Vaccine Information: ZOSTAVAX

ZOSTAVAX- varicella-zoster virus strain oka/merck live antigen injection, powder, lyophilized, for suspension
STERILE DILUENT- water injection
Merck Sharp & Dohme Corp.

1 INDICATIONS AND USAGE

ZOSTAVAX® is a live attenuated virus vaccine indicated for prevention of herpes zoster (shingles) in individuals 50 years of age and older.

Limitations of Use of ZOSTAVAX:

  • ZOSTAVAX is not indicated for the treatment of zoster or postherpetic neuralgia (PHN).
  • ZOSTAVAX is not indicated for prevention of primary varicella infection (Chickenpox).

2 DOSAGE AND ADMINISTRATION

Subcutaneous administration only. Do not inject intravascularly or intramuscularly.

2.1 Recommended Dose and Schedule

Administer ZOSTAVAX as a single 0.65-mL dose subcutaneously in the deltoid region of the upper arm.

2.2 Preparation for Administration

Use only sterile syringes free of preservatives, antiseptics, and detergents for each injection and/or reconstitution of ZOSTAVAX. Preservatives, antiseptics and detergents may inactivate the vaccine virus.

ZOSTAVAX is stored frozen and should be reconstituted immediately upon removal from the freezer.

When reconstituted, ZOSTAVAX is a semi-hazy to translucent, off-white to pale yellow liquid.

Reconstitution:

  • Use only the diluent supplied.
  • Withdraw the entire contents of the diluent into a syringe.
  • To avoid excessive foaming, slowly inject all of the diluent in the syringe into the vial of lyophilized vaccine and gently agitate to mix thoroughly.
  • Withdraw the entire contents of reconstituted vaccine into a syringe, inject the total volume subcutaneously, and discard vial.
  • ADMINISTER IMMEDIATELY AFTER RECONSTITUTION to minimize loss of potency. Discard reconstituted vaccine if not used within 30 minutes. Do not freeze reconstituted vaccine.

3 DOSAGE FORMS AND STRENGTHS

ZOSTAVAX is a lyophilized preparation of live, attenuated varicella-zoster virus (Oka/Merck) to be reconstituted with sterile diluent to give a single dose suspension with a minimum of 19,400 PFU (plaque forming units) when stored at room temperature for up to 30 minutes.

4 CONTRAINDICATIONS

4.1 Hypersensitivity

Do not administer ZOSTAVAX to individuals with a history of anaphylactic/anaphylactoid reaction to gelatin, neomycin or any other component of the vaccine. Neomycin allergy manifested as contact dermatitis is not a contraindication to receiving this vaccine. {1}

4.2 Immunosuppression

Do not administer ZOSTAVAX to individuals who are immunodeficient or immunosuppressed due to disease or therapy, as serious or fatal disseminated vaccine strain varicella-zoster virus disease may occur. Causes of immunodeficiency or immunosuppression may include, but are not limited to, primary or acquired immunodeficiency states, AIDS or other clinical manifestations of infection with human immunodeficiency viruses, leukemia, lymphoma or other malignant neoplasms affecting the bone marrow or lymphatic system, and immunosuppressive therapy.

4.3 Pregnancy

Do not administer ZOSTAVAX to pregnant women. Naturally occurring varicella-zoster virus (VZV) infection is known to sometimes cause fetal harm. Pregnancy should be avoided for 3 months following administration of ZOSTAVAX [see Use in Specific Populations (8.1) and Patient Counseling Information (17)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Serious adverse reactions, including anaphylaxis, have occurred with ZOSTAVAX. Adequate treatment provisions, including epinephrine injection (1:1,000), should be available for immediate use should an anaphylactic/anaphylactoid reaction occur.

5.2 Transmission of Vaccine Virus

Transmission of vaccine virus may occur between vaccinees and susceptible contacts.

5.3 Concurrent Illness

Deferral should be considered in acute illness (for example, in the presence of fever) or in patients with active untreated tuberculosis.

5.4 Limitations of Vaccine Effectiveness

Vaccination with ZOSTAVAX does not result in protection of all vaccine recipients.

The duration of protection beyond 4 years after vaccination with ZOSTAVAX is unknown. The need for revaccination has not been defined.

6 ADVERSE REACTIONS

The most frequent adverse reactions, reported in ≥1% of subjects vaccinated with ZOSTAVAX, were headache and injection-site reactions.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, rates of adverse reactions 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.

