Quantcast

CDC Recommends ZOSTAVAX(R), Merck’s Shingles Vaccine, for All Appropriate Adults Aged 60 and Older

May 15, 2008

The U.S. Centers for Disease Control and Prevention (CDC) has adopted the unanimous recommendation of its Advisory Committee on Immunization Practices (ACIP) for the use of ZOSTAVAX(R) (Zoster Vaccine Live) for the prevention of shingles in adults aged 60 and older. ZOSTAVAX is the only vaccine to prevent shingles, a frequently painful disease marked by a blistering rash that is caused by the reactivation of the chickenpox virus. These final vaccination guidelines were published online today in the CDC’s Morbidity and Mortality Weekly Report (MMWR) and are now available to health care providers.

ZOSTAVAX is indicated for the prevention of herpes zoster (shingles) in people 60 years of age and older. The ACIP recommendations call for routine vaccination of all appropriate people 60 years of age and older with a single dose of ZOSTAVAX (referred to in the guidelines as zoster vaccine). According to the recommendations, people who report a previous episode of shingles and people with chronic medical conditions (e.g., chronic renal failure, diabetes mellitus, rheumatoid arthritis, chronic pulmonary disease) can be vaccinated unless those conditions or other conditions the person may have are contraindications or precautions. ZOSTAVAX is not indicated for the treatment of shingles or the persistent nerve pain that can follow shingles in some people, called postherpetic neuralgia, or PHN. The recommendations also specify that ZOSTAVAX should not be used to prevent people who have shingles from developing PHN. According to the recommendations, before routine administration of ZOSTAVAX, it is not necessary to ask patients about their history of varicella (chickenpox) or to conduct serologic (blood) tests for varicella immunity. Shingles vaccination is also included on the CDC’s 2007-2008 Recommended Adult Immunization Schedule.

“Many adults do not realize that shingles is caused by the same virus that causes chickenpox. Therefore, anyone who has had chickenpox — and more than 90 percent of adults in America have — is at risk for shingles,” said William Schaffner, MD, professor and chairman, Department of Preventive Medicine and professor, Division of Infectious Diseases, Vanderbilt University School of Medicine, and vice president, National Foundation for Infectious Diseases (NFID). “Shingles can be painful. For most people, the pain associated with the shingles rash lessens as the rash heals, but for some adults shingles may lead to pain that can last for months or even years. Health care providers should review this recommendation and discuss the use of ZOSTAVAX for the prevention of shingles with their appropriate patients aged 60 and older.”

More than 43 million adults over the age of 60 in the U.S. are estimated to be at risk for shingles. One out of two people who live to age 85 will have had the disease. Yet, according to results from the CDC’s 2007 National Immunization Survey, relatively few adults are getting vaccinated against shingles and other potentially serious infectious diseases. Also, earlier this year, the National Foundation of Infectious Diseases (NFID) released a survey showing that, aside from the flu, most adults have trouble naming diseases that they might be able to prevent by getting vaccinated. This NFID survey found that only four percent of adults surveyed were aware that a vaccine can help prevent shingles.

ZOSTAVAX is contraindicated in persons with a history of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other component of the vaccine; 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 with AIDS or other clinical manifestations of infection with human immunodeficiency viruses. ZOSTAVAX is a live attenuated varicella-zoster vaccine and administration may result in disseminated disease in individuals who are immunosuppressed. ZOSTAVAX is also contraindicated in persons on immunosuppressive therapy. ZOSTAVAX is not indicated in women of childbearing age and should not be administered to pregnant females.

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

Health care providers should question vaccine recipients about reactions to previous vaccines. Health care providers should also inform vaccine recipients of the benefits and risks of ZOSTAVAX. Patients should be provided with a copy of the Patient Information about ZOSTAVAX, and be given an opportunity to discuss any questions or concerns.

