Vaccine Information: VARIVAX

VARIVAX- varicella-zoster virus strain oka/merck live antigen injection, powder, lyophilized, for suspension
Merck Sharp & Dohme LLC

1 INDICATIONS AND USAGE

VARIVAX is a vaccine indicated for active immunization for the prevention of varicella in individuals 12 months of age and older.

2 DOSAGE AND ADMINISTRATION

​ For Intramuscular or Subcutaneous administration only

2.1 Dose and Schedule

​ A single dose of VARIVAX is approximately 0.5 mL.

Children (12 months to 12 years of age)

The first dose is administered at 12 to 15 months of age but may be given anytime through 12 years of age.

The second dose is administered at 4 to 6 years of age. At least 3 months should elapse between a dose of varicella-containing vaccine and VARIVAX.

At least 1 month should elapse between a dose of measles-containing vaccine and a dose of VARIVAX if the vaccines are not given concurrently [see Clinical Studies (14.1)].

Adolescents (≥13 years of age) and Adults

Two doses of VARIVAX are administered at a minimum interval of 4 weeks [see Clinical Studies (14.1)].

2.2 Reconstitution Instructions

​ The sterile diluent for VARIVAX is provided in either a vial or prefilled syringe.

​ Sterile Diluent Vial

​ Use a sterile syringe free of preservatives, antiseptics, and detergents for each reconstitution and injection of VARIVAX because these substances may inactivate the vaccine virus. When reconstituting the vaccine, use the sterile diluent vial supplied with VARIVAX. The sterile diluent does not contain preservatives or other antiviral substances which might inactivate the vaccine virus.

​ To reconstitute the vaccine, withdraw the entire volume of the supplied sterile diluent from the vial and slowly inject into the lyophilized vaccine vial. Gently agitate to dissolve completely. Discard if the lyophilized vaccine cannot be dissolved.

​ Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Visually inspect the vaccine before and after reconstitution prior to administration. Before reconstitution, the lyophilized vaccine is a white compact crystalline plug. VARIVAX, when reconstituted, is a clear, colorless to pale yellow liquid. Do not use the product if particulates are present or if it appears discolored.

​ Withdraw and administer the entire volume of the reconstituted vaccine.

Administer VARIVAX immediately after reconstitution. Discard if reconstituted vaccine is not used within 30 minutes.

Do not freeze reconstituted vaccine.

Do not combine VARIVAX with any other vaccine through reconstitution or mixing.

​ Sterile Diluent Prefilled Syringe

​ To reconstitute, use the sterile diluent prefilled syringe supplied with the vaccine since it does not contain preservatives or other antiviral substances which might inactivate the vaccine virus.

​ Attach a needle to the prefilled syringe.

​ Reconstitute the vaccine by slowly injecting the entire volume of sterile diluent contained in the prefilled syringe into the lyophilized vaccine vial. Gently agitate to dissolve completely. Discard if the lyophilized vaccine cannot be dissolved.

​ Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Visually inspect the vaccine before and after reconstitution prior to administration. Before reconstitution, the lyophilized vaccine is a white compact crystalline plug. VARIVAX, when reconstituted, is a clear, colorless to pale yellow liquid. Do not use the reconstituted vaccine if particulates are present or if it appears discolored.

​ Withdraw and administer the entire volume of the reconstituted vaccine.

​ Administer VARIVAX immediately after reconstitution. Discard if reconstituted vaccine is not used within 30 minutes.

​ Do not freeze reconstituted vaccine.

​ Do not combine VARIVAX with any other vaccine through reconstitution or mixing.

2.3 Administration

​ Inject the vaccine intramuscularly or subcutaneously.

3 DOSAGE FORMS AND STRENGTHS

VARIVAX is a suspension for injection supplied as a single-dose vial of lyophilized vaccine to be reconstituted using the accompanying sterile diluent [see Dosage and Administration (2.2) and How Supplied/Storage and Handling (16)]. A single dose after reconstitution is approximately 0.5 mL.

4 CONTRAINDICATIONS

4.1 Severe Allergic Reaction

Do not administer VARIVAX to individuals with a history of anaphylactic or severe allergic reaction to any component of the vaccine (including neomycin and gelatin) or to a previous dose of a varicella-containing vaccine.

