant contacts become infected.  Infections are usually mild or asymptomatic but severe cases have occurred.  The incidence and severity of infection are not affected by the interval between contact and Human Varicella-Zoster Immunoglobulin administration. The transplacental passage of Human Varicella-Zoster Immunoglobulin may be assumed. The transfer of immunoglobulin G into the newborn during breast-feeding may be assumed.

            The risk/benefit of Human Varicella-Zoster Immunoglobulin administration should be assessed for each individual case.

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

            There are no indications that Human Varicella-Zoster Immunoglobulin may impair theNo effects on ability to drive orand use machines have been observed.

4.8       Undesirable effects

            As with all intramuscular injections, some short term discomfort can be expected at the injection site.  In rare instances local induration can occur.  Deep intramuscular injection can reduce the risk.  Human Varicella-Zoster Immunoglobulin is well tolerated, although very rarely, anaphylactic reactions may occur in patients, usually with primary antibody deficiency, who have antibodies to IgA, or in patients who have had an atypical reaction to blood transfusions or treatment with plasma derivatives.

            Other side effects which have been reported with intramuscular immunoglobulin are chest pain, dyspnoea, tremor, dizziness, facial oedema, glossitis, buccal ulceration and arthralgia.

To reduce the risk of transmission of infective agents, stringent controls are applied to the selection of blood donors and donations. In addition, virus removal and/or inactivation procedures are included in the production process.

All donations have been tested by validated procedures, and found to be non-reactive for recognised markers of virus infection (hepatitis B surface antigen, antibodies to HIV-1, HIV-2 and HCV).  Plasma pools are also tested negative for these markers and additionally for HCV-RNA.

The organic solvent (Tri-n-butyl Phosphate, TnBP) and detergent (Polysorbate 80) treatment in BPL’s Human Varicella-Zoster Immunoglobulin manufacturing process is used for the inactivation of lipid enveloped viruses such as hepatitis B, hepatitis C and HIV.  Viral inactivation combined with donor and product screening for hepatitis and human immunodeficiency viruses greatly reduces the likelihood of viral contamination of this product.  In virus inactivation studies using a model lipid enveloped virus, the solvent/detergent treatment stage of BPL’s Human Varicella-Zoster Immunoglobulin manufacturing process reduces virus infectivity to undetectable levels, i.e. a minimum 6 log reduction.

When medicinal products prepared from human blood or plasma are administered, the transmission of disease by infective agents of known, and as of yet unknown origin, cannot be totally excluded.

The current procedures applied in the manufacture of medicinal products derived from human blood or plasma are effective against enveloped viruses such as HIV, hepatitis B and hepatitis C viruses, but are of limited value against non-enveloped viruses such as hepatitis A virus.  However, products of this kind have never been known to transmit HAV, probably due to the presence of antibodies to HAV in the preparation.

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

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

4.9       Overdose

            Human Varicella-Zoster Immunoglobulin is a concentrateConsequences of the gammaglobulin fraction of human immune plasma.  Overdosage is unlikely to lead to more frequent or more severe adverse reactions than the recommended dosean overdose are not known.

5.         Pharmacological Properties:

5.1       Pharmacodynamic properties

            Human Varicella-Zoster Immunoglobulin contains specific neutralising antibodies (mainly IgG) which recognise and bind to the invading varicella-zoster antigens.  The complex is removed by either complement activation or phagocytosis.

            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

            Measurable levels of antibodies to varicella-zoster are found in serum approximately twenty minutes after intramuscular injection.  Peak serum levels are achieved two or three days later.

            The biological half-life is 21-22 days, i.e. that time taken for a 50% reduction of peak concentration in the plasma.

            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.

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 rat and mouse showed species specific reactions which bear no relevance to administration in humans.  Repeated dose toxicity testing and embryo-fetalfoetal toxicity studies are impracticable due to induction of, and interference with antibodies to human protein.

6.         Pharmaceutical Particulars:

6.1       List of excipients

            Sodium chloride

   Glycine

   Sodium acetate trihydrate

   Sodium hydroxide

6.2       Incompatibilities

            Pharmaceutical agents should not normally be added to Human Varicella-Zoster Immunoglobulin as their effects on the product have not been established.

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

6.3       Shelf-life

6.4       Special precautions for storage

            Human Varicella-Zoster Immunoglobulin should be stored in the original containervial at 2°C to 8°C.  Keep vial in the outer carton in order to protect from light.

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

            DO NOT FREEZE.

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       Instructions for use and handling and disposal

            Human Varicella-Zoster Immunoglobulin is for single use only; any used materials and unused solution should be discarded by approved means.  The protein concentration to calculate the dose volume, is specified on the label.

            The condition of date-expired, or incorrectly stored product cannot be guaranteed.  Such product may be unsafe, and should not be used.

            Solutions which are cloudy or have deposits should not be used.

7.         Marketing Authorisation Holder

            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 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

            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 08801/0013

9.         Date of First Authorisation/Renewal of Authorisation:

            July 1995

10.       Date of (Partial) Revision of the Text: