Vaccine Information: ZOSTAVAX (Page 2 of 5)

6.2 VZV Rashes Following Vaccination

Within the 42-day postvaccination reporting period in the ZEST, noninjection-site zoster-like rashes were reported by 34 subjects (19 for ZOSTAVAX and 15 for placebo). Of 24 specimens that were adequate for Polymerase Chain Reaction (PCR) testing, wild-type VZV was detected in 10 (3 for ZOSTAVAX, 7 for placebo) of these specimens. The Oka/Merck strain of VZV was not detected from any of these specimens. Of reported varicella-like rashes (n=124, 69 for ZOSTAVAX and 55 for placebo), 23 had specimens that were available and adequate for PCR testing. VZV was detected in one of these specimens in the ZOSTAVAX group; however, the virus strain (wild-type or Oka/Merck strain) could not be determined.

Within the 42-day postvaccination reporting period in the SPS, noninjection-site zoster-like rashes were reported by 53 subjects (17 for ZOSTAVAX and 36 for placebo). Of 41 specimens that were adequate for Polymerase Chain Reaction (PCR) testing, wild-type VZV was detected in 25 (5 for ZOSTAVAX, 20 for placebo) of these specimens. The Oka/Merck strain of VZV was not detected from any of these specimens.

Of reported varicella-like rashes (n=59), 10 had specimens that were available and adequate for PCR testing. VZV was not detected in any of these specimens.

In clinical trials in support of the initial licensure of the frozen formulation of ZOSTAVAX, the reported rates of noninjection-site zoster-like and varicella-like rashes within 42 days postvaccination were also low in both zoster vaccine and placebo recipients. Of 17 reported varicella-like rashes and non-injection site zoster-like rashes, 10 specimens were available and adequate for PCR testing, and 2 subjects had varicella (onset Day 8 and 17) confirmed to be Oka/Merck strain.

6.3 Post-Marketing Experience

The following additional adverse reactions have been identified during post-marketing use of ZOSTAVAX. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to the vaccine.

Gastrointestinal disorders: nausea

Infections and infestations: vaccine strain herpes zoster; disseminated vaccine strain varicella-zoster virus disease including fatal outcomes in immunocompromised patients

Skin and subcutaneous tissue disorders: rash

Musculoskeletal and connective tissue disorders: arthralgia; myalgia

General disorders and administration site conditions: injection-site rash; pyrexia; injection-site urticaria; transient injection-site lymphadenopathy

Immune system disorders: hypersensitivity reactions including anaphylactic reactions

Eye Disorders: necrotizing retinitis (patients on immunosuppressive therapy)

Nervous system disorders: Guillain-Barré syndrome; facial paralysis

Reporting Adverse Events

The U.S. Department of Health and Human Services has established a Vaccine Adverse Event Reporting System (VAERS) to accept all reports of suspected adverse events after the administration of any vaccine. For information or a copy of the vaccine reporting form, call the VAERS toll-free number at 1-800-822-7967 or report online to www.vaers.hhs.gov. {2}

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Other Vaccines

In a randomized clinical study, a reduced immune response to ZOSTAVAX as measured by gpELISA was observed in individuals who received concurrent administration of PNEUMOVAX® 23 and ZOSTAVAX compared with individuals who received these vaccines 4 weeks apart. Consider administration of the two vaccines separated by at least 4 weeks [see Clinical Studies (14.4)].

For concomitant administration of ZOSTAVAX with inactivated influenza vaccine [see Clinical Studies (14.4)].

7.2 Antiviral Medications

Concurrent administration of ZOSTAVAX and antiviral medications known to be effective against VZV has not been evaluated.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

ZOSTAVAX is contraindicated for use in pregnant women because the vaccine contains live, attenuated varicella-zoster virus, and it is known that wild-type varicella-zoster virus, if acquired during pregnancy, can cause congenital varicella syndrome [see Contraindications (4.3) and Patient Counseling Information (17)].

Available data on inadvertent administration of ZOSTAVAX to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

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.

8.2 Lactation

Risk Summary

It is not known whether varicella-zoster vaccine virus is excreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOSTAVAX, and any potential adverse effects on the breastfed child from ZOSTAVAX 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

ZOSTAVAX is not indicated for prevention of primary varicella infection (Chickenpox) and should not be used in children and adolescents.