4.2 Immunosuppression

Do not administer VARIVAX to individuals who are immunodeficient or immunosuppressed due to disease or medical therapy.

Disseminated varicella disease and extensive vaccine-associated rash have been reported in individuals who are immunosuppressed or immunodeficient who were inadvertently vaccinated with a varicella-containing vaccine.

4.3 Moderate or Severe Febrile Illness

Do not administer VARIVAX to individuals with an active febrile illness with fever >101.3°F (>38.5°C).

4.4 Active Untreated Tuberculosis

Do not administer VARIVAX to individuals with active, untreated tuberculosis (TB).

4.5 Pregnancy

Do not administer VARIVAX to individuals who are pregnant or planning on becoming pregnant in the next 3 months. Wild-type varicella is known to cause fetal harm [see Use in Specific Populations (8.1) and Patient Counseling Information (17)].

5 WARNINGS AND PRECAUTIONS

5.1 Family History of Immunodeficiency

Vaccination should be deferred in individuals with a family history of congenital or hereditary immunodeficiency until the individual’s immune status has been evaluated and the individual has been found to be immunocompetent.

5.2 Use in HIV-Infected Individuals

The Advisory Committee on Immunization Practices (ACIP) has recommendations on the use of varicella vaccine in HIV-infected individuals.

5.3 Risk of Vaccine Virus Transmission

Post-marketing experience suggests that transmission of varicella vaccine virus (Oka/Merck) resulting in varicella infection including disseminated disease may 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.

Due to the concern for transmission of vaccine virus, vaccine recipients should attempt to avoid whenever possible close association with susceptible high-risk individuals for up to six weeks following vaccination with VARIVAX. Susceptible high-risk individuals include:

• Immunocompromised individuals;
• Pregnant women without documented history of varicella or laboratory evidence of prior infection;
• Newborn infants of mothers without documented history of varicella or laboratory evidence of prior infection and all newborn infants born at <28 weeks gestation regardless of maternal varicella immunity.

5.4 Immune Globulins and Transfusions

Immune Globulins (IG) and other blood products should not be given concomitantly with VARIVAX [see Drug Interactions (7.2)]. These products may contain antibodies that interfere with vaccine virus replication and decrease the expected immune response.

The ACIP has specific recommendations for intervals between administration of antibody-containing products and live virus vaccines.

5.5 Salicylate Therapy

Avoid use of salicylates (aspirin) or salicylate-containing products in children and adolescents 12 months through 17 years of age for six weeks following vaccination with VARIVAX because of the association of Reye syndrome with salicylate therapy and wild-type varicella infection [see Drug Interactions (7.1)].

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 clinical practice. Vaccine-related adverse reactions reported during clinical trials were assessed by the study investigators to be possibly, probably, or definitely vaccine-related and are summarized below.

In clinical trials {1–8}, VARIVAX was administered subcutaneously to over 11,000 healthy children, adolescents, and adults.

In a double– blind, placebo– controlled study among 914 healthy children and adolescents who were serologically confirmed to be susceptible to varicella, the only adverse reactions that occurred at a significantly (p<0.05) greater rate in vaccine recipients than in placebo recipients were pain and redness at the injection site {1}.

Children 1 to 12 Years of Age

One-Dose Regimen in Children

In clinical trials involving healthy children monitored for up to 42 days after a single dose of VARIVAX, the frequency of fever, injection– site complaints, or rashes were reported as shown in Table 1:

Table 1: Fever, Local Reactions, and Rashes (%) in Children 1 to 12 Years of Age 0 to 42 Days After Receipt of a Single Dose of VARIVAX

Reaction		N	% Experiencing Reaction	Peak Occurrence During Postvaccination Days
Fever ≥102.0°F (38.9°C) Oral		8827	14.7%	0 to 42
Injection-site complaints		8916	19.3%	0 to 2
	(pain/soreness, swelling and/or erythema, rash, pruritus, hematoma, induration, stiffness)
Varicella-like rash (injection site)		8916	3.4%	8 to 19
Median number of lesions			2
Varicella-like rash (generalized)		8916	3.8%	5 to 26
Median number of lesions			5

In addition, adverse events occurring at a rate of ≥1% are listed in decreasing order of frequency: upper respiratory illness, cough, irritability, fatigue, disturbed sleep, diarrhea, loss of appetite, vomiting, otitis, headache, malaise, abdominal pain, other rash, nausea, chills, lymphadenopathy, myalgia, lower respiratory illness, allergic reactions (including allergic rash, hives), stiff neck, arthralgia, itching.

