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 MRC5 cells including DNA and protein; and trace quantities of neomycin and bovine calf serum. The product contains no preservatives.
|
CLINICAL PHARMACOLOGY
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.]
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.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
ZOSTAVAX has not been evaluated for its carcinogenic or mutagenic potential, or its potential to impair fertility.
|
CLINICAL STUDIES
Efficacy of ZOSTAVAX was evaluated in the Shingles Prevention Study (SPS), a placebo-controlled, double-blind clinical trial in which 38,546 subjects 60 years of age or older were randomized to receive a single dose of either ZOSTAVAX (n=19,270) or placebo (n=19,276). Subjects were followed for the development of zoster for a median of 3.1 years (range 31 days to 4.90 years). The study excluded people who were immunocompromised or using corticosteroids on a regular basis, anyone with a previous history of HZ, and those with conditions that might interfere with study evaluations, including people with cognitive impairment, severe hearing loss, those who were non-ambulatory and those whose survival was not considered to be at least 5 years. Randomization was stratified by age, 60-69 and ≥70 years of age. Suspected zoster cases were confirmed by Polymerase Chain Reaction (PCR) [93%], viral culture [1%], or in the absence of viral detection, as determined by the Clinical Evaluation Committee [6%]. Individuals in both vaccination groups who developed zoster were given famciclovir, and, as necessary, pain medications. The primary efficacy analysis included all subjects randomized in the study who were followed for at least 30 days postvaccination and did not develop an evaluable case of HZ within the first 30 days postvaccination (Modified Intent-To-Treat [MITT] analysis).
ZOSTAVAX significantly reduced the risk of developing zoster when compared with placebo (Table 3). Vaccine efficacy for the prevention of HZ was highest for those subjects 60-69 years of age and declined with increasing age.
Table 3: Efficacy of ZOSTAVAX on HZ Incidence Compared with Placebo in the Shingles Prevention Study
Age group
(yrs.) | ZOSTAVAX | Placebo |
Vaccine Efficacy
(95% CI)
|
# subjects | # HZ cases | Incidence rate of HZ per 1000 person-yrs. | # subjects | # HZ cases | Incidence rate of HZ per 1000 person-yrs. |
Overall | 19254 | 315 | 5.4 | 19247 | 642 | 11.1 | 51% (44%, 58%) |
60-69 | 10370 | 122 | 3.9 | 10356 | 334 | 10.8 | 64% (56%, 71%) |
70-79 | 7621 | 156 | 6.7 | 7559 | 261 | 11.4 | 41% (28%, 52%) |
≥80 | 1263 | 37 | 9.9 | 1332 | 47 | 12.2 | 18% (-29%, 48%) |
Forty-five subjects were excluded from the MITT analysis (16 in the group of subjects who received ZOSTAVAX and 29 in the group of subjects who received placebo), including 24 subjects with evaluable HZ cases that occurred in the first 30 days postvaccination (6 evaluable HZ cases in the group of subjects who received ZOSTAVAX and 18 evaluable HZ cases in the group of subjects who received placebo).
Suspected HZ cases were followed prospectively for the development of HZ-related complications. Table 4 compares the rates of PHN defined as HZ-associated pain (rated as 3 or greater on a 10-point scale by the study subject and occurring or persisting at least 90 days) following the onset of rash in evaluable cases of HZ.
Table 4: Postherpetic Neuralgia (PHN)
in the Shingles Prevention Study
Age group (yrs.)
| ZOSTAVAX | Placebo |
Vaccine efficacy against PHN in subjects who develop HZ postvaccination
(95% CI)
|
# subjects | # HZ cases | # PHN cases | Incidence rate of PHN per 1,000 person-yrs. | % HZ cases with PHN | # subjects | # HZ cases | # PHN cases | Incidence rate of PHN per 1,000 person-yrs. | % HZ cases with PHN |
Overall | 19254 | 315 | 27 | 0.5 | 8.6% | 19247 | 642 | 80 | 1.4 | 12.5% |
39%
(7%, 59%) |
60-69 | 10370 | 122 | 8 | 0.3 | 6.6% | 10356 | 334 | 23 | 0.7 | 6.9% |
5%
(-107%, 56%) |
70-79 | 7621 | 156 | 12 | 0.5 | 7.7% | 7559 | 261 | 45 | 2.0 | 17.2% |
55%
(18%, 76%) |
≥80 | 1263 | 37 | 7 | 1.9 | 18.9% | 1332 | 47 | 12 | 3.1 | 25.5% |
26%
(-69%, 68%) |
The median duration of clinically significant pain (defined as ≥3 on a 0-10 point scale) among HZ cases in the group of subjects who received ZOSTAVAX as compared to the group of subjects who received placebo was 20 days vs. 22 days based on the confirmed HZ cases.
Overall, the benefit of ZOSTAVAX in the prevention of PHN can be primarily attributed to the effect of the vaccine on the prevention of herpes zoster. Vaccination with ZOSTAVAX in the SPS reduced the incidence of PHN in individuals 70 years of age and older who developed zoster postvaccination. Other prespecified zoster-related complications were reported less frequently in subjects who received ZOSTAVAX compared to subjects who received placebo. Among HZ cases, zoster-related complications were reported at similar rates in both vaccination groups (Table 5).
Table 5: Specific complications
of zoster among HZ cases in the Shingles Prevention Study
Complication
|
ZOSTAVAX
(N = 19,270)
|
Placebo
(N = 19,276)
|
|
(n = 321)
|
% Among
Zoster Cases |
(n = 659)
|
% Among
Zoster Cases |
N=number of subjects randomized n=number of zoster cases, including those cases occurring within 30 days postvaccination, with these data available |
Allodynia | 135 | 42.1 | 310 | 47.0 |
Bacterial Superinfection | 3 | 0.9 | 7 | 1.1 |
Dissemination | 5 | 1.6 | 11 | 1.7 |
Impaired Vision | 2 | 0.6 | 9 | 1.4 |
Ophthalmic Zoster | 35 | 10.9 | 69 | 10.5 |
Peripheral Nerve Palsies (motor) | 5 | 1.6 | 12 | 1.8 |
Ptosis | 2 | 0.6 | 9 | 1.4 |
Scarring | 24 | 7.5 | 57 | 8.6 |
Sensory Loss | 7 | 2.2 | 12 | 1.8 |
Visceral complications reported by fewer than 1% of subjects with zoster included 3 cases of pneumonitis and 1 case of hepatitis in the placebo group, and 1 case of meningoencephalitis in the vaccine group.
Immune responses to vaccination were evaluated in a subset of subjects enrolled in the Shingles Prevention Study (N=1395). VZV antibody levels (Geometric Mean Titers, GMT), as measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) 6 weeks postvaccination, were increased 1.7-fold (95% CI: [1.6 to 1.8]) 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.
In a double-blind, controlled substudy, 374 adults in the US, 60 years of age and older (median age = 66 years), were randomized to receive trivalent inactivated influenza vaccine (TIV) and ZOSTAVAX concurrently (N=188), or TIV alone followed 4 weeks later by ZOSTAVAX alone (N=186). The antibody responses to both vaccines at 4 weeks postvaccination were similar in both groups.
|