VARIVAX powder and solvent for suspension for injection

[Varicella Vaccine (live)]

After reconstitution, one dose (0.5 mL) contains:

Varicella virus** Oka/Merck strain (live, attenuated) 1350 PFU***

**Produced in human diploid cells (MRC-5)

***PFU = Plaque-forming units

This vaccine may contain a trace amount of neomycin (see sections 4.3 and 4.4).

Excipients:

For a full list of excipients, see section 6.1.

Powder and solvent for suspension for injection.

White to off-white powder and clear, colorless liquid solvent.

Varivax is indicated for vaccination against varicella in individuals from 12 months of age.

VARIVAX may also be administered to susceptible individuals who have been exposed to varicella. Vaccination within 3 days of exposure may prevent a clinically apparent infection or modify the course of the infection. In addition, there are limited data that indicate that vaccination up to 5 days after exposure may modify the course of the infection (see section 5.1).

VARIVAX is to be used on the basis of applicable official recommendations.

Posology

Individuals less than 12 months of age

VARIVAX should not be administered to individuals less than 12 months of age.

Individuals from 12 months to 12 years of age

Individuals from 12 months of age should receive two doses of VARIVAX to ensure optimal protection against varicella (see section 5.1). At least one month must elapse between the first and second dose of VARIVAX. In clinical studies, intervals of 1 month to six years between doses have been used (see section 5.1). The timing for a second dose may vary, according to the local applicable official recommendations.

Note: applicable official recommendations may vary regarding the need for one or two doses and the interval between doses of varicella-containing vaccines.

Individuals 12 months to 12 years of age with asymptomatic HIV infection [CDC Class 1] with an age-specific CD4+ T-lymphocyte percentage 25% should receive two doses of 0.5 mL given 12 weeks apart.

Individuals from 13 years of age and older

Individuals 13 years of age and older should receive two doses of 0.5 mL given 4-8 weeks apart. If the interval between doses exceeds 8 weeks, the second dose should be given as soon as possible. Some individuals may not be protected until after the second dose has been administered.

There are data available on protective efficacy for up to 9 years post-vaccination (see section 5.1). However, the need for booster doses has not been determined as yet.

If VARIVAX is to be administered to seronegative subjects before a period of planned or possible future immunosuppression (such as those awaiting organ transplantation and those in remission from a malignant disease), the timing of the vaccinations should take into account the interval after the second dose before maximal protection might be expected (see sections 4.3, 4.4, and 5.1).

Elderly

There are no data on protective efficacy or immune responses to VARIVAX in seronegative persons over 65 years of age.

Method of administration

The vaccine is to be injected intramuscularly (IM) or subcutaneously (SC).

The preferred injection sites are the anterolateral area of the thigh in younger children and the deltoid area in older children, adolescents, and adults.

The vaccine should be administered subcutaneously in patients with thrombocytopenia or any coagulation disorder.

DO NOT INJECT INTRAVASCULARLY.

Precautions to be taken before manipulating or administering the product: See section 6.6.

• History of hypersensitivity to any varicella vaccine, to any of the excipients or to gelatin or neomycin (which may be present as trace residues, see sections 4.4 and 6.1).

• Blood dyscrasias, leukaemia, lymphomas of any type, or other malignant neoplasms affecting the hemic and lymphatic systems.

• Individuals receiving immunosuppressive therapy (including high doses of corticosteroids).

• Individuals with humoral or cellular (primary or acquired) immunodeficiency, including hypogammaglobulinemia and individuals with AIDS, or symptomatic HIV infection or a CDC Class 2 or higher or an age-specific CD4+ T-lymphocyte percentage <25% (see section 4.4).

• Individuals with a family history of congenital or hereditary immunodeficiency, unless the immune competence of the potential vaccine recipient is demonstrated.

• Active untreated tuberculosis.

• Any illness with fever >38.5°C; however, low-grade fever itself is not a contraindication to vaccination.

• Pregnancy (see also sections 4.4 and 4.6).

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic reaction following the administration of the vaccine.

As for other vaccines, there is the possibility of hypersensitivity reactions, not only to the active principle, but also to the following excipients and trace residuals present in the vaccine: hydrolysed gelatin and neomycin (see sections 2 and 6.1).

