4.1. Therapeutic indications

VARIVAX is indicated for vaccination against varicella in individuals from 12 months of age (see sections 4.2 and 5.1).

VARIVAX can be administered to infants from 9 months of age under special circumstances, such as to conform with national vaccination schedules or in outbreak situations (see sections 4.2, 4.5, and 5.1).

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).

4.2. Posology and method of administration

Posology

The use of VARIVAX should be based on official recommendations.

Individuals less than 9 months of age

VARIVAX should not be administered to individuals less than 9 months of age.

Individuals from 9 months of age

Individuals should receive two doses of VARIVAX to ensure optimal protection against varicella (see section 5.1).

• Individuals from 9 to 12 months of age

In settings in which vaccination is initiated between 9 and 12 months of age, a second dose is needed and should be given after a minimum interval of 3 months (see section 5.1).

• Individuals from 12 months to 12 years of age

For individuals from 12 months to 12 years of age, at least one month must elapse between the first and second dose (see section 5.1).

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 given 12 weeks apart.

• Individuals from 13 years of age and older

Individuals from 13 years of age and older should receive two doses given 4-8 weeks apart. If the interval between doses exceeds 8 weeks, the second dose should be given as soon as possible (see section 5.1).

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 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).

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.

4.3. Contraindications

• Hypersensitivity to any varicella vaccine, to any of the excipients listed in section 6.1, or neomycin (which may be present as a trace residue, see sections 2 and 4.4).

• 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) (see section 4.8).

• Severe humoral or cellular (primary or acquired) immunodeficiency, e.g., severe combined immunodeficiency, agammaglobulinaemia and AIDS or symptomatic HIV infection or an age-specific CD4+ T-lymphocyte percentage in children below 12 months: CD4+ <25%; children between 12-35 months: CD4+ <20%; children between 36-59 months: CD4+ <15% (see sections 4.4 and 4.8).

• 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. Furthermore, pregnancy should be avoided for 1 month following vaccination (see section 4.6).

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

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 any of the excipients listed in section 6.1 or neomycin (which may be present as a trace residue, see sections 2 and 4.3).

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).

Vaccination may be considered in patients with selected immune deficiencies where the benefits outweigh the risks (e.g., asymptomatic HIV subjects, IgG subclass deficiencies, congenital neutropenia, chronic granulomatous disease, and complement deficiency diseases).

Immunocompromised patients who have no contraindication for this vaccination (see section 4.3) may not respond as well as immunocompetent subjects; therefore, some of these patients may acquire varicella in case of contact, despite appropriate vaccine administration. These patients should be monitored carefully for signs of varicella.

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

Transmission

Transmission of varicella vaccine virus (Oka/Merck strain) resulting in varicella infection including disseminated disease may rarely occur between vaccine recipients (who develop or do not develop a varicella-like rash) and contacts susceptible to varicella including healthy as well as high-risk individuals (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;

• New-borns of mothers without documented positive history of chickenpox or laboratory evidence of prior infection.

Encephalitis

Encephalitis has been reported during post-marketing use of live attenuated varicella vaccines. In a few cases, fatal outcomes have been observed, especially in patients who were immunocompromised (see section 4.3). Vaccinees/parents should be instructed to seek prompt medical attention if they/their child experience, after vaccination, symptoms suggestive of encephalitis such as loss or reduced levels of consciousness, convulsions or ataxia accompanied by fever and headache.

Sodium

This medicinal product contains less than 1 mmol (23 mg) sodium per dose and is considered to be essentially 'sodium-free'.

Potassium

This medicinal product contains less than 1 mmol (39 mg) potassium per dose and is considered to be essentially 'potassium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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.

VARIVAX can be given concomitantly at separate injection sites with a pneumococcal conjugate vaccine.

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 syndrome has been reported following use of salicylates during wild-type varicella infection (see section 4.4).

4.6. Fertility, pregnancy and lactation

Fertility

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

Pregnancy

Pregnant women should not be vaccinated with VARIVAX.

Studies have not been conducted with VARIVAX in pregnant women.

However, foetal damage has not been documented when varicella vaccines have been given to pregnant women. It is not known whether VARIVAX can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity.

Pregnancy should be avoided for 1 month following vaccination. Women who intend to become pregnant should be advised to delay.

