Vaccine Information: TicoVac (Page 2 of 3)

6.2 Postmarketing Experience

The following adverse reactions have been reported spontaneously (postmarketing) with the use of TICOVAC in the European Union (EU). Because these reactions 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.

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Infections and infestations: herpes zoster (triggered in pre-exposed individuals)

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Immune system disorders: anaphylactic reaction, hypersensitivity, precipitation or aggravation of autoimmune disorders (e.g., multiple sclerosis)

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Nervous system disorders: convulsion, convulsion (including febrile), demyelinating disorders (acute disseminated encephalomyelitis, Guillain-Barré syndrome, myelitis, transverse myelitis), encephalitis, sensory abnormalities and motor dysfunction (hemiparesis, hemiplegia, VIIth nerve paralysis/facial paresis, paralysis, paresis, neuritis, neuralgia, optic neuritis), polyneuropathy, meningism, dizziness, aseptic meningitis

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Eye disorders: visual impairment, photophobia, eye pain

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Ear and labyrinth disorders: tinnitus

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Cardiac disorders: tachycardia

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Respiratory, thoracic and mediastinal disorders: dyspnea

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Skin and subcutaneous tissue disorders: urticaria, rash (erythematous, maculo-papular, vesicular), pruritus, dermatitis, erythema, hyperhidrosis

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Musculoskeletal and connective tissue disorders: back pain, joint swelling, neck pain, musculoskeletal stiffness (including neck stiffness), pain in extremity

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General disorders and administration site conditions: injection site joint movement impairment, injection site joint pain, injection site nodule, injection site inflammation, influenza-like illness, chills, gait disturbance, asthenia, edema

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There are no adequate and well-controlled studies of TICOVAC in pregnant women. Available human data are insufficient to establish the presence or absence of vaccine-associated risk during pregnancy.

Developmental and reproductive toxicity studies in animals have not been conducted with TICOVAC.

8.2 Lactation

Risk Summary

Human data are not available to assess the impact of TICOVAC on milk production, its presence in breast milk, or its effects on the breastfed. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TICOVAC and any potential adverse effects on the breastfed child from TICOVAC or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

Safety and effectiveness of TICOVAC have not been established in infants below 1 year of age.

8.5 Geriatric Use

Clinical studies of TICOVAC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. A clinical study (Study 690601, NCT00460486) of TICOVAC enrolled 73 subjects 60 years of age and older, including 31 subjects 65 years of age and older.

11 DESCRIPTION

TICOVAC (tick-borne encephalitis vaccine) is a sterile, off-white, homogenous, opalescent suspension for intramuscular injection. TICOVAC is prepared from tick-borne encephalitis (TBE) virus propagated in chick embryo fibroblast (CEF) cells. The harvested virus suspension is inactivated by treatment with formaldehyde, purified by sucrose gradient centrifugation and adsorbed onto aluminum hydroxide. TICOVAC is available in a 0.5 mL adult presentation and a 0.25 mL pediatric presentation.

Each 0.5 mL dose is formulated to contain 2.4 microgram (µg) TBE inactivated virus, 0.5 mg human serum albumin, 0.35 mg aluminum hydroxide, 3.45 mg sodium chloride, 0.22 mg dibasic sodium phosphate, and 0.045 mg of monobasic potassium phosphate. From the manufacturing process, each 0.5 mL may also contain formaldehyde (≤5 µg), sucrose (≤15 mg), protamine sulfate (≤0.5 µg), and trace amounts of chick protein and DNA from CEF cells, neomycin and gentamicin. The 0.25 mL dose of TICOVAC contains the same components as the 0.5 mL dose in half of the quantities.

TICOVAC is formulated without preservatives.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Following administration, TICOVAC induces TBEV-neutralizing antibodies, which are believed to confer protection. However, a protective antibody level has not been defined.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

TICOVAC has not been evaluated for the potential to cause carcinogenicity, genotoxicity or impairment of fertility.

14 CLINICAL STUDIES

14.1 Immunogenicity

Primary Immunization Course

The immunogenicity of TICOVAC described in this section is based on results from the following studies:

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Study 209: Healthy subjects 1 through 15 years of age TBE seronegative at baseline received three vaccinations with TICOVAC. The first two vaccinations were given 1 month apart followed by the third vaccination 6 months after the first vaccination.

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Study 213: Healthy subjects 16 to 64 years of age TBE seronegative at baseline who had received two vaccinations in Study 208 given one month apart, received a third vaccination with TICOVAC 6 months after the first vaccination in Study 208.

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Study 690601: Healthy subjects 16 years of age and older TBE seronegative at baseline received three vaccinations with TICOVAC. The first two vaccinations were given 14 days apart followed by the third vaccination 6 months after the first vaccination.

Table 6 shows neutralization test (NT) seropositivity rates 21 days after the third vaccination in subjects 1 through 15 years of age vaccinated with TICOVAC in Study 209.

Table 6:Seropositivity Rates (NT)* by Age Group; Post Dose 3† (Study 209)

Age Group	% (n/N)	(95% CI) ‡
Abbreviations: CI=confidence interval; NT=neutralization test.
Clinical trial identifier: NCT00161863.
* Seropositivity was defined as NT ≥1:10 (Neudoerfl TBE strain). † Evaluated 21 days after Dose 3. ‡ Exact 2-sided CI calculated using the Clopper and Pearson method.
1–5 Years	99.2% (125/126)	(95.7%, 100.0%)
6–15 Years	99.6% (240/241)	(97.7%, 100.0%)
Total	99.5% (365/367)	(98.0%, 99.9%)

Table 7 shows NT seropositivity rates 21 days after the third vaccination in subjects 16 years of age and older vaccinated with TICOVAC in Study 690601 and Study 213.

Table 7:Seropositivity Rates (NT)* by Age Group; Post Dose 3† TICOVAC (Studies 213 and 690601)

Age Group (Study Number)	% (n/N)	(95% CI) ‡
Abbreviations: CI=confidence interval; NT=neutralization test.
Clinical trial identifiers: NCT00161876 and NCT00460486.
* Seropositivity was defined as NT ≥1:10 (Neudoerfl TBE strain). † Evaluated 21 days after Dose 3. ‡ Exact 2-sided CI calculated using the Clopper and Pearson method.
16–64 Years (Study 213)	98.8% (411/416)	(97.2%, 99.6%)
16–49 Years (Study 690601)	100.0% (144/144)	(97.5%, 100.0%)
≥50 Years (Study 690601)	98.7% (151/153)	(95.4%, 99.8%)

Seven days after the third vaccination, 90.6% of the subjects 16 years of age and older were seropositive (Study 690601).

Seropersistence and Booster Vaccination

Two open-label, multi-center, follow-up studies which enrolled subjects who were seropositive 1 month after the third vaccination from Studies 213 (N=252, ages 16 through 65 at the time of first TICOVAC dose) and 209 (N=358, ages 1 through 15 at the time of first TICOVAC dose) were conducted to assess the seropersistence of TBE antibodies after completion of the primary vaccination series and the antibody response to a booster administration. Three years after the primary series of TICOVAC , NT seropositivity in follow-up studies 223 and 700401 ranged from 82.9% to 100% depending on age. Following a booster dose the NT seropositivity rates were 100%.