As with other vaccines, VARIVAX does not completely protect all individuals from naturally acquired varicella. Clinical trials have only assessed efficacy beginning 6 weeks after a single dose in healthy individuals up to 12 years of age or 6 weeks after the second dose in older subjects (see section 5.1).

There are limited data on the safety and efficacy of the vaccine in individuals 12 months of age and older who are known to be infected with human immunodeficiency virus with and without evidence of immunosuppression. However, VARIVAX may be given to individuals 12 months to 12 years of age with asymptomatic HIV infection [CDC Class 1] with an age-specific CD4+ T-lymphocytes percentage 25% (see section 4.3).

Vaccine recipients should avoid use of salicylates for 6 weeks after vaccination (see section 4.5).

Pregnancy and breastfeeding

Before vaccination of women of child-bearing potential, pregnancy must be excluded and effective contraception must be used for 3 months following vaccination (see sections 4.3 and 4.6).

In addition, VARIVAX is not generally recommended for breastfeeding mothers (see section 4.6).

Transmission

Transmission of vaccine virus may rarely occur between healthy vaccinees who develop or do not develop a varicella-like rash and healthy susceptible contacts, pregnant contacts and immunosuppressed contacts (see section 4.8).

Therefore, vaccine recipients should attempt to avoid, whenever possible, close association with susceptible high-risk individuals for up to 6 weeks following vaccination.

In circumstances where contact with high-risk individuals is unavoidable, before vaccination, the potential risk of transmission of the vaccine virus should be weighed against the risk of acquiring and transmitting the wild-type varicella virus (see section 4.8).

Susceptible high-risk individuals include:

• Immunocompromised individuals (see section 4.3);

• Pregnant women without documented positive history of chickenpox or laboratory evidence of prior infection;

• Newborns of mothers without documented positive history of chickenpox or laboratory evidence of prior infection.

VARIVAX must not be mixed with any other vaccine or other medicinal product in the same syringe. Other injectable vaccines or other medicinal products must be given as separate injections and at different body sites.

Concomitant administration with other vaccines

VARIVAX has been administered to toddlers at the same time as, but at a different injection site from, a combined measles, mumps, and rubella vaccine, Haemophilus influenzae type b conjugate vaccine, hepatitis B vaccine, diphtheria/tetanus/whole-cell pertussis vaccine, and oral polio virus vaccine. There was no evidence of a clinically relevant difference in the immune responses to any of the antigens when co-administered with VARIVAX. If varicella vaccine (live) (Oka/Merck strain) is not given concomitantly with measles, mumps, and rubella virus vaccine live, a 1-month interval between the 2 live virus vaccines should be observed.

Concurrent administration of VARIVAX and tetravalent, pentavalent or hexavalent (diphtheria, tetanus, and acellular pertussis [DTaP])-based vaccines has not been evaluated.

Vaccination should be deferred for at least 5 months following blood or plasma transfusions, or administration of normal human immune globulin or varicella zoster immune globulin (VZIG).

Administration of varicella zoster virus antibody-containing blood products, including VZIG or other immune globulin preparations, within 1 month following a dose of VARIVAX may reduce the immune response to the vaccine and hence reduce its protective efficacy. Therefore, administration of any of these products should be avoided within 1 month after a dose of VARIVAX unless considered to be essential.

Vaccine recipients should avoid use of salicylates for 6 weeks after vaccination with VARIVAX as Reye's syndrome has been reported following use of salicylates during wild-type varicella infection (see section 4.4).

Fertility

Animal reproduction studies have not been conducted with VARIVAX. VARIVAX has not been evaluated for potential to impair fertility.

Pregnancy

Studies with the vaccine have not been conducted in pregnant women. It is not known whether the vaccine can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. However, wild-type varicella is known to cause foetal harm, and is associated with an increased risk of herpes zoster in the first year of life and severe chickenpox in the newborn infant. Therefore, VARIVAX must not be administered to pregnant women (see section 4.3). Before vaccination of women of child-bearing potential, pregnancy must be excluded and effective contraception must be used for 3 months following vaccination.

Breastfeeding

Due to the theoretical risk of transmission of the vaccine viral strain from mother to infant, VARIVAX is not generally recommended for breastfeeding mothers (see also section 4.4). Vaccination of exposed women with negative history of varicella or known to be seronegative to varicella should be assessed on an individual basis.