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

About Shingles

In people who have had chickenpox, shingles can occur at any time, without warning. The risk for shingles increases as people get older. The first signs of shingles are often felt and may not be seen, and may include itching, tingling, or burning. A few days later, a rash of fluid-filled blisters appears, usually on one side of the body or face. The blisters may take two to four weeks to heal. The rash can be painful, with the pain ranging from mild to severe. For most people, the pain from the shingles rash lessens as it heals. But for some people, shingles can cause long-term nerve pain, called postherpetic neuralgia, or PHN. This persistent nerve pain has been described as burning, stabbing, throbbing, or shooting pain. Other problems that may result from shingles include skin infection, muscle weakness, scarring, and decrease or loss of vision or hearing. There are approximately one million cases of shingles in the U.S. each year – an estimated half of which occur in people 60 years and older.

Access and Reimbursement for ZOSTAVAX

Over 50,000 physicians’ offices, pharmacies and public health clinics have ordered ZOSTAVAX since FDA approval. Approximately 3,000 pharmacies are currently participating in the Merck Adult Vaccination Program. This program, designed to help expand access to adult vaccines, including ZOSTAVAX, assists health care providers who want to refer patients to a pharmacy or vaccine service provider location that provides adult vaccinations. Physicians, other health care providers, and consumers can search for participating locations by visiting MerckAdultVaccinationLocator.com or by calling Merck at 1-800-261-5579.

Health plans covering approximately 94 percent of privately-insured lives in the U.S. have approved reimbursement for ZOSTAVAX. Additionally, ZOSTAVAX is eligible for reimbursement under the Medicare Part D prescription drug benefit, and plans covering more than 90 percent of Part D enrollees are reimbursing for ZOSTAVAX. However, individual coverage and reimbursement for privately insured lives and Part D enrollees are subject to the individual’s benefit design, including any applicable co-pays, co-insurance and/or deductibles. People 60 and older are encouraged to contact their insurance provider to inquire about their coverage for ZOSTAVAX.

The U.S. Veterans Health Administration makes ZOSTAVAX available to veterans who are patients at VA medical facilities nationwide. Also, TRICARE, the health care plan for the U.S. Department of Defense Military Health System, made ZOSTAVAX a covered medical benefit for plan beneficiaries ages 60 and older. TRICARE administers the health care plan for the uniformed services, retirees and their families.

ZOSTAVAX is part of Merck’s Vaccine Patient Assistance Program in the U.S. Through this program, currently available in private physicians’ offices and private clinics, Merck makes available, free of charge, ZOSTAVAX and other Merck vaccines indicated for use in eligible individuals ages 19 and older, to people who are uninsured and who are unable to afford vaccines. For more information on the Merck Vaccine Patient Assistance Program, go to www.merckhelps.com.

Selected Important Information about ZOSTAVAX

ZOSTAVAX is a live attenuated virus vaccine indicated for prevention of herpes zoster (shingles) in individuals 60 years of age and older. ZOSTAVAX is not indicated for the treatment of zoster or PHN.

ZOSTAVAX is contraindicated in persons with a history of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other component of the vaccine; 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 with AIDS or other clinical manifestations of infection with human immunodeficiency viruses. ZOSTAVAX is a live attenuated varicella-zoster vaccine and administration may result in disseminated disease in individuals who are immunosuppressed. ZOSTAVAX is also contraindicated in persons on immunosuppressive therapy. ZOSTAVAX is not indicated in women of childbearing age and should not be administered to pregnant females.

Transmission of vaccine virus may occur rarely between vaccinees and susceptible contacts. ZOSTAVAX is not indicated for prevention of primary varicella infection (chickenpox). Vaccination with ZOSTAVAX may not result in protection of all vaccine recipients.

Vaccine-related, injection-site and systemic adverse experiences in =>1 percent of individuals in the Adverse Event Monitoring Substudy (AEMS), a subgroup of individuals from the Shingles Prevention Study (SPS) who received ZOSTAVAX (n=3,345), included headache (1.4 percent) and the following injection-site reactions: erythema (33.7 percent), pain/tenderness (33.4 percent), swelling (24.9 percent), hematoma (1.4 percent), pruritus (6.6 percent), and warmth (1.5 percent). Most of these adverse experiences were reported as mild in intensity.

