Vaccine Information: VAQTA

VAQTA- hepatitis a virus strain cr 326f antigen (formaldehyde inactivated) injection, suspension
Merck Sharp & Dohme Corp.

1 INDICATIONS AND USAGE

1.1 Indications and Use

VAQTA^® [Hepatitis A Vaccine, Inactivated] is indicated for the prevention of disease caused by hepatitis A virus (HAV) in persons 12 months of age and older. The primary dose should be given at least 2 weeks prior to expected exposure to HAV.

2 DOSAGE AND ADMINISTRATION

FOR INTRAMUSCULAR ADMINISTRATION ONLY.

2.1 Dosage and Schedule

Children/Adolescents (12 months through 18 years of age): The vaccination schedule consists of a primary 0.5-mL dose administered intramuscularly, and a 0.5-mL booster dose administered intramuscularly 6 to 18 months later.

Adults (19 years of age and older): The vaccination schedule consists of a primary 1-mL dose administered intramuscularly, and a 1-mL booster dose administered intramuscularly 6 to 18 months later.

Booster Immunization Following Another Manufacturer’s Hepatitis A Vaccine: A booster dose of VAQTA may be given at 6 to 12 months following a primary dose of HAVRIX [see Clinical Studies (14.6)].

2.2 Preparation and Administration

Shake the single-dose vial or single-dose prefilled syringe well to obtain a slightly opaque, white suspension before withdrawal and use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the suspension does not appear homogenous or if extraneous particulate matter remains or discoloration is observed.

For single-dose vials, withdraw and administer entire dose of VAQTA intramuscularly using a sterile needle and syringe. Discard vial after use.

For single-dose prefilled syringes, securely attach a needle by twisting in a clockwise direction and administer dose of VAQTA intramuscularly. Discard syringe after use.

For adults, adolescents, and children older than 2 years of age, the deltoid muscle is the preferred site for intramuscular injection. For children 12 through 23 months of age, the anterolateral area of the thigh is the preferred site for intramuscular injection.

3 DOSAGE FORMS AND STRENGTHS

Suspension for injection available in four presentations:

• 0.5-mL pediatric dose in single-dose vials and prefilled syringes
• 1-mL adult dose in single-dose vials and prefilled syringes

[See Description (11) for listing of vaccine components and How Supplied/Storage and Handling (16).]

4 CONTRAINDICATIONS

Do not administer VAQTA to individuals with a history of immediate and/or severe allergic or hypersensitivity reactions (e.g. , anaphylaxis) after a previous dose of any hepatitis A vaccine, or to individuals who have had an anaphylactic reaction to any component of VAQTA, including neomycin [see Description (11)].

5 WARNINGS AND PRECAUTIONS

5.1 Prevention and Management of Allergic Vaccine Reactions

Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine [see Contraindications (4)].

5.2 Hypersensitivity to Latex

The vial stopper and the syringe plunger stopper and tip cap contain dry natural latex rubber that may cause allergic reactions in latex-sensitive individuals [see How Supplied/Storage and Handling (16)].

5.3 Altered Immunocompetence

Immunocompromised persons, including individuals receiving immunosuppressive therapy, may have a diminished immune response to VAQTA and may not be protected against HAV infection after vaccination [see Use in Specific Populations (8.6)].

5.4 Limitations of Vaccine Effectiveness

Hepatitis A virus has a relatively long incubation period (approximately 20 to 50 days). VAQTA may not prevent hepatitis A infection in individuals who have an unrecognized hepatitis A infection at the time of vaccination. Vaccination with VAQTA may not result in a protective response in all susceptible vaccinees.

6 ADVERSE REACTIONS

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.

The safety of VAQTA has been evaluated in over 10,000 subjects 1 year to 85 years of age. Subjects were given one or two doses of the vaccine. The second (booster dose) was given 6 months or more after the first dose.