No studies on the effects on the ability to drive and use machines have been performed.

a. Summary of the safety profile

In clinical trials, frozen and refrigerator-stable formulations of varicella vaccine (live) (Oka/Merck strain) were administered to approximately 17,000 healthy individuals 12 months of age who were monitored for up to 42 days after each dose. There appeared to be no increased risk for adverse events with the use of VARIVAX in seropositive individuals. The safety profile of refrigerator-stable varicella vaccine (live) (Oka/Merck strain) was generally similar to the safety profile for earlier formulations of the vaccine.

In a double-blind, placebo-controlled study among 956 healthy individuals 12 months to 14 years of age, 914 of whom were serologically confirmed to be susceptible to varicella, the only adverse events that occurred at a significantly greater rate in vaccine recipients than in placebo recipients were pain (26.7% versus 18.1%) and redness (5.7% versus 2.4%) at the injection site and non-injection-site varicella-like rash (2.2% versus 0.2%).

In a clinical trial, 752 children received VARIVAX, either intramuscularly or subcutaneously. The general safety profile of either administration routes were comparable, although injection-site reactions were less frequent in the IM group (20,9%) compared with the SC group (34,3%).

In a post-marketing study with varicella vaccine (live) (Oka/Merck strain), conducted to evaluate short-term safety (follow-up of 30 or 60 days) in approximately 86,000 children, 12 months to 12 years of age, and in 3600 individuals, 13 years of age and older, no vaccine-related serious adverse events were reported.

b. Tabulated summary of adverse reactions

Clinical studies

Across clinical studies in which causality was assessed (5185 subjects), the following adverse events were reported in temporal association with vaccination:

Adverse events are ranked under headings of frequency using the following convention:

Very common ( 1/10), Common ( 1/100, <1/10), Uncommon ( 1/1000, <1/100), Rare ( 1/10,000, <1/1000)

Healthy individuals 12 months to 12 years of age (1 dose)

Healthy individuals 12 months to 12 years of age (2 doses received 3 months apart)

The following serious adverse events temporally associated with the vaccination were reported in individuals 12 months to 12 years of age given varicella vaccine (live) (Oka/Merck strain): diarrhoea, febrile seizure, fever, post-infectious arthritis, vomiting.

The rates of systemic clinical adverse events after a second dose of VARIVAX were generally similar to, or lower than, those seen with the first dose. The rates of injection-site reactions (primarily erythema and swelling) were higher after a second dose (see section 5.1 for study description).

Healthy individuals 13 years of age and older (majority received 2 doses 4 to 8 weeks apart)

Causality was not assessed in individuals 13 years of age and older with the exception of serious adverse events.

However, across clinical studies (1648 subjects) the following events were temporally associated with vaccination:

Post-Marketing Surveillance

The following adverse events have been spontaneously reported in temporal relation to Varivax during worldwide post-marketing use:

⁺ Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. Consequently, the frequency of these adverse events is qualified as "not known".

* These selected adverse events reported with varicella vaccine (live) (Oka/Merck strain) are also a consequence of wild-type varicella infection. There is no indication of an increased risk of these adverse events following vaccination compared with wild-type disease from active post-marketing surveillance studies or passive post-marketing surveillance reporting (see section 5.1 and Post-Marketing Clinical Studies).

^‡ See section c.

Postvaccination rashes in which the Oka/Merck strain was isolated were generally mild (see section 5.1).

c. Description of selected adverse reactions

Cases of herpes zoster in clinical studies

In clinical trials, 12 cases of herpes zoster have been reported in 9543 vaccinated individuals 12 months to 12 years of age during 84,414 person-years of follow-up. This resulted in a calculated incidence of at least 14 cases per 100,000 person-years, compared with 77 cases per 100,000 person-years following wild-type varicella infection. In 1652 vaccinated individuals 13 years of age and older, 2 cases of herpes zoster were reported. All 14 cases were mild and no sequelae were reported. The long-term effect of varicella vaccine (live) (Oka/Merck strain) on the incidence of herpes zoster, particularly in those vaccinees exposed to wild-type varicella, is unknown at present.

In another clinical study in individuals 12 months to 12 years of age, there were 2 cases of herpes zoster reported in the group receiving one dose of the vaccine and no cases were reported in the two-dose group. The subjects were followed for 10 years postvaccination.