From Day zero to 42 post vaccination, in the overall study population, serious adverse experiences (SAEs) occurred at a similar rate (1.4 percent) in subjects vaccinated with ZOSTAVAX or placebo. In the AEMS, the rate of SAEs was increased in the group who received ZOSTAVAX (1.9 percent) as compared to the placebo group (1.3 percent) from Day zero to 42 post vaccination. Over the course of the entire study, in the overall study population, investigator-determined, vaccine-related serious adverse experiences were reported for two subjects vaccinated with ZOSTAVAX (asthma exacerbation and polymyalgia rheumatica) and three subjects who received placebo (Goodpasture’s syndrome, anaphylactic reaction, and polymyalgia rheumatica).

Among reported serious adverse events in the SPS (Days 0-42 post vaccination), serious cardiovascular events occurred more frequently in subjects who received ZOSTAVAX (20 (0.6 percent)) than in subjects who received placebo (12 (0.4 percent)) in the AEMS. The frequencies of serious cardiovascular events were similar in subjects who received ZOSTAVAX (81 (0.4 percent)) and in subjects who received placebo (72 (0.4 percent)) in the entire SPS study cohort (Days 0-42 post vaccination).

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

Forward-Looking Statement

This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management’s current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck’s business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck’s Form 10-K for the year ended Dec. 31, 2007, and in any risk factors or cautionary statements contained in the Company’s periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

Prescribing information and patient product information for ZOSTAVAX(R) is attached and is also available at www.zostavax.com.

Product photos and photos of people being vaccinated with ZOSTAVAX(R) are available at www.pimsmultimedia.com/ZOSTAVAX.

ZOSTAVAX(R) is a registered trademark of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A.

You should read this summary of information about ZOSTAVAX(1) before you are vaccinated. If you have any questions about ZOSTAVAX after reading this leaflet, you should ask your health care provider. This information does not take the place of talking about ZOSTAVAX with your doctor, nurse, or other health care provider. Only your health care provider can decide if ZOSTAVAX is right for you.

What is ZOSTAVAX and how does it work?

ZOSTAVAX is a vaccine that is used for adults 60 years of age or older to prevent shingles (also known as zoster).

ZOSTAVAX contains a weakened chickenpox virus (varicella-zoster virus).

ZOSTAVAX works by helping your immune system protect you from getting shingles. If you do get shingles even though you have been vaccinated, ZOSTAVAX may help prevent the nerve pain that can follow shingles in some people.

ZOSTAVAX may not protect everyone who gets the vaccine. ZOSTAVAX cannot be used to treat shingles once you have it.

What do I need to know about shingles and the virus that causes it?

Shingles is caused by the same virus that causes chickenpox. Once you have had chickenpox, the virus can stay in your nervous system for many years. For reasons that are not fully understood, the virus may become active again and give you shingles. Age and problems with the immune system may increase your chances of getting shingles.

Shingles is a rash that is usually on one side of the body. The rash begins as a cluster of small red spots that often blister. The rash can be painful. Shingles rashes usually last up to 30 days and, for most people, the pain associated with the rash lessens as it heals.

Who should not get ZOSTAVAX?

You should not get ZOSTAVAX if you:

— are allergic to any of its ingredients.

— are allergic to gelatin or neomycin.

— have a weakened immune system (for example, an immune deficiency, leukemia, lymphoma, or HIV/AIDS).

— take high doses of steroids by injection or by mouth.

— are pregnant or plan to get pregnant.

You should not get ZOSTAVAX to prevent chickenpox.

Children should not get ZOSTAVAX.

How is ZOSTAVAX given?

ZOSTAVAX is given as a single dose by injection under the skin.

What should I tell my health care provider before I get ZOSTAVAX?

You should tell your health care provider if you:

— have or have had any medical problems.

— take any medicines, including non-prescription medicines, and dietary supplements.

— have any allergies, including allergies to neomycin or gelatin.

— had an allergic reaction to another vaccine.

— are pregnant or plan to become pregnant.

— are breast-feeding.

Tell your health care provider if you expect to be in close contact (including household contact) with newborn infants, someone who may be pregnant and has not had chickenpox or been vaccinated against chickenpox, or someone who has problems with their immune system. Your health care provider can tell you what situations you may need to avoid.

What are the possible side effects of ZOSTAVAX?

The most common side effects that people in the clinical studies reported after receiving the vaccine include:

— redness, pain, itching, swelling, warmth, or bruising where the shot was given.

— headache.

