Vaccine Information: TicoVac

TICOVAC- tick-borne encephalitis purified antigen (formaldehyde inactivated) injection
Pfizer Laboratories Div Pfizer Inc

1 INDICATIONS AND USAGE

TICOVAC™ is indicated for active immunization to prevent tick-borne encephalitis (TBE). TICOVAC is approved for use in individuals 1 year of age and older.

2 DOSAGE AND ADMINISTRATION

For intramuscular use only.

2.1 Dosage and Vaccination Schedule

•

1 through 15 years of age: each dose 0.25 mL

•

16 years of age and older: each dose 0.5 mL

Primary Vaccination: Three doses

Table 1: Primary Vaccination Schedule — TICOVAC

	1 through 15 years of age	16 years of age and older
First dose	Day 0	Day 0
Second dose	1 to 3 months after the first vaccination	14 days to 3 months after the first vaccination
Third dose	5 to 12 months after the second vaccination	5 to 12 months after the second vaccination

Complete the primary immunization series at least 1 week prior to potential exposure to TBEV (tick-borne encephalitis virus) [see Clinical Studies (14.1)].

A booster dose (fourth dose) may be given at least 3 years after completion of the primary immunization series if ongoing exposure or re-exposure to TBEV is expected.

2.2 Administration

Bring the vaccine to room temperature before administration. Shake well prior to administration to thoroughly mix the vaccine suspension. After shaking, the vaccine should be a homogenous off-white, opalescent suspension. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer if particulate matter or discoloration remains after shaking. Administer vaccine by intramuscular injection.

3 DOSAGE FORMS AND STRENGTHS

TICOVAC is a suspension for injection supplied as a 0.25 mL or 0.5 mL single-dose in pre-filled syringes.

4 CONTRAINDICATIONS

Severe allergic reaction (e.g. anaphylaxis) to any component of TICOVAC [see Description (11)].

5 WARNINGS AND PRECAUTIONS

5.1 Management of Acute Allergic Reactions

Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of TICOVAC.

5.2 Altered Immunocompetence

Some individuals with altered immunocompetence may have reduced immune responses to TICOVAC.

5.3 Human Albumin

TICOVAC contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote. No cases of transmission of viral diseases, CJD or vCJD have ever been identified for licensed albumin or albumin contained in other licensed products.

5.4 Limitation of Vaccine Effectiveness

Vaccination with TICOVAC may not protect all individuals.

6 ADVERSE REACTIONS

In clinical studies, the most common adverse reactions in subjects 1 through 15 years of age who received TICOVAC were local tenderness (18.1%), local pain (11.2%), headache (11.1%), fever (9.6%), and restlessness (9.1%).

The most common adverse reactions in subjects 16 through 65 years of age who received TICOVAC were local tenderness (29.9%), local pain (13.2%), fatigue (6.6%), headache (6.3%), and muscle pain (5.1%).

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

Among a total of 10 clinical trials, 3240 healthy children 1 through 15 years of age received at least one dose of TICOVAC. A total of 4427 healthy adults 16 years of age and older received at least one dose of TICOVAC in 10 clinical trials.

Study 209 was a multicenter, open-label study to investigate the safety of TICOVAC in 2,417 healthy children 1 through 15 years of age who received three vaccinations (Day 0, 1 and 6 months after the first vaccination). The incidence rates for local and systemic solicited adverse reactions within 4 days after each dose are presented in Table 2.