ZOSTAVAX Efficacy and Safety Trial (ZEST) in Subjects 50 to 59 Years of Age

In the ZEST study, subjects received a single dose of either ZOSTAVAX (N=11,184) or placebo (N=11,212). The racial distribution across both vaccination groups was similar: White (94.4%); Black (4.2%); Hispanic (3.3%) and Other (1.4%) in both vaccination groups. The gender distribution was 38% male and 62% female in both vaccination groups. The age distribution of subjects enrolled, 50 to 59 years, was similar in both vaccination groups. All subjects received a vaccination report card (VRC) to record adverse events occurring from Days 1 to 42 postvaccination.

In the ZEST study, serious adverse events occurred at a similar rate in subjects vaccinated with ZOSTAVAX (0.6%) or placebo (0.5%) from Days 1 to 42 postvaccination.

In the ZEST study, all subjects were monitored for adverse reactions. An anaphylactic reaction was reported for one subject vaccinated with ZOSTAVAX.

Most Common Adverse Reactions and Experiences in the ZEST Study

The overall incidence of vaccine-related injection-site adverse reactions within 5 days postvaccination was greater for subjects vaccinated with ZOSTAVAX as compared to subjects who received placebo (63.6% for ZOSTAVAX and 14.0% for placebo). Injection-site adverse reactions occurring at an incidence ≥1% within 5 days postvaccination are shown in Table 1.

Table 1: Injection-Site Adverse Reactions Reported in ≥1% of Adults Who Received ZOSTAVAX or Placebo Within 5 Days Postvaccination in the ZOSTAVAX Efficacy and Safety Trial
*
Solicited on the Vaccination Report Card

Injection-Site

Adverse Reaction

ZOSTAVAX

(N = 11094)

Placebo

(N = 11116)

Solicited *

Pain

Erythema

Swelling

53.9

48.1

40.4

9.0

4.3

2.8

Unsolicited

Pruritus

Warmth

Hematoma

Induration

11.3

3.7

1.6

1.1

0.7

0.2

1.6

0.0

Systemic adverse reactions and experiences reported during Days 1-42 at an incidence of ≥1% in either vaccination group were headache (ZOSTAVAX 9.4%, placebo 8.2%) and pain in the extremity (ZOSTAVAX 1.3%, placebo 0.8%), respectively.

The overall incidence of systemic adverse experiences reported during Days 1-42 was higher for ZOSTAVAX (35.4%) than for placebo (33.5%).

Shingles Prevention Study (SPS) in Subjects 60 Years of Age and Older

In the SPS, the largest clinical trial of ZOSTAVAX, subjects received a single dose of either ZOSTAVAX (n=19,270) or placebo (n=19,276). The racial distribution across both vaccination groups was similar: White (95%); Black (2.0%); Hispanic (1.0%) and Other (1.0%) in both vaccination groups. The gender distribution was 59% male and 41% female in both vaccination groups. The age distribution of subjects enrolled, 59-99 years, was similar in both vaccination groups.

The Adverse Event Monitoring Substudy of the SPS, designed to provide detailed data on the safety profile of the zoster vaccine (n=3,345 received ZOSTAVAX and n=3,271 received placebo) used vaccination report cards (VRC) to record adverse events occurring from Days 0 to 42 postvaccination (97% of subjects completed VRC in both vaccination groups). In addition, monthly surveillance for hospitalization was conducted through the end of the study, 2 to 5 years postvaccination.

The remainder of subjects in the SPS (n=15,925 received ZOSTAVAX and n=16,005 received placebo) were actively followed for safety outcomes through Day 42 postvaccination and passively followed for safety after Day 42.

Serious Adverse Events Occurring 0-42 Days Postvaccination

In the overall SPS study population, serious adverse events occurred at a similar rate (1.4%) in subjects vaccinated with ZOSTAVAX or placebo.

In the AE Monitoring Substudy, the rate of SAEs was increased in the group of subjects who received ZOSTAVAX as compared to the group of subjects who received placebo (Table 2).

Table 2: Number of Subjects with ≥1 Serious Adverse Events (0-42 Days Postvaccination) in the Shingles Prevention Study
Cohort ZOSTAVAXn/N% Placebon/N% Relative Risk(95% CI)
N=number of subjects in cohort with safety follow-upn=number of subjects reporting an SAE 0-42 Days postvaccination
Overall Study Cohort(60 years of age and older) 255/186711.4% 254/187171.4% 1.01(0.85, 1.20)
60-69 years old 113/101001.1% 101/100951.0% 1.12(0.86, 1.46)
70-79 years old 115/73511.6% 132/73331.8% 0.87(0.68, 1.11)
≥80 years old 27/12202.2% 21/12891.6% 1.36(0.78, 2.37)
AE Monitoring Substudy Cohort(60 years of age and older) 64/33261.9% 41/32491.3% 1.53 (1.04, 2.25)
60-69 years old 22/17261.3% 18/17091.1% 1.21(0.66, 2.23)
70-79 years old 31/13832.2% 19/13671.4% 1.61(0.92, 2.82)
≥80 years old 11/2175.1% 4/1732.3% 2.19(0.75, 6.45)