The most common local adverse reactions and systemic adverse events (≥15%) reported in different clinical trials across different age groups when VAQTA was administered alone or concomitantly were:

• Children — 12 through 23 months of age: injection-site pain/tenderness (37.0%), injection-site erythema (21.2%), fever (16.4% when administered alone, and 27.0% when administered concomitantly).
• Children/Adolescents — 2 through 18 years of age: injection-site pain (18.7%)
• Adults — 19 years of age and older: injection-site pain, tenderness, or soreness (67.0%), injection-site warmth (18.2%) and headache (16.1%)

Allergic Reactions

Local and/or systemic allergic reactions that occurred in <1% of over 10,000 children/adolescents or adults in clinical trials regardless of causality included: injection-site pruritus and/or rash; bronchial constriction; asthma; wheezing; edema/swelling; rash; generalized erythema; urticaria; pruritus; eye irritation/itching; dermatitis [see Contraindications (4) and Warnings and Precautions (5.1)].

Children — 12 through 23 Months of Age

Across five clinical trials, 4374 children 12 to 23 months of age received one or two 25U doses of VAQTA, including 3885 children who received 2 doses of VAQTA and 1250 children who received VAQTA concomitantly with one or more other vaccines, including Measles, Mumps, and Rubella Virus Vaccine, Live (M-M-R II^®), Varicella Vaccine, Live (VARIVAX^®), Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine, Adsorbed (Tripedia or INFANRIX), Measles, Mumps, Rubella, and Varicella Vaccine, Live (ProQuad^®), Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM_197, Prevnar), or Haemophilus B Conjugate Vaccine (Meningococcal Protein Conjugate, PedvaxHIB^®). Overall, the race distribution of study subjects was as follows: 64.7% Caucasian; 15.7% Hispanic-American; 12.3% Black; 4.8% other; 1.4% Asian; and 1.1% Native American. The distribution of subjects by gender was 51.8% male and 48.2% female.

In an open-label clinical trial, 653 children 12 to 23 months of age were randomized to receive a first dose of VAQTA with ProQuad and Prevnar concomitantly (N=330) or a first dose of ProQuad and pneumococcal 7-valent conjugate vaccine concomitantly, followed by a first dose of VAQTA 6 weeks later (N=323). Approximately 6 months later, subjects received either the second doses of ProQuad and VAQTA concomitantly or the second doses of ProQuad and VAQTA separately. The race distribution of the study subjects was as follows: 60.3% Caucasian; 21.6% African-American; 9.5% Hispanic-American; 7.2% other; 1.1% Asian; and 0.3% Native American. The distribution of subjects by gender was 50.7% male and 49.3% female.

Table 1 presents rates of solicited local reactions at the VAQTA injection site and rates of elevated temperatures (≥100.4°F and ≥102.2°F) that occurred within 5 days following each dose of VAQTA and elevated temperatures >98.6°F for a total of 14 days after vaccination; occurrences of these events were recorded daily on diary cards. Table 2 presents rates of unsolicited systemic adverse events that occurred within 14 days at ≥5% in any group following each dose of VAQTA.

Table 1: Incidences of Solicited Local Adverse Reactions at the VAQTA Injection Site and Elevated Temperatures Following Each Dose of VAQTA in Healthy Children 12-23 Months of Age Receiving VAQTA Alone or Concomitantly With ProQuad and PREVNAR *

	Dose 1		Dose 2
Adverse reaction: Days 1-5 unless noted	VAQTA alone	VAQTA + ProQuad + Prevnar concomitantly	VAQTA alone	VAQTA + ProQuad concomitantly
N=number of subjects for whom data are available.
* Pneumococcal 7-valent Conjugate Vaccine
Injection site adverse reactions	N=274	N=311	N=251	N=263
Injection site erythema	11.7%	9.6%	12.7%	9.5%
Injection site pain/tenderness	15.3%	20.9%	20.3%	17.5%
Injection site swelling	9.5%	6.8%	7.6%	6.1%
Temperature > 98.6°F or feverish (Days 1-14)	12.4%	35.7%	10.8%	10.3%
	N=243	N=285	N=221	N=237
Temperature ≥ 100.4°F	10.3%	16.8%	10%	4.2%
Temperature ≥ 102.2 °F	2.1%	3.5%	2.3%	2.5%