Pneumonitis has been reported rarely (<1%) in children vaccinated with VARIVAX.

Febrile seizures have occurred at a rate of <0.1% in children vaccinated with VARIVAX.

Two-Dose Regimen in Children

Nine hundred eighty-one (981) subjects in a clinical trial received 2 doses of VARIVAX 3 months apart and were actively followed for 42 days after each dose. The 2-dose regimen of varicella vaccine had a safety profile comparable to that of the 1-dose regimen. The overall incidence of injection-site clinical complaints (primarily erythema and swelling) observed in the first 4 days following vaccination was 25.4% Postdose 2 and 21.7% Postdose 1, whereas the overall incidence of systemic clinical complaints in the 42-day follow-up period was lower Postdose 2 (66.3%) than Postdose 1 (85.8%).

Adolescents (13 Years of Age and Older) and Adults

In clinical trials involving healthy adolescents and adults, the majority of whom received two doses of VARIVAX and were monitored for up to 42 days after any dose, the frequencies of fever, injection-site complaints, or rashes are shown in Table 2.

Table 2: Fever, Local Reactions, and Rashes (%) in Adolescents and Adults 0 to 42 Days After Receipt of VARIVAX

Reaction		N	% PostDose 1	Peak Occurrence inPostvaccination Days	N	% PostDose 2	Peak Occurrence inPostvaccination Days
Fever ≥100.0°F (37.8°C) Oral		1584	10.2%	14 to 27	956	9.5%	0 to 42
Injection-site complaints		1606	24.4%	0 to 2	955	32.5%	0 to 2
	(soreness, erythema, swelling, rash, pruritus, pyrexia, hematoma, induration, numbness)
Varicella-like rash (injection site)		1606	3%	6 to 20	955	1%	0 to 6
Median number of lesions			2			2
Varicella-like rash (generalized)		1606	5.5%	7 to 21	955	0.9%	0 to 23
Median number of lesions			5			5.5

In addition, adverse events reported at a rate of ≥1% are listed in decreasing order of frequency: upper respiratory illness, headache, fatigue, cough, myalgia, disturbed sleep, nausea, malaise, diarrhea, stiff neck, irritability, lymphadenopathy, chills, abdominal pain, loss of appetite, arthralgia, otitis, itching, vomiting, other rashes, lower respiratory illness, allergic reactions (including allergic rash, hives).

In a randomized open-label clinical trial (NCT00432523), conducted in France and Germany, 752 children 12 months through 18 months of age received M-M-R II concomitantly administered with VARIVAX at a separate site, by either the intramuscular (n=374) or subcutaneous (n=378) route. In the overall population, 55.3% were male and the median age was 13.2 months. Local and systemic solicited adverse reactions were recorded by parents or guardians using standardized diary cards. Local solicited reactions were recorded for 4 days after vaccination, and systemic solicited adverse reactions were recorded for 42 days after vaccination. In the event that a participant experienced a rash or a mumps-like illness, parents and/or guardians were instructed to contact the investigator for an examination as soon as possible and no later than 72 hours following onset of symptoms. The nature of any rash was characterized by principal investigator either as measles-like, rubella-like, varicella-like or “other”. Study investigators reviewed the diary card with the participant or participant’s legal guardian 42 days after vaccination to ensure consistency with protocol definitions. Table 3 below presents the frequency of solicited adverse reactions based on the final assessment by the study investigators.