Transmission

Based on isolated case reports from post-marketing surveillance, the vaccine virus may rarely be transmitted to contacts of vaccinees who develop or do not develop a varicella-like rash (see section 4.4).

Concomitant use of varicella vaccine (live) (Oka/Merck strain) with other pediatric vaccines

When varicella vaccine (live) (Oka/Merck strain) was given concurrently with measles, mumps, rubella vaccine (M-M-R II) to 12- to 23-month-old individuals, fever (38.9°C; oral equivalent, Days 0 to 42 postvaccination) was reported at a rate of 26-40% (see also section 4.5).

d. Other special population

Elderly

Clinical trial experience has not identified differences in the safety profile between the elderly (individuals 65 years of age) and younger subjects.

Accidental administration of more than the recommended dose of varicella vaccine (live) (Oka/Merck strain) has been reported (either a larger dose than recommended was injected, more than one injection was given, or the interval between injections was shorter than that recommended). Of these cases, the following adverse events were reported: injection-site redness, soreness, inflammation; irritability; gastrointestinal complaints (i.e., hematemesis, fecal emesis, gastroenteritis with vomiting and diarrhea); cough and viral infection. None of the cases had long-term sequelae.

Pharmacotherapeutic group: virus vaccines - varicella viruses

ATC code: J07BK

Evaluation of clinical efficacy

One-dose regimen in healthy individuals 12 months to 12 years of age

In combined clinical trials using earlier formulations of the varicella vaccine (live) (Oka/Merck strain) at doses ranging from approximately 1000 to 17,000 PFU, the majority of subjects who received the varicella vaccine (live) (Oka/Merck strain) and were exposed to wild-type virus were either completely protected from chickenpox or developed a milder form of the disease.

In particular, the protective efficacy of varicella vaccine (live) (Oka/Merck strain) beginning 42 days postvaccination was evaluated in three different ways:

1) by a double-blind, placebo-controlled trial over 2 years (N=956; efficacy 95 to 100%; formulation containing 17,430 PFU);

2) by assessment of protection from disease following household exposure over 7 to 9 years of observation (N=259; efficacy 81 to 88%; formulation containing 1000-9000 PFU); and

3) by comparing chickenpox rates over 7 to 9 years in vaccinees versus historical control data from 1972 through 1978 (N=5404; efficacy 83 to 94%; formulation containing 1000-9000 PFU).

In a group of 9202 individuals 12 months to 12 years of age who had received a dose of the varicella vaccine (live) (Oka/Merck strain), 1149 cases of infection (occurring more than 6 weeks postvaccination) were observed over a follow-up period of up to 13 years. Out of these 1149 cases, 20 (1.7%) were classified as severe (number of lesions 300, oral body temperature 37.8°C). The above-mentioned data, compared with the 36% proportion of severe cases observed following the wild-type virus infection in the unvaccinated historical controls, corresponds to a 95% relative decrease in the proportion of severe cases observed in the vaccinees who acquired infection after vaccination.

Prophylaxis of varicella by vaccination up to 3 days following exposure has been investigated in two small controlled trials. The first study demonstrated that none of 17 children developed varicella following household exposure compared with 19 of 19 unvaccinated contacts. In a second placebo-controlled trial of post-exposure prophylaxis, one of 10 children in the vaccine group versus 12 of 13 in the placebo group developed varicella. In an uncontrolled trial in a hospital setting, 148 patients, of whom 35 were immunocompromised, received a dose of varicella vaccine 1 to 3 days post-exposure and none developed varicella.

Published data on prevention of varicella at 4 to 5 days post-exposure are limited. In a double-blind trial, 26 susceptible siblings of children with active varicella were randomized to placebo or varicella vaccine. In the varicella vaccine group, 4 of 13 children (30.8%) developed varicella, of whom 3 children were vaccinated on Days 4 to 5. However, the disease was mild (1, 2, and 50 lesions). In contrast, 12 of 13 children (92.3%) in the placebo group developed typical varicella (60 to 600 lesions). Thus, vaccination 4 to 5 days after exposure to varicella may modify the course of any secondary cases of varicella.