Table 2: Incidences of Unsolicited Systemic Adverse Events ≥5% in Any Group Following Each Dose of VAQTA in Healthy Children 12-23 Months of Age Receiving VAQTA Alone or Concomitantly With ProQuad and PREVNAR *

	Dose 1		Dose 2
Adverse Event: Days 1-14	VAQTA alone	VAQTA + ProQuad + PREVNAR concomitantly	VAQTA alone	VAQTA + ProQuad concomitantly
* Pneumococcal 7-valent Conjugate Vaccine
	N=274	N=311	N=251	N=263
General Disorders and Administration Site Conditions
Irritability	3.6%	6.1%	2.8%	2.7%
Infections and Infestations
Upper respiratory tract infection	3.3%	6.1%	4.8%	5.7%
Skin and Subcutaneous Tissue Disorders
Dermatitis diaper	1.1%	6.1%	2.4%	3.4%

In Stage I of an open, multicenter, randomized study, children 15 months of age were randomized to receive the first dose of VAQTA alone (N=151) or concomitantly with PedvaxHIB and INFANRIX (N=155); another group of children 15 months of age were randomized to receive the first dose of VAQTA alone (N=152) or concomitantly with PedvaxHIB (N=159). All groups received the second dose of VAQTA alone at least 6 months following the first dose. The race distribution of Stage I study subjects was: 63.9% Caucasian; 17.5% Hispanic-American; 14.7% Black; 2.6% other; and 1.3% Asian. The distribution of subjects by gender was 54.0% male and 46.0% female. In Stage II of this study, an additional 654 children 12-17 months of age received the first dose of VAQTA alone followed by the second dose of VAQTA 6 months later. The race distribution of Stage II of the study subjects was: 66.1% Caucasian; 10.6% Hispanic-American; 16.8% Black; 4.7% other; and 1.5% Asian. The distribution of subjects by gender was 51.2% male and 48.8% female.

Table 3 presents rates of solicited local reactions at the VAQTA injection-site and rates of elevated temperatures (≥100.4°F and ≥102.2°F) that occurred within 5 days following each dose of VAQTA and elevated temperatures >98.6°F for a total of 14 days following each dose of VAQTA. Occurrences of these events were recorded daily on diary cards. Table 4 presents rates of unsolicited systemic adverse events that occurred within 14 days at ≥5% following each dose of VAQTA.

Table 3: Incidences of Solicited Local Adverse Reactions at the VAQTA Injection Site and Elevated Temperatures Following Each Dose of VAQTA in Healthy Children 12-23 Months of Age Receiving VAQTA Alone or Concomitantly with PedvaxHIB With or Without INFANRIX (Stage I) and those Receiving VAQTA Alone at Both Doses (Stage II)

	Stage I			Stage II
	Dose 1		Dose 2	Dose 1	Dose 2
Adverse Reaction: Days 1-5 unless noted	VAQTA alone	VAQTA + PedvaxHIB and Infanrix or VAQTA + PedvaxHIB concomitantly	VAQTA alone	VAQTA alone	VAQTA alone
N= number of subjects for whom data is available
Injection site adverse reactions	N=256	N=302	N=503	N=647	N=599
Injection site erythema	18.0%	19.9%	21.5%	11.7%	16.2%
Injection site pain/tenderness	21.9%	36.4%	27.4%	20.1%	22.9%
Injection site swelling	10.2%	14.2%	10.1%	7.1%	7.0%
Temperature > 98.6°F or feverish (Days 1-14)	10.2%	17.2%	10.7%	10.0%	8.2%
	N=234	N=290	N=473	N=631	N=591
Temperature ≥ 100.4°F	9.0%	16.9%	9.1%	9.4%	8.6%
Temperature ≥ 102.2 °F	3.8%	3.1%	3.2%	2.9%	2.4%

Table 4: Incidences of Unsolicited Systemic Adverse Events ≥5% in Any Group Following Each Dose of VAQTA in Healthy Children 12-23 Months of Age Receiving VAQTA Alone or Concomitantly with PedvaxHIB With or Without INFANRIX (Stage I) and Those Receiving VAQTA Alone at Both Doses (Stage II)