8.5 Geriatric Use

The median age of subjects enrolled in the largest (N=38,546) clinical study of ZOSTAVAX was 69 years (range 59-99 years). Of the 19,270 subjects who received ZOSTAVAX, 10,378 were 60-69 years of age, 7,629 were 70-79 years of age, and 1,263 were 80 years of age or older.

11 DESCRIPTION

ZOSTAVAX is a lyophilized preparation of the Oka/Merck strain of live, attenuated varicella-zoster virus (VZV). ZOSTAVAX, when reconstituted as directed, is a sterile suspension for subcutaneous administration. Each 0.65-mL dose contains a minimum of 19,400 PFU (plaque-forming units) of Oka/Merck strain of VZV when reconstituted and stored at room temperature for up to 30 minutes.

Each dose contains 31.16 mg of sucrose, 15.58 mg of hydrolyzed porcine gelatin, 3.99 mg of sodium chloride, 0.62 mg of monosodium L-glutamate, 0.57 mg of sodium phosphate dibasic, 0.10 mg of potassium phosphate monobasic, 0.10 mg of potassium chloride; residual components of MRC-5 cells including DNA and protein; and trace quantities of neomycin and bovine calf serum. The product contains no preservatives.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The risk of developing zoster appears to be related to a decline in VZV-specific immunity. ZOSTAVAX was shown to boost VZV-specific immunity, which is thought to be the mechanism by which it protects against zoster and its complications. [See Clinical Studies (14).]

Herpes zoster (HZ), commonly known as shingles or zoster, is a manifestation of the reactivation of varicella zoster virus (VZV), which, as a primary infection, produces chickenpox (varicella). Following initial infection, the virus remains latent in the dorsal root or cranial sensory ganglia until it reactivates, producing zoster. Zoster is characterized by a unilateral, painful, vesicular cutaneous eruption with a dermatomal distribution.

Pain associated with zoster may occur during the prodrome, the acute eruptive phase, and the postherpetic phase of the infection. Pain occurring in the postherpetic phase of infection is commonly referred to as postherpetic neuralgia (PHN).

Serious complications, such as PHN, scarring, bacterial superinfection, allodynia, cranial and motor neuron palsies, pneumonia, encephalitis, visual impairment, hearing loss, and death can occur as the result of zoster.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

ZOSTAVAX has not been evaluated for its carcinogenic or mutagenic potential, or its potential to impair fertility.

14 CLINICAL STUDIES

In two large clinical trials (ZEST and SPS), ZOSTAVAX significantly reduced the risk of developing zoster when compared with placebo (see Table 4 and Table 5).

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

Efficacy of ZOSTAVAX was evaluated in the ZOSTAVAX Efficacy and Safety Trial (ZEST), a placebo-controlled, double-blind clinical trial in which 22,439 subjects 50 to 59 years of age were randomized to receive a single dose of either ZOSTAVAX (n=11,211) or placebo (n=11,228). Subjects were followed for the development of zoster for a median of 1.3 years (range 0 to 2 years). Confirmed zoster cases were determined by Polymerase Chain Reaction (PCR) [86%] or, in the absence of virus detection, by a Clinical Evaluation Committee [14%]. The primary efficacy analysis included all subjects randomized in the study (intent-to-treat [ITT] analysis).

Compared with placebo, ZOSTAVAX significantly reduced the risk of developing zoster by 69.8% (95% CI: 54.1, 80.6%) in subjects 50 to 59 years of age (Table 4).

Table 4: Efficacy of ZOSTAVAX on HZ Incidence Compared with Placebo in the ZOSTAVAX Efficacy and Safety Trial *
*
The analysis was performed on the intent-to-treat (ITT) population that included all subjects randomized in the ZEST study.
ZOSTAVAX Placebo
Age group (yrs.) # subjects # HZ cases Incidence rate of HZ per 1000 person-yrs. # subjects # HZ cases Incidence rate of HZ per 1000 person-yrs. Vaccine Efficacy(95% CI)
50-59 11211 30 1.994 11228 99 6.596 69.8% (54.1%, 80.6%)

Immune responses to vaccination were evaluated in a random 10% subcohort (n=1,136 for ZOSTAVAX and n=1,133 for placebo) of the subjects enrolled in the ZEST study. VZV antibody levels (Geometric Mean Titers, GMT), as measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) 6 weeks postvaccination, were increased 2.3-fold (95% CI: 2.2, 2.4) in the group of subjects who received ZOSTAVAX compared to subjects who received placebo; the specific antibody level that correlates with protection from zoster has not been established.

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