Among reported serious adverse events in the SPS (Days 0 to 42 postvaccination), serious cardiovascular events occurred more frequently in subjects who received ZOSTAVAX (20 [0.6%]) than in subjects who received placebo (12 [0.4%]) in the AE Monitoring Substudy. The frequencies of serious cardiovascular events were similar in subjects who received ZOSTAVAX (81 [0.4%]) and in subjects who received placebo (72 [0.4%]) in the entire study cohort (Days 0 to 42 postvaccination).

Serious Adverse Events Occurring Over the Entire Course of the Study

Rates of hospitalization were similar among subjects who received ZOSTAVAX and subjects who received placebo in the AE Monitoring Substudy, throughout the entire study.

Fifty-one individuals (1.5%) receiving ZOSTAVAX were reported to have congestive heart failure (CHF) or pulmonary edema compared to 39 individuals (1.2%) receiving placebo in the AE Monitoring Substudy; 58 individuals (0.3%) receiving ZOSTAVAX were reported to have congestive heart failure (CHF) or pulmonary edema compared to 45 (0.2%) individuals receiving placebo in the overall study.

In the SPS, all subjects were monitored for vaccine-related SAEs. Investigator-determined, vaccine-related serious adverse experiences were reported for 2 subjects vaccinated with ZOSTAVAX (asthma exacerbation and polymyalgia rheumatica) and 3 subjects who received placebo (Goodpasture’s syndrome, anaphylactic reaction, and polymyalgia rheumatica).

Deaths

The incidence of death was similar in the groups receiving ZOSTAVAX or placebo during the Days 0-42 postvaccination period; 14 deaths occurred in the group of subjects who received ZOSTAVAX and 16 deaths occurred in the group of subjects who received placebo. The most common reported cause of death was cardiovascular disease (10 in the group of subjects who received ZOSTAVAX, 8 in the group of subjects who received placebo). The overall incidence of death occurring at any time during the study was similar between vaccination groups: 793 deaths (4.1%) occurred in subjects who received ZOSTAVAX and 795 deaths (4.1%) in subjects who received placebo.

Most Common Adverse Reactions and Experiences in the AE Monitoring Substudy of the SPS

Injection-site adverse reactions reported at an incidence ≥1% are shown in Table 3. Most of these adverse reactions were reported as mild in intensity. The overall incidence of vaccine-related injection-site adverse reactions was significantly greater for subjects vaccinated with ZOSTAVAX versus subjects who received placebo (48% for ZOSTAVAX and 17% for placebo).

Table 3: Injection-Site Adverse Reactions * in ≥1% of Adults Who Received ZOSTAVAX or Placebo Within 5 Days Postvaccination from the AE Monitoring Substudy of the Shingles Prevention Study
Adverse Reaction

ZOSTAVAX

(N = 3345)

Placebo

(N = 3271)

*
Patients instructed to report adverse experiences on a Vaccination Report Card
Solicited on the Vaccination Report Card

Solicited

Erythema

Pain/Tenderness

Swelling

35.6

34.3

26.1

6.9

8.3

4.5

Unsolicited

Hematoma

Pruritus

Warmth

1.6

6.9

1.6

1.4

1.0

0.3

Headache was the only systemic adverse reaction reported on the vaccine report card between Days 0-42 by ≥1% of subjects in the AE Monitoring Substudy in either vaccination group (ZOSTAVAX 1.4%, placebo 0.8%).

The numbers of subjects with elevated temperature (≥38.3°C [≥101.0°F]) within 42 days postvaccination were similar in the ZOSTAVAX and the placebo vaccination groups [27 (0.8%) vs. 27 (0.9%), respectively].

The following adverse experiences in the AE Monitoring Substudy of the SPS (Days 0 to 42 postvaccination) were reported at an incidence ≥1% and greater in subjects who received ZOSTAVAX than in subjects who received placebo, respectively: respiratory infection (65 [1.9%] vs. 55 [1.7%]), fever (59 [1.8%] vs. 53 [1.6%]), flu syndrome (57 [1.7%] vs. 52 [1.6%]), diarrhea (51 [1.5%] vs. 41 [1.3%]), rhinitis (46 [1.4%] vs. 36 [1.1%]), skin disorder (35 [1.1%] vs. 31 [1.0%]), respiratory disorder (35 [1.1%] vs. 27 [0.8%]), asthenia (32 [1.0%] vs. 14 [0.4%]).

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