Table 2: Incidence Rates of Solicited Local and Systemic Adverse Reactions Within 4 Days After Each Dose of TICOVAC, Children 1 through 15 Years of Age (Study 209)

		Percentage (%) of Subjects
Age Group *	Adverse Reaction	Dose 1 N=2417	Dose 2 N=2410	Dose 3 N=2390
Abbreviation: N=total number of subjects who received TICOVAC at each dose for each age group.
Clinical trial identifier: NCT 00161863.
* Some symptoms were solicited using different terms in younger and older children, to be age appropriate.
Local Reaction
1–15 Years	Tenderness	18.1	12.9	13.3
	Local pain	11.2	7.9	9.7
	Erythema	3.0	1.5	2.8
	Induration	2.2	1.3	2.1
	Swelling	1.9	1.1	2.5
	Itching	<0.1	<0.1	0
	Ecchymosis	0	0	<0.1
	Hematoma	<0.1	0	0
Systemic Reaction
1–15 Years	Fever	9.6	2.3	2.4
	Headache	11.1	3.9	3.4
	Muscle pain	3.6	2.0	1.8
	Loss of appetite	3.1	1.5	1.2
	Nausea	3.3	1.0	0.8
	Changes in sleeping behavior	2.8	1.0	0.8
	Vomiting	1.7	0.7	0.3
	Joint pain	1.2	0.6	0.5
	Swelling of the axillary /inguinal lymph nodes	0.2	0.3	0.2
		N=584	N=581	N=576
1–5 Years	Restlessness	9.1	3.6	3.5
		N=1833	N=1829	N=1814
6–15 Years	Fatigue	6.3	2.4	2.5
	Malaise	4.8	1.6	1.8

Incidence rates of fever reported within 4 days after each dose of TICOVAC, by age group, in Study 209 are presented in Table 3.

Table 3: Fever Rates Within 4 Days After Each Dose of TICOVAC by Age Group (Study 209)

Dose Age Group	Percentage (%) of Subjects
	38.0–38.4°C (100.4–101.1°F)	38.5–38.9°C (101.2–102.0°F)	39.0–40.0°C (102.1–104°F)	>40°C (>104°F)
Abbreviation: N=total number of subjects who received TICOVAC at each dose for each age group.
Clinical trial identifier: NCT 00161863.
Dose 1
1–2 Years of Age (N=186)	23.7	5.9	5.9	0
3–6 Years of Age (N=563)	4.6	5.0	3.0	0
7–15 Years of Age (N=1668)	3.4	2.0	0.3	0
Total (N=2417)	5.2	3.0	1.4	0
Dose 2
1–2 Years of Age (N=185)	9.2	2.2	0.5	0.5
3–6 Years of Age (N=561)	1.2	0.4	0.5	0
7–15 Years of Age (N=1664)	0.8	0.4	<0.1	0
Total (N=2410)	1.6	0.5	0.2	<0.1
Dose 3
1–2 Years of Age (N=184)	7.1	3.8	1.6	0
3–6 Years of Age (N=557)	1.4	0.4	0.7	0.2
7–15 Years of Age (N=1649)	0.6	0.3	0.2	0
Total (N=2390)	1.3	0.6	0.5	<0.1

The following additional adverse reactions to the vaccine have been reported in <1% of subjects 1 through 15 years of age who received TICOVAC in clinical trials (N=3240): vertigo, dizziness, sensory abnormalities, abdominal pain, diarrhea, dyspepsia, injection site pruritus, and urticaria.

Study 208 was a randomized, comparative, single-blind study that assessed the safety of TICOVAC. Healthy subjects 16 through <65 years of age (N=3966) were randomized 3:1 to receive two vaccinations with either TICOVAC or a non-US licensed TBE vaccine comparator administered 21 to 35 days apart. Study 213 was an open-label follow-up study to Study 208; all subjects who had received two vaccinations in Study 208 (regardless of which vaccine they had received) were eligible and received a third vaccination with TICOVAC 6 months after the first vaccination in Study 208 (N=3705).

Incidence rates of solicited local and systemic adverse reactions reported in Study 208 (Doses 1 and 2) and Study 213 (Dose 3) are presented in Table 4.