The following additional side effects have been reported in general use with ZOSTAVAX:

— allergic reactions, which may be serious and may include difficulty in breathing or swallowing. If you have an allergic reaction, call your doctor right away.

— fever.

Tell your healthcare provider if you have any new or unusual symptoms after you receive ZOSTAVAX.

What are the ingredients of ZOSTAVAX?

Active Ingredient: a weakened form of the varicella-zoster virus.

Inactive Ingredients: sucrose, hydrolyzed porcine gelatin, sodium chloride, monosodium L-glutamate, sodium phosphate dibasic, potassium phosphate monobasic, potassium chloride.

What else should I know about ZOSTAVAX?

Vaccinees and their health care providers are encouraged to call (800) 986-8999 to report any exposure to ZOSTAVAX during pregnancy.

This leaflet summarizes important information about ZOSTAVAX.

If you would like more information, talk to your health care provider or visit the website at www.ZOSTAVAX.com or call 1-800-622-4477.

Rx Only

Issued November 2007

Dist. by: Merck & Co., Inc.

(1) Registered trademark of Merck & Co., Inc. Copyright (C) 2006 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserved

ZOSTAVAX(R)

Zoster Vaccine Live 9815604

9815604

(1) Registered trademark of Merck & Co., Inc.

Copyright (C) 2006 Merck & Co., Inc.

Whitehouse Station, NJ, USA

All rights reserved

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ZOSTAVAX(1) safely and effectively. See full prescribing information for ZOSTAVAX.

ZOSTAVAX(R)

Zoster Vaccine Live

Lyophilized preparation for subcutaneous injection

Initial U.S. Approval: 2006

INDICATIONS AND USAGE

ZOSTAVAX is a live attenuated virus vaccine indicated for prevention of herpes zoster (shingles) in individuals 60 years of age and older (1).

ZOSTAVAX is not indicated for the treatment of zoster or postherpetic neuralgia (PHN) (1).

DOSAGE AND ADMINISTRATION

Single 0.65 mL subcutaneous injection (2.1)

DOSAGE FORMS AND STRENGTHS

A lyophilized preparation for reconstitution containing not less than 19,400 plaque-forming units (PFU) per 0.65 mL dose supplied as single dose vials (2.1, 3, 16).

CONTRAINDICATIONS

— History of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other component of the vaccine (4.1).

— History of primary or acquired immunodeficiency states (4.2).

— On immunosuppressive therapy (4.2).

— ZOSTAVAX is not indicated in women of child-bearing age and should not be administered to pregnant females (4.3, 8.1, 17.1).

WARNINGS AND PRECAUTIONS

— ZOSTAVAX is not indicated for prevention of primary varicella infection (Chickenpox) (5.2, 8.4).

— Transmission of vaccine virus may occur rarely between vaccinees and susceptible contacts (5.1).

— Defer vaccination in patients with active untreated tuberculosis (5.5).

ADVERSE REACTIONS

The rate of serious adverse events (SAEs) from Days 0 to 42 postvaccination may be increased in recipients of ZOSTAVAX compared to recipients of placebo (Table 1, 6.1.1).

The most frequent vaccine-related adverse events, reported in =>1% of subjects vaccinated with ZOSTAVAX, were headache and injection site reactions (6.1.1).

To report vaccine exposure during pregnancy call 1-800-986-8999.

To report SUSPECTED ADVERSE REACTIONS, contact Merck & Co., Inc. at 1-877-888-4231 or VAERS at 1-800-822-7967 and www.fda.gov/vaers.

See 17 for PATIENT COUNSELING INFORMATION and FDA-Approved Patient Labeling.

Revised: 11/2007

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose and Schedule

2.2 Preparation for Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Hypersensitivity

4.2 Immunosuppression

4.3 Pregnancy

5 WARNINGS AND PRECAUTIONS

5.1 Transmission of Vaccine Virus

5.2 Primary Varicella Disease

5.3 Preventing and Managing Allergic Vaccine Reactions

5.4 Limitations of Vaccine Effectiveness

5.5 Concurrent Illness

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-Marketing Experience

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Other Vaccines

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Instructions

17.2 FDA-Approved Patient Labeling

*SECTIONS OR SUBSECTIONS OMITTED FROM THE FULL PRESCRIBING INFORMATION ARE NOT LISTED.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

ZOSTAVAX is a live attenuated virus vaccine indicated for 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 (PHN).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose and Schedule

ZOSTAVAX should be administered as a single 0.65 mL dose subcutaneously in the deltoid region of the upper arm.