Two-dose regimen in healthy individuals 12 months to 12 years of age

In a study comparing 1-dose (N=1114) and 2-doses (N=1102) given 3 months apart, the estimated efficacy against all severities of varicella disease for the 10-year observation period was 94% for 1-dose and 98% for 2 doses (p<0.001). The cumulative rate of varicella over the 10-year observation period was 7.5% after 1 dose and 2.2% after 2 doses. Most cases of varicella reported in recipients of 1 dose or 2 doses were mild.

Two-dose regimen in healthy individuals 13 years of age and older

Protective efficacy following two doses given 4 or 8 weeks apart in individuals 13 years of age or older was evaluated based on household exposure over 6 to 7 years after vaccination. The clinical efficacy rate ranged from approximately 80 to 100%.

Immunogenicity of varicella vaccine (live) (Oka/Merck strain)

One-dose regimen in individuals 12 months to 12 years of age

Clinical studies have established that the immunogenicity of the refrigerator-stable formulation is similar to the immunogenicity of earlier formulations that were evaluated for efficacy.

A titer 5 gpELISA units/mL (gpELISA is a highly sensitive assay that is not commercially available) at 6 weeks postvaccination has been shown to be an approximate correlate of clinical protection. However, it is not known whether a titer of 0.6 gpELISA units/mL correlates with long-term protection.

Humoral immune response in individuals 12 months to 12 years of age

Seroconversion (based on assay cutoff that generally corresponds to 0.6 gpELISA units/mL) was observed in 98% of 9610 susceptible individuals 12 months to 12 years of age who received doses ranging from 1000 to 50,000 PFU. Varicella antibody titers 5 gpELISA units/mL were induced in approximately 83% of these individuals.

In individuals 12 to 23 months of age, the administration of VARIVAX refrigerated (8000 PFU/dose or 25,000 PFU/dose) induced varicella antibody titers 5 gpELISA units/mL at 6 weeks postvaccination, in 93% of individuals vaccinated.

Humoral immune response in individuals 13 years of age and older

In 934 individuals 13 years of age and older, several clinical trials with varicella vaccine (live) (Oka/Merck strain) at doses ranging from approximately 900 to 17,000 PFU, have shown a seroconversion rate (varicella antibody titer 0.6 gpELISA units/mL) after 1 dose of vaccine ranging from 73 to 100%. The proportion of subjects with antibody titers 5 gpELISA units/mL ranged from 22 to 80%.

After 2 doses of vaccine (601 subjects) at doses ranging from approximately 900 to 9000 PFU, the seroconversion rate ranged from 97 to 100% and the proportion of subjects with antibody titers 5 gpELISA units/mL ranged from 76 to 98%.

There are no data on immune responses to VARIVAX in Varicella-zoster virus (VZV)-seronegative persons 65 years of age.

Humoral immunity according to route of administration

A comparative study in 752 subjects who received VARIVAX either by intramuscular route or subcutaneous route demonstrated a similar immunogenicity profile with both administration routes.

Two-dose regimen in healthy individuals 12 months to 12 years of age

In a multicenter study, healthy children 12 months to 12 years of age received either 1 dose of VARIVAX or 2 doses administered 3 months apart. The immunogenicity results are shown in the following table.

The results from this study and other studies in which a second dose of vaccine was administered 3 to 6 years after the initial dose demonstrate significant boosting of the VZV antibody response with a second dose. VZV antibody levels after 2 doses given 3 to 6 years apart are comparable to those obtained when the 2 doses are given 3 months apart. The seroconversion rates were approximately 100% after the first dose and 100% after the second dose. The vaccine seroprotection rates (5 gpELISA units/mL) were approximately 85% after the first and 100% after the second dose and the geometric mean titer (GMT) rose an average of approximately 10-fold after the second dose (for safety see section 4.8).

Duration of immune response

One-dose regimen in individuals 12 months to 12 years of age

In those clinical studies involving healthy individuals 12 months to 12 years of age who have been followed long-term after single-dose vaccination, detectable varicella antibodies (gpELISA 0.6 units/mL) were present in 99.1% (3092/3120) at 1 year, 99.4% (1382/1391) at 2 years, 98.7% (1032/1046) at 3 years, 99.3% (997/1004) at 4 years, 99.2% (727/733) at 5 years, and 100% (432/432) at 6 years postvaccination.

