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3 Indications and Usage • ZOSTAVAX is indicated for the prevention of herpes zoster shingles in individuals 60 years of age and older.. Indications and Usage • ZOSTAVAX®[Zoster Vaccine L

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[Zoster Vaccine Live (Oka/Merck)]

Approved by the Food and Drug

Administration on May 25, 2006

• Contains no preservatives.

Description

• ZOSTAVAX®[Zoster Vaccine Live (Oka/Merck)] is a lyophilized preparation

of the Oka/Merck strain of live, attenuated VZV

• Each 0.65-mL dose of the vaccine contains a minimum of 19,400 plaque-forming

units (PFU) of attenuated virus

• Each dose also contains sucrose, hydrolyzed porcine gelatin, sodium chloride,

monosodium L-glutamate, sodium phosphate dibasic, potassium phosphate

monobasic, and potassium chloride; residual components of MRC-5 cells, including

DNA and protein, and trace quantities of neomycin and bovine

calf serum

• The product does not contain preservatives

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Indications and Usage

• ZOSTAVAX is indicated for the prevention of herpes zoster (shingles) in individuals 60 years of age and older

• ZOSTAVAX is not indicated for the treatment of zoster or postherpetic neuralgia

Indications and Usage

• ZOSTAVAX®[Zoster Vaccine Live (Oka/Merck)] is indicated for the prevention of

herpes zoster (or shingles) in individuals 60 years of age and older

• ZOSTAVAX is not indicated for the treatment of zoster or postherpetic neuralgia

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Contraindications

• ZOSTAVAX should not be administered to individuals:

– With a history of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other component of the vaccine (see WARNINGS).

– With a history of primary or acquired immunodeficiency states including leukemia; lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system;

or AIDS or other clinical manifestations of infection with human immunodeficiency viruses (see WARNINGS).

– On immunosuppressive therapy, including high-dose corticosteroids.

– With active untreated tuberculosis.

– Who are or may be pregnant (see PRECAUTIONS, Pregnancy).

Contraindications

ZOSTAVAX®[Zoster Vaccine Live (Oka/Merck)] is contraindicated in individuals who:

• Have a history of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any

other component of the vaccine (see WARNINGS)

• Have a history of primary or acquired immunodeficiency states including leukemia;

lymphomas of any type, or other malignant neoplasms affecting the bone marrow or

lymphatic system; or AIDS or other clinical manifestations of infection with human

immunodeficiency viruses (see WARNINGS)

• Are on immunosuppressive therapy, including high-dose corticosteroids

• Have active untreated tuberculosis

• Are or may be pregnant (Please refer to PRECAUTIONS, Pregnancy in the

Prescribing Information.)

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Clinical Pharmacology:

The Shingles Prevention Study Design

Oxman MN, Levin MJ, Johnson GR, et al N Engl J Med 2005;352:2271–2284.

Subjects Enrolled N=38,546

Age 60 to 69 years n=20,747

Age ≥70 years n=17,799

Zoster vaccine n=10,378

Placebo n=10,369

Zoster vaccine n=8,892

Placebo n=8,907

Adverse Event (AE) Substudy n=6,616 Immunogenicity Substudy n=1,395

Clinical Pharmacology: The Shingles Prevention Study Design

• The Shingles Prevention Study was a placebo-controlled, randomized, double-blind

study.1

• The study enrolled a total of 38,546 subjects who were 60 years of age or older.1

• Randomization was stratified by age1:

– 60 to 69 years of age

– ≥70 years of age

• Subjects were randomized to receive either a single dose of zoster vaccine (n=19,270)

or placebo (n=19,276).1

• The median follow-up of the study was 3.1 years (range 31 days to 4.9 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

• The clinical trial included 2 substudies1:

– The Adverse Event (AE) Monitoring Substudy, which comprised

6,616 subjects

– An immunogenicity substudy, which comprised 1,395 subjects

• Zoster cases were confirmed by polymerase chain reaction (93%), viral

culture (1%), or in the absence of viral detection, by the Clinical Evaluation Committee

(6%)

• Individuals in both vaccination groups who developed zoster were given famciclovir

and, as necessary, pain medications.1

Reference:

1 Oxman MN, Levin MJ, Johnson GR, et al A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

N Engl J Med 2005;352:2271–2284.

248 (1.3)

265 (1.4) Hispanic

420 (2.2)

395 (2.0) Black

18,381 (95.4) 18,393 (95.4)

White

Race n (%)

7,919 (41.1) 7,867 (40.8)

Female

11,357 (58.9) 11,403 (59.2)

Male

Gender n (%)

8,907 (46.2) 8,892 (46.1)

≥70 years

10,369 (53.8) 10,378 (53.9)

60 to 69 years

Age n (%)

Placebo Group N=19,276

Vaccine Group N=19,270 Characteristic

Oxman MN, Levin MJ, Johnson GR, et al N Engl J Med 2005;352:2271–2284.