Do not inject intravascularly or intramuscularly. 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.

2.2 Preparation for Administration

ZOSTAVAX is stored frozen and should be reconstituted immediately upon removal from the freezer. The diluent should be stored separately at room temperature or in the refrigerator.

Use separate sterile needles for reconstitution and administration of ZOSTAVAX.

To reconstitute the vaccine: Use only the diluent supplied. Withdraw the entire contents of the diluent into a syringe. Inject all of the diluent in the syringe into the vial of lyophilized vaccine and gently agitate to mix thoroughly.

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

Withdraw the entire contents of reconstituted vaccine into a syringe and inject the total volume subcutaneously.

THE VACCINE SHOULD BE ADMINISTERED IMMEDIATELY AFTER RECONSTITUTION, TO MINIMIZE LOSS OF POTENCY.

DISCARD RECONSTITUTED VACCINE IF IT IS NOT USED WITHIN 30 MINUTES.

DO NOT FREEZE RECONSTITUTED VACCINE.

Needles should be disposed of properly and should not be recapped.

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 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. ZOSTAVAX is a live attenuated varicella-zoster vaccine and administration may result in disseminated disease in individuals who are immunosuppressed. Do not administer ZOSTAVAX to individuals on immunosuppressive therapy.

4.3 Pregnancy

ZOSTAVAX is not indicated in women of child-bearing age and should not be administered to pregnant females (see Pregnancy (8.1)).

5 WARNINGS AND PRECAUTIONS

5.1 Transmission of Vaccine Virus

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

5.2 Primary Varicella Disease

ZOSTAVAX is not indicated for prevention of primary varicella infection (Chickenpox).

5.3 Preventing and Managing Allergic Vaccine Reactions

As with any vaccine, adequate treatment provisions, including epinephrine injection (1:1000), should be available for immediate use should an anaphylactic/anaphylactoid reaction occur.

5.4 Limitations of Vaccine Effectiveness

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

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

5.5 Concurrent Illness

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

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse event 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 practice.

6.1.1 Shingles Prevention Study

In clinical trials, ZOSTAVAX has been evaluated for safety in approximately 21,000 adults. In the largest of these trials, the Shingles Prevention Study (SPS), 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 1).

 Table 1 Number of Subjects with =>1 Serious Adverse Events (0-42 Days Postvaccination) in the Shingles Prevention Study  ZOSTAVAX   Placebo n/N       n/N     Relative %         %         Risk Cohort                                                      (95% CI) ---------------------------------------------------------------------- Overall Study Cohort                  255/18671 254/18717     1.01 (all ages)                              1.4%      1.4%    (0.85, 1.20) ---------------------------------------------------------------------- 60-69 years old                   113/10100 101/10095     1.12 1.1%      1.0%    (0.86, 1.46) 70-79 years old                   115/7351  132/7333      0.87 1.6%      1.8%    (0.68, 1.11) =>80 years old                     27/1220   21/1289      1.36 2.2%      1.6%    (0.78, 2.37) ---------------------------------------------------------------------- AE Monitoring Substudy Cohort          64/3326   41/3249      1.53 (all ages)                              1.9%      1.3%    (1.04, 2.25) ---------------------------------------------------------------------- 60-69 years old                    22/1726   18/1709      1.21 1.3%      1.1%    (0.66, 2.23) 70-79 years old                    31/1383   19/1367      1.61 2.2%      1.4%    (0.92, 2.82) =>80 years old                     11/217     4/173       2.19 5.1%      2.3%    (0.75, 6.45) ---------------------------------------------------------------------- N=number of subjects in cohort with safety follow-up n=number of subjects reporting an SAE 0-42 Days postvaccination 