Two-dose regimen in individuals 12 months to 12 years of age

Over 9 years of follow-up, the GMTs and percent of subjects with VZV antibody titers 5 gpELISA units/mL in the 2-dose recipients were higher than those in the 1-dose recipients for the first year of follow-up and comparable during the entire follow-up period. The cumulative rate of VZV antibody persistence with both regimens remained very high at year 9 (99.0% for the 1-dose group and 98.8% for the 2-dose group).

Individuals 13 years of age and older

In clinical studies involving healthy individuals 13 years of age and older who received 2 doses of vaccine, detectable varicella antibodies (gpELISA 0.6 units/mL) were present in 97.9% (568/580) at 1 year, 97.1% (34/35) at 2 years, 100% (144/144) at 3 years, 97.0% (98/101) at 4 years, 97.5% (78/80) at 5 years, and 100% (45/45) at 6 years postvaccination.

A boost in antibody levels has been observed in vaccinees following exposure to wild-type varicella, which could account for the apparent long-term persistence of antibody levels after vaccination in these studies. The duration of immune response following administration of varicella vaccine (live) (Oka/Merck strain) in the absence of wild-type boosting is unknown (see section 4.2).

Immune memory was demonstrated by administering a booster dose of varicella vaccine (live) (Oka/Merck strain) 4 to 6 years after the first vaccination in 419 individuals who were 1 to 17 years of age at the time of the first injection. The GMT prior to the booster dose was 25.7 gpELISA units/mL and increased to 143.6 gpELISA units/mL approximately 7-10 days after the booster dose.

Evaluation of pharmacokinetic properties is not required for vaccines.

Traditional preclinical safety studies were not performed, but there are no preclinical concerns considered relevant to clinical safety beyond data included in other sections of the SPC.

Powder:

Sucrose

Hydrolysed gelatin

Urea

Sodium chloride

Monosodium L-glutamate

Anhydrous disodium phosphate

Potassium dihydrogen phosphate

Potassium chloride

For information regarding residual components in trace quantities, see sections 2, 4.3 and 4.4.

Solvent:

Water for Injections

The vaccine should not be mixed with other medicinal products.

The vaccine must not be reconstituted with other medicinal products except those mentioned in section 6.6.

2 years.

After reconstitution, the vaccine should be used immediately. However, the in-use stability has been demonstrated for 30 minutes between +20^oC and +25 ^oC.

Discard the vaccine if it is not used within 30 minutes after its preparation.

Store in a refrigerator at +2°C to +8°C. Keep vial in the outer carton to protect from light.

Do not freeze.

Vial

3 mL vial (glass) with stopper (butyl rubber) and flip-off cap (aluminum).

Pre-filled syringe

1 mL pre-filled syringe (glass) with plunger stopper (chlorobutyl rubber) and tip cap (styrene-butadiene rubber), without needle, 1 mL pre-filled syringe (glass) with plunger stopper (chlorobutyl rubber) and tip cap (styrene-butadiene rubber), with 2 separate needles in the blister, or 1 mL pre-filled syringe (glass) with plunger stopper (chlorobutyl rubber) with needle.

Pack of one and ten doses.

Not all pack sizes may be marketed.

Directions for the vaccine preparation

Avoid contact with disinfectants.

To reconstitute the vaccine, use only water for injections provided in the prefilled syringe.

2 separate needles may be available in the secondary packaging of the presentations containing prefilled syringes without attached needle: one needle would be used for reconstitution and another for injection.

The needle should be firmly placed on the tip of the syringe and secured by rotating a quarter of a turn (90°).

Inject the entire content of the pre-filled syringe into the vial containing the powder. Gently agitate to mix thoroughly. Withdraw the entire content in the same provided syringe and inject the vaccine by subcutaneous route or intramuscularly.

The reconstituted vaccine should be inspected visually for any foreign particulate matter and/or variation in physical appearance. The vaccine must not be used if any particulate matter is noted or if the appearance is not a clear colourless to pale yellow liquid after reconstitution.

It is important to use a separate sterile syringe and needle for each patient to prevent transmission of infectious agents from one individual to another.

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

Sanofi Pasteur MSD Limited

Mallards Reach

Bridge Avenue

Maidenhead

Berkshire

SL6 1QP

PL 06745/0124

27 January 2004

06/2011