Breast-feeding

Due to the theoretical risk of transmission of the vaccine viral strain from mother to infant, VARIVAX is not generally recommended for breast-feeding 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.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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 was 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)

Adverse events

Frequency

Blood and the lymphatic system disorders

Lymphadenopathy, Lymphadenitis, Thrombocytopenia

Rare

Nervous system disorders

Headache, Somnolence

Uncommon

Apathy, Agitation, Hypersomnia, Gait abnormality, Febrile seizure, Tremor

Rare

Eye disorders

Conjunctivitis

Uncommon

Acute conjunctivitis, Tearing, Oedema of the eyelid, Irritation

Rare

Ear and labyrinth disorders

Ear pain

Rare

Respiratory, thoracic and mediastinal disorders

Cough, Nasal congestion, Respiratory congestion, Rhinorrhoea

Uncommon

Sinusitis, Sneezing, Pulmonary congestion, Rhinitis, Wheezing, Bronchitis, Respiratory infection, Pneumonia

Rare

Metabolism and nutrition disorders

Anorexia

Uncommon

Infections and infestations

Upper respiratory infection

Common

Gastroenteritis, Otitis, Otitis media, Pharyngitis, Varicella, Viral exanthema, Viral infection

Uncommon

Infection, Flu-like illness

Rare

Gastrointestinal disorders

Diarrhoea, Vomiting

Uncommon

Abdominal pain, Nausea, Haematochezia, Mouth ulcer

Rare

Skin and subcutaneous tissue disorders

Rash, Maculopapular rash, Varicella-like rash (generalised median 5 lesions)

Common

Contact dermatitis, Erythema, Pruritus, Urticaria

Uncommon

Flushing, Vesicle, Atopic dermatitis, Hive-like rash, Contusion, Dermatitis, Drug eruption, Skin infection

Rare

Musculoskeletal and connective site conditions

Musculoskeletal pain, Myalgia, Stiffness

Rare

Vascular disorders

Extravasation

Rare

General disorders and administration site conditions

Fever

Very common

Injection site erythema, Rash, Pain/Tenderness/Soreness, Swelling, and Varicella-like rash (injection site median 2 lesions)

Common

Asthenia/Fatigue, Injection site ecchymosis, Haematoma, Induration, Rash, Malaise

Uncommon

Injection site eczema, Lump, Warmth, Hive-like rash, Discolouration, Inflammation, Stiffness, Oedema/Swelling, Warm sensation, Warm to touch

Rare

Psychiatric disorders

Irritability

Common

Crying, Insomnia, Sleep disorder

Uncommon

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:

Adverse events

Frequency

Skin and subcutaneous tissue disorders

Varicella-like rash (generalised median 5 lesions)

Common

General disorders and administration site conditions

Fever ≥37.7°C oral, Injection‑site erythema, Soreness and Swelling

Very common

Injection‑site rash, Pruritus and Varicella-like rash (injection site median 2 lesions)

Common

Injection‑site ecchymosis, Haematoma, Induration, Numbness and Warmth

Uncommon

Hyperpigmentation, Stiffness

Rare

Post-marketing surveillance

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

Adverse events+

Blood and the lymphatic system disorders

Aplastic anaemia, Thrombocytopenia (including idiopathic thrombocytopenic purpura (ITP)), Lymphadenopathy

Nervous system disorders

Cerebrovascular accident, Febrile and non-febrile convulsions, Guillain-Barré syndrome, Transverse myelitis, Bell's palsy, Ataxia*, Vertigo/Dizziness, Paraesthesia, Syncope

Respiratory, thoracic and mediastinal disorders

Pneumonitis

Skin and subcutaneous tissue disorders

Stevens-Johnson syndrome, Erythema multiforme, Henoch-Schönlein purpura, Secondary bacterial infections of skin and soft tissues, including Cellulitis

Infections and infestations

Encephalitis*‡, Pharyngitis, Pneumonia*, Varicella (vaccine strain), Herpes zoster*‡, Aseptic meningitis‡

General disorders and administration site conditions

Irritability

Immune system disorders

Anaphylaxis (including anaphylactic shock) and related phenomena such as Angioneurotic Oedema, Facial Oedema, and Peripheral Oedema, Anaphylaxis in individuals with or without an allergic history

Gastrointestinal disorders

Nausea, Vomiting

+ 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).

‡ 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.

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.

Active surveillance data in children vaccinated with varicella vaccine (live) (Oka/Merck strain) and followed for 14 years after vaccination showed no increase in the frequency of herpes zoster compared to children with prior wild-type varicella during the pre-vaccine era. However, the long-term effect of varicella vaccine (live) (Oka/Merck strain) on the incidence of herpes zoster is unknown at present (see section 5.1).

Complications associated with varicella

Complications of varicella from vaccine strain, including herpes zoster and disseminated disease such as aseptic meningitis and encephalitis, have been reported in immunocompromised and immunocompetent individuals. A few cases of encephalitis with a fatal outcome have been observed following vaccination with live attenuated varicella vaccines, especially in immunocompromised people (see section 4.4).

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 paediatric 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

Immunocompromised individuals (see section 4.3)

Necrotising retinitis has been reported post-marketing in immunocompromised individuals.

Elderly

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

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 at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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., haematemesis, faecal emesis, gastroenteritis with vomiting and diarrhoea); cough and viral infection. None of the cases had long-term sequelae.