Table 4: Incidence Rates of Specifically Solicited Local and Systemic Adverse Reactions Within 4 Days After Each Dose of TICOVAC, Subjects 16 through <65 Years of Age (Study 208/213)

	Percentage (%) of Subjects
Adverse Reaction	Dose 1 N=2977 *	Dose 2 N=2950 †	Dose 3 ‡ N=2790 ‡
Clinical trial identifiers: NCT00161824 and NCT00161876.
* N=total number of subjects who received 1 dose of TICOVAC in Study 208. † N=total number of subjects who received 2 doses of TICOVAC in Study 208. ‡ N=total number of subjects who received 2 doses of TICOVAC in Study 208 and received TICOVAC in Study 213.
Local Reaction
Tenderness	29.9	27.4	25.7
Local pain	13.2	13.5	12.0
Erythema	3.6	2.3	3.4
Induration	2.0	1.5	2.6
Swelling	1.6	1.4	2.0
Hematoma	<0.1	<0.1	0.1
Ecchymosis	<0.1	0	<0.1
Systemic Reaction
Fever	0.8	0.5	0.5
Fatigue	6.6	4.1	5.3
Headache	6.3	4.4	4.9
Muscle pain	5.1	3.7	3.8
Malaise	4.9	3.3	3.7
Joint pain	1.4	1.1	1.4
Nausea	2.1	0.9	1.0
Swelling of the lymph nodes	0.6	0.3	0.7
Vomiting	0.2	0.1	<0.1

The following additional adverse reactions have been reported in <1% of subjects 16 through <65 years of age who received TICOVAC in clinical trials (N=4427): hypersensitivity, somnolence, vertigo, diarrhea, abdominal pain, injection site pruritus, and injection site warmth.

Subjects who were seropositive either by ELISA or NT 1 month after the third dose in Studies 209 and 208/213, were invited to participate in follow-up Studies 700401 and 223 (studies assessing antibody persistence and response to a booster dose at 3 years), respectively. A total of 156 subjects received a fourth dose of TICOVAC (0.25 mL), and 240 subjects received a fourth dose of TICOVAC (0.5 mL) in these clinical trials.

Incidence rates of solicited local and systemic adverse reactions reported in Study 223 and 70401 after the booster are presented in Table 5.

Table 5: Incidence Rates of Specifically Solicited Symptoms of Local and Systemic Adverse Reactions Within 4 Days After 4^th Dose of TICOVAC

		Percentage (%) of Subjects
		Study 223 (N * =240) TICOVAC (0.5 mL)	Study 700401 (N † =156) TICOVAC (0.25 mL)
Abbreviation: NA=not applicable.
Note: Solicited symptoms with onset date between Day 0 (vacciantion day) and Day 4 were included in the analysis.
* N=total number of subjects who received 4 doses of TICOVAC (0.5 mL) in Studies 208/213 and 223. † N=total number of subjects who received 4 doses of TICOVAC (0.25 mL) in Studies 209 and 700401.
Local Reaction	Tenderness	4.6	10.3
	Injection Site Pain	3.8	14.7
	Erythema	0.4	1.3
	Induration	0.4	3.2
	Swelling	0.8	3.2
	Hematoma	0	0
	Ecchymosis	0	0
Systemic Reaction	Fever	0	0
	Fatigue	0	0.6
	Headache	0.4	3.2
	Muscle Pain	0.4	3.2
	Malaise	0.4	1.3
	Joint Pain	0	1.3
	Nausea	0	0.6
	Swelling of the Lymphnodes	0	0
	Vomiting	0	0
	Loss of Appetite	NA	1.9
	Changes in sleeping behavior	NA	0

Among 3240 subjects who received TICOVAC (0.25 mL) in clinical trials, serious adverse events (SAEs) and death were reported in 62 subjects and 1 subject, respectively. Among 4427 subjects who received TICOVAC (0.5 mL) in clinical trials, SAEs and deaths were reported in 54 subjects and 2 subjects, respectively. None of these events was considered related to the vaccine. Only one SAE in TICOVAC (0.25 mL) was considered possibly related to vaccine (febrile convulsion reported in a 12-month old male two days after vaccination in Study 197, a postmarketing safety surveillance study).