	Stage I			Stage II
	Dose 1		Dose 2	Dose 1	Dose 2
Adverse Event: Days 1-14	VAQTA alone	VAQTA + PedvaxHIB and Infanrix orVAQTA + PedvaxHIB concomitantly	VAQTA alone	VAQTA alone	VAQTA alone
	N=256	N=302	N=503	N=647	N=599
Gastrointestinal Disorders
Diarrhea	3.9%	8.3%	3.8%	4.6%	3.8%
Teething	3.1%	2.3%	1.4%	5.7%	4.3%
General Disorders and Administration Site Conditions
Irritability	6.3%	9.6%	4.0%	8.8%	6.5%
Infections and Infestations
Upper respiratory tract infection	2.3%	3.3%	3.0%	4.9%	5.2%
Respiratory, Thoracic and Mediastinal Disorders
Rhinorrhea	2.0%	4.0%	3.8%	6.2%	3.8%

Data presented in Tables 1 through 4 on solicited local reactions, and solicited and unsolicited systemic adverse events with incidence ≥5% following each dose of VAQTA are representative of other clinical trials of VAQTA in children 12 through 23 months of age. Across the five studies conducted in children 12-23 months of age, ≥39.9% of subjects experienced local adverse reactions and ≥55.7% of subjects experienced systemic adverse events. The majority of local and systemic adverse events were mild to moderate in intensity.

The following additional unsolicited local adverse reactions and systemic adverse events were observed at a common frequency of ≥1% to <10% in any individual clinical study. This listing includes only the adverse reactions not reported elsewhere in the label. These local adverse reactions and systemic adverse events occurred among recipients of VAQTA alone or VAQTA given concomitantly within 14 days following any dose of VAQTA across four clinical studies.

Eye disorders:

Conjunctivitis

Gastrointestinal disorders:

Constipation; vomiting

General disorders and administration site conditions:

Injection-site bruising; injection-site ecchymosis

Infections and infestations:

Otitis media; nasopharyngitis; rhinitis; viral infection; croup; pharyngitis streptococcal; laryngotracheobronchitis; viral exanthema; gastroenteritis viral; roseola

Metabolism and nutrition disorders:

Anorexia

Psychiatric disorders:

Insomnia; crying

Respiratory, thoracic and mediastinal disorders:

Cough; nasal congestion; respiratory congestion

Skin and subcutaneous tissue disorders:

Rash vesicular; measles-like/rubella-like rash; varicella-like rash; rash morbilliform

Serious Adverse Events (Children 12 through 23 Months of Age): Across the five studies conducted in subjects 12-23 months of age, 0.7% (32/4374) of subjects reported a serious adverse event following any dose of VAQTA, and 0.1% (5/4374) of subjects reported a serious adverse event judged to be vaccine related by the study investigator. The serious adverse events were collected over the period defined in each protocol (14, 28, or 42 days). Vaccine-related serious adverse events which occurred following any dose of VAQTA with or without concomitant vaccines included febrile seizure (0.05%), dehydration (0.02%), gastroenteritis (0.02%), and cellulitis (0.02%).

Children/Adolescents — 2 Years through 18 Years of Age

In 11 clinical trials, 2615 healthy children 2 years through 18 years of age received at least one dose of VAQTA. These studies included administration of VAQTA in varying doses and regimens (1377 children received one or more 25U doses). The race distribution of the study subjects who received at least one dose of VAQTA in these studies was as follows: 84.7% Caucasian; 10.6% American Indian; 2.3% African-American; 1.5% Hispanic-American; 0.6% other; 0.2% Oriental. The distribution of subjects by gender was 51.2% male and 48.8% female.

In a double-blind, placebo-controlled efficacy trial (i.e. The Monroe Efficacy Study), 1037 healthy children and adolescents 2 through 16 years of age were randomized to receive a primary dose of 25U of VAQTA and a booster dose of VAQTA 6, 12, or 18 months later, or placebo (alum diluent). All study subjects were Caucasian: 51.5% were male and 48.5% were female. Subjects were followed days 1 to 5 postvaccination for fever and local adverse reactions and days 1 to 14 for systemic adverse events. The most common adverse events/reactions were injection-site reactions, reported by 6.4% of subjects. Table 5 summarizes local adverse reactions and systemic adverse events reported in ≥1% of subjects. There were no significant differences in the rates of any adverse events or adverse reactions between vaccine and placebo recipients after Dose 1.