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

Adverse Events Reported in the AE Monitoring Substudy of the SPS

Injection-site and systemic adverse events reported at an incidence =>1% are shown in Table 2. Most of these adverse events 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 2 Injection-Site and Systemic Adverse Experiences Reported by Vaccine Report Card in =>1% of Adults Who Received ZOSTAVAX or Placebo (0-42 Days Postvaccination) in the AE Monitoring Substudy of the Shingles Prevention Study  ZOSTAVAX             Placebo  (N = 3345)          (N = 3271) Adverse Experience                     %                    % ---------------------------------------------------------------------- Injection Site Erythema+                         33.7                 6.4 Pain/tenderness+                  33.4                 8.3 Swelling+                         24.9                 4.3 Hematoma                          1.4                  1.4 Pruritus                          6.6                  1.0 Warmth                            1.5                  0.3 ---------------------------------------------------------------------- Systemic Headache                          1.4                  0.8 ---------------------------------------------------------------------- + Designates a solicited adverse experience. Injection-site adverse experiences were solicited only from Days 0-4 postvaccination. 

The numbers of subjects with elevated temperature (=>38.3(degree)C (=>101.0(degree)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%)).

6.1.2 VZV Rashes Following Vaccination

Within the 42-day post vaccination reporting period in the SPS, non-injection-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 noninjection-site, zoster-like rashes, 10 specimens were available and adequate for PCR testing. The Oka/Merck strain was identified by PCR analysis from the lesion specimens of two subjects who reported varicella-like rashes (onset on Day 8 and 17).

6.2 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.

General disorders and administration site conditions: pyrexia.

Immune system disorders: hypersensitivity reactions including anaphylactic reactions.

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

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

7.1 Concomitant Administration with Other Vaccines

For administration of ZOSTAVAX with trivalent inactivated influenza vaccine, (see Clinical Studies (14)).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C: Animal reproduction studies have not been conducted with ZOSTAVAX. It is also not known whether ZOSTAVAX can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. However, naturally occurring VZV infection is known to sometimes cause fetal harm. ZOSTAVAX is not indicated in women of child-bearing age and should not be administered to pregnant females.

Vaccinees and health care providers are encouraged to report any exposure to ZOSTAVAX during pregnancy by calling (800) 986-8999.

8.3 Nursing Mothers

ZOSTAVAX is not indicated in women who are nursing. It is not known whether VZV is secreted in human milk. Therefore, because some viruses are secreted in human milk, caution should be exercised if ZOSTAVAX is administered to a nursing woman.

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 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

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*   ZOSTAVAX ------------------------------- Age group**                  #     # HZ   Incidence rate (yrs.)                 subjects cases    of HZ per 1000 person-yrs. ---------------------------------------------------------------------- Overall                                 19254    315        5.4 ---------------------------------------------------------------------- 60-69                                   10370    122        3.9 ---------------------------------------------------------------------- 70-79                                    7621    156        6.7 ---------------------------------------------------------------------- =>80                                     1263    37         9.9 ----------------------------------------------------------------------  Placebo -------------------------------- Age group**          #     # HZ   Incidence rate     Vaccine (yrs.)         subjects cases    of HZ per         Efficacy 1000 person-yrs.    (95% CI) ---------------------------------------------------------------------- Overall                 19247    642        11.1       51% (44%, 58%) ---------------------------------------------------------------------- 60-69                   10356    334        10.8       64% (56%, 71%) ---------------------------------------------------------------------- 70-79                    7559    261        11.4       41% (28%, 52%) ---------------------------------------------------------------------- =>80                     1332    47         12.2       18% (-29%, 48%) ----------------------------------------------------------------------  * The analysis was performed on the Modified Intent-To-Treat (MITT) population that 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. ** Age strata at randomization were 60-69 and =>70 years of age. 