Patient Demographics in the Shingles Prevention Study

• Baseline patient characteristics were similar in both vaccination groups

in the Shingles Prevention Study.1

– The age distribution of enrolled patients was 59 to 99 years in

both groups

– The gender distribution was 59% male and 41% female.1

– The racial distribution of white (95%), black (2%), Hispanic (1%), and other

(1%) was also similar in both groups.1

Reference:

1 Oxman MN, Levin MJ, Johnson GR, et al A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

N Engl J Med 2005;352:2271–2284.

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0 100 200 300 400 500 600 700

Placebo ZOSTAVAX

–51%

(95% CI: 44%, 58%)

Incidence rate of zoster per 1,000 person-years

11.1 5.4 10.8 3.9 11.4 6.7 12.2 9.9

Prevention of Herpes Zoster

• ZOSTAVAX®[Zoster Vaccine Live (Oka/Merck)] significantly reduced the risk of

developing zoster compared with placebo*: 315/19,254 cases (5.4 cases per 1,000

person-years) vs 642/19,247 cases [11.1 cases per 1,000 person-years]) The

protective efficacy was 51% (95% CI: 44%, 58%).1

– Vaccine efficacy for the prevention of zoster was highest for those subjects

60 to 69 years of age and declined with increasing age

– ZOSTAVAX reduced the incidence of zoster by 64% in individuals

60 to 69 years of age (ZOSTAVAX, n=10,370; placebo, n=10,356);

by 41% in individuals 70 to 79 years of age (ZOSTAVAX, n=7,621; placebo, n=7,559); and by 18% in individuals 80 years of age or

older (ZOSTAVAX, n=1,263; placebo, n=1,332)

• As with any vaccine, vaccination with ZOSTAVAX may not result in protection

of all vaccine recipients

• The duration of protection after vaccination with ZOSTAVAX is unknown In the

Shingles Prevention Study, protection from zoster was demonstrated through 4

years of follow-up The need for revaccination has not been defined

*Primary analysis was performed on the modified intent-to-treat (MITT) population that

included all randomized patients who were followed for at least 30 days postvaccination and

did not develop an evaluable case of zoster within the first 30 days postvaccination

Reference:

1 Oxman MN, Levin MJ, Johnson GR, et al A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

N Engl J Med 2005;352:2271–2284.

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Postherpetic Neuralgia* in the

Shingles Prevention Study

*Zoster-associated pain rated as ≥3 on a 10-pt scale and occurring or persisting at least 90 days after rash onset.

**Age-adjusted estimate based on the age strata (60–69 and ≥70 years of age) at randomization.

6.9 12.5

10 20 30 40 50

Postherpetic Neuralgia in the Shingles Prevention Study

• Postherpetic neuralgia was defined as zoster-associated pain (rated as ≥3 on a

10-point scale by the patient) occurring or persisting at least 90 days following the

onset of rash in evaluable cases of zoster

• Overall, the benefit of ZOSTAVAX®[Zoster Vaccine Live (Oka/Merck)] in the

prevention of postherpetic neuralgia can be primarily attributed to the effect of the

vaccine on the prevention of zoster Vaccination with ZOSTAVAX reduced the

incidence of postherpetic neuralgia in individuals 70 years of age and older who

developed zoster postvaccination

• Following completion of the Shingles Prevention Study, a separate analysis was

conducted to evaluate the reduction in PHN in the group of individuals who have

been vaccinated with ZOSTAVAX, but who had developed zoster In the analysis,

the overall efficacy of ZOSTAVAX for reduction of postherpetic neuralgia in patients

who developed zoster following vaccination was 39% (95% CI: 7%, 59%) This is an

age-adjusted estimate calculated based on the age strata of 60 to 69 and 70 years

of age and older at randomization

• The vaccine efficacy against postherpetic neuralgia in patients who developed

zoster following vaccination was 5% (95% CI: –107%, 56%) in patients 60 to 69

years of age; 55% (95% CI: 18%, 76%) in patients 70 to 79 years of age: and 26%

(95% CI: –69%, 68%) in patients 80 years of age and older

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12 57 9 12 69 9 11 7 310 (n = 659) Zoster Cases% Among

% Among Zoster Cases ( n = 321)

7 24 2 5 35 2 5 3 135

1.4 0.6

Impaired Vision

47.0 42.1

Allodynia

1.1 0.9

Bacterial Superinfection

1.7 1.6

Dissemination

10.5 10.9

Ophthalmic Zoster

1.8 1.6

Peripheral Nerve Palsies (motor)

1.4 0.6

Ptosis

8.6 7.5

Scarring

1.8 2.2

*Complications reported at a frequency of ≥1% in at least one vaccination group among patients with zoster.