Table 5: Local Adverse Reactions and Systemic Adverse Events (≥1%) in Healthy Children and Adolescents from the Monroe Efficacy Study

Adverse Event	VAQTA(N=519)		Placebo (Alum Diluent)*, †, ‡(N=518)Rate (Percent)
	Dose 1*Rate (Percent)	BoosterRate (Percent)
N=Number of subjects enrolled/randomized.
Percent=percentage of subjects for whom data are available with adverse event
n=number of subjects for whom adverse events available
* No statistically significant differences between the two groups. † Second injection of placebo not administered because code for the trial was broken. ‡ Placebo (Alum diluent) = amorphous aluminum hydroxyphosphate sulfate. § Adverse Reactions at the injection site (VAQTA) Days 1-5 after vaccination with VAQTA ¶ Systemic adverse events reported Days 1-15 after vaccination, regardless of causality.
Injection Site §	n=515	n=475	n=510
Pain	6.4%	3.4%	6.3%
Tenderness	4.9%	1.7%	6.1%
Erythema	1.9%	0.8%	1.8%
Swelling	1.7%	1.5%	1.6%
Warmth	1.7%	0.6%	1.6%
Systemic ¶	n=519	n=475	n=518
Abdominal pain	1.2%	1.1%	1.0%
Pharyngitis	1.2%	0%	0.8%
Headache	0.4%	0.8%	1.0%

Adults — 19 Years of Age and Older

In an open-label clinical trial, 240 healthy adults 18 to 54 years of age were randomized to receive either VAQTA (50U/1-mL) with Typhim Vi (Typhoid Vi polysaccharide vaccine) and YF-Vax (yellow fever vaccine) concomitantly (N=80), typhoid Vi polysaccharide and yellow fever vaccines concomitantly (N=80), or VAQTA alone (N=80). Approximately 6 months later, subjects who received VAQTA were administered a second dose of VAQTA. The race distribution of the study subjects who received VAQTA with or without typhoid Vi polysaccharide and yellow fever vaccine was as follows: 78.3% Caucasian; 14.2% Oriental; 3.3% other; 2.1% African-American; 1.7% Indian; 0.4% Hispanic-American. The distribution of subjects by gender was 40.8% male and 59.2% female. Subjects were monitored for local adverse reactions and fever for 5 days and systemic adverse events for 14 days after each vaccination. In the 14 days after the first dose of VAQTA, the proportion of subjects with adverse events was similar between recipients of VAQTA given concomitantly with typhoid Vi polysaccharide and yellow fever vaccines compared to recipients of typhoid Vi polysaccharide and yellow fever vaccines without VAQTA. Table 6 summarizes solicited local adverse reactions and Table 7 summarizes unsolicited systemic adverse events reported in ≥5% in adults who received one or two doses of VAQTA alone and for subjects who received VAQTA concomitantly with typhoid Vi polysaccharide and yellow fever vaccines. There were no solicited systemic complaints reported at a rate ≥5%. Fever ≥101°F occurred in 1.3% of subjects in each group.

Table 6: Incidences of Solicited Local Adverse Reactions in Healthy Adults ≥19 Years of Age Occurring at ≥5% After Any Dose

Adverse Event	VAQTA administered alone(N=80)	VAQTA + ViCPS * and Yellow Fever vaccines administered concomitantly †(N=80)
	Rate (Percent)
N=Number of subjects enrolled/randomized.
Percent=percentage of subjects with adverse event.
* ViCPS=Typhoid Vi polysaccharide vaccine. † VAQTA administered concomitantly with typhoid Vi polysaccharide (ViCPS) and yellow fever vaccines. ‡ Adverse Reactions at the injection site (VAQTA) Days 1-5 after vaccination
Injection-site ‡
Pain/tenderness/soreness	78.8%	70.3%
Warmth	23.7%	23.7%
Swelling	16.2%	8.8%
Erythema	17.5%	6.3%