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**   ZOSTAVAX -------------------------------------- Age group               #     # HZ  # PHN  Incidence  % HZ (yrs.) +             subjects cases cases   rate of   cases PHN per   with 1,000     PHN person-yrs. ---------------------------------------------------------------------- Overall                          19254    315   27       0.5     8.6% ---------------------------------------------------------------------- 60-69                            10370    122    8       0.3     6.6% ---------------------------------------------------------------------- 70-79                             7621    156   12       0.5     7.7% ---------------------------------------------------------------------- =>80                              1263    37     7       1.9     18.9% ----------------------------------------------------------------------  Placebo --------------------------------------- Age group       #     # HZ  # PHN  Incidence  % HZ  Vaccine efficacy (yrs.) +    subjects cases cases   rate of   cases  against PHN in PHN per   with    subjects who 1,000     PHN     develop HZ person-yrs.       postvaccination (95% CI) ---------------------------------------------------------------------- Overall                                                    39%++ 19247    642   80       1.4     12.5%    (7%, 59%) ---------------------------------------------------------------------- 5% 60-69           10356    334   23       0.7     6.9%    (-107%, 56%) ---------------------------------------------------------------------- 55% 70-79            7559    261   45       2.0     17.2%    (18%, 76%) ---------------------------------------------------------------------- =>80                                                        26% 1332    47    12       3.1     25.5%   (-69%, 68%) ----------------------------------------------------------------------  * PHN was defined as HZ-associated pain rated as =>3 (on a 0-10 scale), persisting or appearing more than 90 days after onset of HZ rash using Zoster Brief Pain Inventory (ZBPI)(3). ** The table is based on the Modified Intent-To-Treat (MITT) population that 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. + Age strata at randomization were 60-69 and =>70 years of age. ++ Age-adjusted estimate based on the age strata (60-69 and =>70 years of age) at randomization. 

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  ZOSTAVAX               Placebo Complication                  (N = 19,270)           (N = 19,276) ---------------------------------------------------------------------- % Among                % Among (n = 321) Zoster Cases (n = 659) Zoster Cases ---------------------------------------------------------------------- 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 ---------------------------------------------------------------------- N=number of subjects randomized n=number of zoster cases, including those cases occurring within 30 days postvaccination, with these data available * Complications reported at a frequency of =>1% in at least one vaccination group among subjects with zoster. 

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.

15 REFERENCES

1. Reitschel RL, Bernier R. Neomycin sensitivity and the MMR vaccine. JAMA 1981;245(6):571.

2. Atkinson WL, Pickering LK, Schwartz B, Weniger BG, Iskander JK, Watson JC. General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR 2002;51(RR02):1-36.

3. Coplan PM, Schmader K, Nikas A, Chan ISF, Choo P, Levin MJ, et al. Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: Adaptation of the brief pain inventory. J Pain 2004;5(6):344-56.

16 HOW SUPPLIED/STORAGE AND HANDLING

No. 4963-00 — ZOSTAVAX is supplied as follows: (1) a package of 1 single-dose vial of lyophilized vaccine, NDC 0006-4963-00 (package A); and (2) a separate package of 10 vials of diluent (package B).

No. 4963-41 — ZOSTAVAX is supplied as follows: (1) a package of 10 single-dose vials of lyophilized vaccine, NDC 0006-4963-41 (package A); and (2) a separate package of 10 vials of diluent (package B).

Handling and Storage

During shipment, to ensure that there is no loss of potency, the vaccine must be maintained at a temperature of -15(degree)C (+5(degree)F) or colder.

ZOSTAVAX SHOULD BE STORED FROZEN at an average temperature of -15(degree)C (+5(degree)F) or colder until it is reconstituted for injection. Any freezer, including frost-free, that has a separate sealed freezer door and reliably maintains an average temperature of -15(degree)C or colder is acceptable for storing ZOSTAVAX.

For information regarding stability under conditions other than those recommended, call 1-800-MERCK-90.

Before reconstitution, protect from light.

The diluent should be stored separately at room temperature (20 to 25(degree)C, 68 to 77(degree)F), or in the refrigerator (2 to 8(degree)C, 36 to 46(degree)F).

17 PATIENT COUNSELING INFORMATION

(See FDA-Approved Patient Labeling (17.2).)

17.1 Instructions

The health care provider should question the vaccine recipient about reactions to previous vaccines. The health care provider should also inform the vaccine recipient of the benefits and risks of ZOSTAVAX. Patients should be provided with a copy of the Patient Information about ZOSTAVAX at the end of this insert, and be given an opportunity to discuss any questions or concerns.

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

Patients should be instructed to report any adverse reactions to their health care provider.

Dist. by:

Issued November 2007

Printed in USA

9815604

17.2 FDA-Approved Patient Labeling




comments powered by Disqus