Table 3: Proportion of Participants Reporting Solicited Adverse Reactions Following Vaccination with VARIVAX Concomitantly Administered with M-M-R II, by the Intramuscular or Subcutaneous Route

	IntramuscularN=374%	Subcutaneous N=376%
N=total number of participants in the group
* During the post vaccination monitoring period (0-42 days), eight participants experienced a varicella-like injection-site rash at the VARIVAX injection site. All were reported in the subcutaneous group. † Intensity of injection site reaction: mild or ≤2.5 cm; moderate or >2.5 to ≤5.0 cm; severe or >5.0 cm. ‡ Intensity of pain: mild: awareness of symptom but easily tolerated; moderate: definitely acting like something is wrong; severe: extremely distressed or unable to do usual activities. § Testing to distinguish between rash caused by wild-type or vaccine virus was not performed. Reports of measles-, rubella-, and varicella-like rash included 3 reports of measles, 1 report of rubella, and 1 report of varicella, all with onset within 15 days post-vaccination. ¶ The percentage of fever is defined within the population who had valid temperature measurements. One participant in IM group and two participants in SC group did not have temperature measurements and were excluded from the denominator; resulting in N=374 and N=376, respectively. # In the IM Group 92.3% of fevers were documented using the rectal route of measurement and 7.7% of fevers were documented only by the axillary route of measurement. In the SC Group 89.6% of fevers were documented using the rectal route of measurement and 10.4% of fevers were documented only by the axillary route of measurement.
Solicited local reactions at Varivax injection site (Days 0 to 4)*
Erythema †	8.8	16.8
Mild	8.0	12.8
Moderate	0.5	3.7
Severe	0	0
Missing	0.3	0.3
Pain ‡	7.0	8.5
Mild	4.8	7.2
Moderate	2.1	1.3
Severe	0	0
Swelling †	3.2	4.8
Mild	1.6	3.5
Moderate	1.1	0.5
Severe	0	0
Missing	0.5	0.8
Solicited systemic adverse reactions (Days 0 to 42)
Measles-like rash (Days 0 to 42)§	2.9	2.7
Rubella-like rash (Days 0 to 42)§	2.7	2.7
Varicella-like rash (Days 0 to 42)§	0.5	3.2
Mumps-like illness (Days 0 to 42)	0	0.3
Fever (temperature ≥38.0°C) (Days 0 to 42)¶, #	66.5	66.8
38.0-38.5°C	20.4	22.2
>38.5-39.0°C	17.4	16.6
>39.0-39.5°C	14.2	13.4
>39.5-40.0°C	11.8	11.0
>40.0°C	2.7	3.7

Unsolicited adverse events that occurred within 42 days following vaccination were recorded using diary cards supplemented by medical review. Data on unsolicited adverse events were transcribed into the study database during an on-site visit at day 42. The rates and types of reported adverse events (AEs) across groups were similar and included common clinical events that are often reported in the evaluated populations. Serious adverse events occurred at rates of 0.3% and 1% in the intramuscular and subcutaneous groups, respectively. One moderate intensity case of otitis media occurred in a participant in the subcutaneous group was considered related to the vaccination.

Herpes Zoster

Overall, 9454 healthy children (12 months to 12 years of age) and 1648 adolescents and adults (13 years of age and older) have been vaccinated with VARIVAX in clinical trials. Eight cases of herpes zoster have been reported in children during 42,556 person-years of follow-up in clinical trials, resulting in a calculated incidence of at least 18.8 cases per 100,000 person-years. The completeness of this reporting has not been determined. One case of herpes zoster has been reported in the adolescent and adult age group during 5410 person-years of follow-up in clinical trials, resulting in a calculated incidence of 18.5 cases per 100,000 person-years. All 9 cases were mild and without sequelae. Two cultures (one child and one adult) obtained from vesicles were positive for wild-type VZV as confirmed by restriction endonuclease analysis {11}. The long-term effect of VARIVAX on the incidence of herpes zoster, particularly in those vaccinees exposed to wild-type varicella, is unknown at present.

In children, the reported rate of herpes zoster in vaccine recipients appears not to exceed that previously determined in a population-based study of healthy children who had experienced wild-type varicella {12}. The incidence of herpes zoster in adults who have had wild-type varicella infection is higher than that in children.