Table 7: Incidences of Unsolicited Systemic Adverse Events in Adults ≥19 Years of Age Occurring at ≥5% After Any Dose

Body System	VAQTA administered alone(N=80)	VAQTA + ViCPS * and Yellow Fever vaccines administered concomitantly †(N=80)
Adverse Event
	Rate (Percent)
N=Number of subjects enrolled/randomized with data available.
Percent=percentage of subjects with adverse event for whom data are available.
* ViCPS=Typhoid Vi polysaccharide vaccine. † VAQTA administered concomitantly with typhoid Vi polysaccharide (ViCPS) and yellow fever vaccines. ‡ Systemic Adverse Events reported Days 1-15 after vaccination, regardless of causality.
General disorders and administration site reactions ‡
Asthenia/fatigue	7.5%	11.3%
Chills	1.3%	7.5%
Gastrointestinal disorders ‡
Nausea	7.5%	12.5%
Musculoskeletal and connective tissue disorders ‡
Myalgia	5.0%	10.0%
Arm pain	0.0%	6.3%
Nervous system disorders ‡
Headache	23.8%	26.3%
Infections and infestations ‡
Upper respiratory infection	7.5%	3.8%
Pharyngitis	2.5%	6.3%

In four clinical trials involving 1645 healthy adults 19 years of age and older who received one or more 50U doses of hepatitis A vaccine, subjects were followed for fever and local adverse reactions 1 to 5 days postvaccination and for systemic adverse events 1 to 14 days postvaccination. One single-blind study evaluated doses of VAQTA with varying amounts of viral antigen and/or alum content in healthy adults ≥170 pounds and ≥30 years of age (N=210 adults administered 50U/1-mL dose). One open-label study evaluated VAQTA given with immune globulin (IG) or alone (N=164 adults who received VAQTA alone). A third study was single-blind and evaluated 3 different lots of VAQTA (N=1112). The fourth study that was also single-blind evaluated doses of VAQTA with varying amounts of viral antigen in healthy adults ≥170 pounds and ≥30 years of age (N=159 adults administered the 50U/1-mL dose). Overall, the race distribution of the study subjects who received at least one dose of VAQTA was as follows: 94.2% Caucasian; 2.2% Black; 1.5% Hispanic; 1.5% Oriental; 0.4% other; 0.2% American Indian. 47.6% of subjects were male and 52.4% were female. The most common adverse event/reaction was injection-site pain/soreness/tenderness reported by 67.0% of subjects. Of all reported injection-site reactions 99.8% were mild (i.e., easily tolerated with no medical intervention) or moderate (i.e., minimally interfered with usual activity possibly requiring little medical intervention). Listed below in Table 8 are the local adverse reactions and systemic adverse events reported by ≥5% of subjects, in decreasing order of frequency within each body system.

Table 8: Incidences of Local Adverse Reactions and Systemic Adverse Events ≥5% in Adults 19 Years of Age and Older

Body System	VAQTA (Any Dose)(N=1645)
Adverse Events	Rate (n/total n)
N=Number of subjects enrolled/randomized.
n=Number of subjects in each category with data available.
Percent=percentage of subjects for whom data are available with adverse event.
* Systemic Adverse Events reported Days 1 to 14 after vaccination, regardless of causality. † Adverse Reactions at the injection site (VAQTA) and measured fever Days 1 to 5 after vaccination.
Nervous system disorders *	n=1641
Headache	16.1%
General disorders and administration site reactions †	n=1640
Injection-site pain/tenderness/soreness	67.0%
Injection-site warmth	18.2%
Injection-site swelling	14.7%
Injection-site erythema	13.7%

The following additional unsolicited systemic adverse events were observed among recipients of VAQTA that occurred within 14 days at a common frequency of ≥1% to <10% following any dose not reported elsewhere in the label. These adverse reactions have been reported across 4 clinical studies.

Musculoskeletal and connective tissue disorders:

Back pain; stiffness

Reproductive system and breast disorders:

Menstruation disorders