Specific Complications* of Zoster Among

HZ Cases in the Shingles Prevention Study

Specific Complications of Zoster Among HZ Cases in the Shingles Prevention

Study

• The table shows the number of patients with specific complications of zoster among

zoster cases that were reported in the Shingles Prevention Study at a frequency of

≥1% in at least one vaccination group among subjects with zoster

– The number of zoster cases included the cases that developed within 30

days after vaccination

• Prespecified zoster-related complications were reported less frequently in subjects

who received ZOSTAVAX®[Zoster Vaccine Live (Oka/Merck)] compared to subjects

who received placebo

• Among HZ cases, zoster-related complications were reported at similar rates in both

vaccination groups

• 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

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Immunogenicity Substudy

*As measured by gpELISA=glycoprotein enzyme-linked immunosorbent assay.

In the Shingles Prevention Study, ZOSTAVAX elicited higher VZV-specific antibody responses at 6 weeks after vaccination compared with placebo

ZOSTAVAX Placebo

(95% CI: 1.6, 1.8)

Immunogenicity Substudy

• Immune responses to vaccination were evaluated in a subset of 1,395 subjects

enrolled in the Shingles Prevention Study

• The vaccine elicited higher VZV-specific antibody responses at 6 weeks after

vaccination compared with placebo

– There was a 1.7-fold increase in VZV antibody geometric mean titers (GMT)

as measured by gpELISA* (95% CI: 1.6, 1.8)

– The specific antibody level that correlates with protection from zoster has not

been established

*gpELISA = glycoprotein enzyme-linked immunosorbent assay

are immunosuppressed Safety and efficacy of ZOSTAVAX have not been evaluated in individuals on immunosuppressive therapy, nor in individuals receiving daily topical or inhaled corticosteroids or low-dose oral corticosteroids

• Neomycin allergy commonly manifests as a contact dermatitis, which is not a contraindication to receiving this vaccine Persons with a history of anaphylactic reaction to topically or systemically administered neomycin should not receive ZOSTAVAX (see CONTRAINDICATIONS).

• ZOSTAVAX is not a substitute for VARIVAX* [Varicella Virus Vaccine Live (Oka/Merck)] and should not be used in children.

*Registered trademark of Merck & Co., Inc.

Warnings

• Vaccination with a live attenuated vaccine, such as ZOSTAVAX®[Zoster Vaccine

Live (Oka/Merck)], may result in a more extensive vaccine-associated rash or

disseminated disease in individuals who are immunosuppressed

• Safety and efficacy of ZOSTAVAX have not been evaluated in individuals on

immunosuppressive therapy, nor in individuals receiving daily topical or inhaled

corticosteroids or low-dose oral corticosteroids

• Neomycin allergy commonly manifests as a contact dermatitis, which is not a

contraindication to receiving this vaccine Persons with a history of anaphylactic

reaction to topically or systemically administered neomycin should not receive

ZOSTAVAX (see CONTRAINDICATIONS)

• ZOSTAVAX is not a substitute for VARIVAX* [Varicella Virus Vaccine Live

(Oka/Merck)] and should not be used in children

*Registered trademark of Merck & Co., Inc

– Deferral of vaccination should be considered in acute illness (eg, fever >38.5°C [>101.3°F])

– The duration of protection is unknown In the Shingles Prevention Study, protection from zoster was demonstrated through 4 years

of follow-up The need for revaccination has not been defined.

– As with any vaccine, vaccination with ZOSTAVAX may not result in protection of all

vaccine recipients.

– The use of ZOSTAVAX in individuals with a previous history

of zoster has not been studied.

Selected Precautions

• As with any vaccine, adequate treatment provisions, including epinephrine injection

(1:1000), should be available for immediate use should an

anaphylactic/anaphylactoid reaction occur

• Deferral of vaccination should be considered in acute illness (eg, fever >38.5°C

[>101.3°F])

• The duration of protection after vaccination with ZOSTAVAX®[Zoster Vaccine Live

(Oka/Merck)] is unknown In the Shingles Prevention Study, protection from zoster

was demonstrated through 4 years of follow-up The need for revaccination has not

– Transmission of vaccine virus from varicella vaccine recipients without a VZV-like rash has been reported but has not been confirmed

– The risk of transmitting the attenuated vaccine virus to a susceptible individual should be weighed against the risk of developing natural zoster that could be transmitted to a susceptible individual

– Vaccinees should be informed of the theoretical risk of transmitting the vaccine virus to varicella-susceptible individuals, including pregnant women who have not had chickenpox.

Selected Precautions (cont)

• Transmission of the vaccine virus has not been reported in clinical trials

• Postmarketing experience with varicella vaccines suggests that transmission of

vaccine virus may occur rarely between vaccinees who develop a varicella-like rash

and susceptible contacts

• Transmission of vaccine virus from varicella vaccine recipients without a VZV-like

rash has been reported but has not been confirmed

• The risk of transmitting the attenuated vaccine virus to a susceptible individual

should be weighed against the risk of developing natural zoster that could be

transmitted to a susceptible individual

• Vaccinees should be informed of the theoretical risk of transmitting the vaccine virus

to varicella-susceptible individuals, including pregnant women who have not had

chickenpox