The U.S. Food and Drug Administration (FDA) has approved Merck’s new vaccine ZOSTAVAX(R) (Zoster Vaccine Live (Oka/Merck)) for prevention of herpes zoster (shingles) in individuals 60 years of age and older.
Shingles is a frequently painful disease marked by a blistering rash. Caused by the reactivation of the virus that causes chickenpox, shingles can lead to severe complications including long-term nerve pain (postherpetic neuralgia), which can last for months or even years. ZOSTAVAX is not a treatment for shingles or postherpetic neuralgia. ZOSTAVAX is given as a single dose by injection.
“ZOSTAVAX is the first and only medical option approved for the prevention of shingles,” said William Schaffner, M.D., professor of preventive medicine, Vanderbilt University School of Medicine, Nashville. “Approval of a vaccine against shingles represents a major public health advance for people 60 and older.”
Anyone who has been infected with chickenpox — that’s more than 90 percent of adults in the United States — is at risk for developing shingles. The incidence and severity of shingles, as well as the frequency and severity of its complications, increase with age. About 40 to 50 percent of the estimated 1 million cases of shingles that occur in the United States each year occur in people age 60 and older. Shingles can be unpredictable and can occur without warning at any time.
“This vaccine is clinically important because it can prevent a disease that may cause pain in some patients,” said Ann Arvin, M.D., professor of pediatrics, infectious diseases and microbiology and immunology, Stanford University School of Medicine, who studied the vaccine. “ZOSTAVAX is unique because in contrast to other vaccines that help prevent a primary infection, ZOSTAVAX helps prevent reactivation of a virus that’s already inside the body.”
Shingles usually starts as an unusual or painful sensation on one side of the body or face, followed by a blistering rash. Pain from shingles can be mild to severe and may occur just prior to the development of the rash, during the eruption of the rash and as long-term nerve pain (postherpetic neuralgia). Postherpetic neuralgia has been described as tender, burning, throbbing, stabbing, shooting and/or sharp pain. Other complications, such as scarring, allodynia (pain from an innocuous stimulus such as the touch of soft clothing or a light breeze), pneumonia, visual impairment and hearing loss also can occur as the result of shingles. Treating shingles and postherpetic neuralgia can be difficult, often requiring a multifaceted approach.
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; with AIDS or other clinical manifestations of infection with human immunodeficiency viruses; and with active untreated tuberculosis. ZOSTAVAX is also contraindicated in persons on immunosuppressive therapy including high-dose corticosteroids and in women who are or may be pregnant.
Vaccination with a live, attenuated vaccine, such as ZOSTAVAX, 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. The use of ZOSTAVAX in individuals with a previous history of shingles has not been studied.
Studies of ZOSTAVAX Included More Than 40,000 People
The approval of ZOSTAVAX is based on studies of more than 40,000 people, more than 21,000 of whom received active vaccine. The efficacy and safety of a single dose of ZOSTAVAX was evaluated in the largest of these studies, the landmark Shingles Prevention Study (SPS) of 38,546 men and women age 60 and over who had no previous history of shingles. This randomized, double-blind, placebo-controlled study was a Department of Veterans Affairs study conducted in collaboration with the National Institute of Allergy and Infectious Diseases at the National Institutes of Health and Merck at 22 U.S. research sites.
In the study, participants were randomized to groups given either ZOSTAVAX (N=19,270) or a placebo (N=19,276) and followed for the development of shingles for a median duration of 3.1 years. All subjects with clinically diagnosed shingles were offered antiviral treatment, as well as standard-of-care treatment for pain, as necessary.
ZOSTAVAX significantly reduced the risk of developing shingles compared with placebo by 51 percent (315 cases (5.4 cases per 1,000 person-years) vs. 642 cases (11.1 cases per 1,000 person-years), respectively; Greater Than or Equal to 0.001) in the SPS. Efficacy of ZOSTAVAX for the prevention of shingles was highest for those 60 to 69 years of age and declined with increasing age.
Overall, the benefit of ZOSTAVAX in the prevention of long-term nerve pain from shingles (postherpetic neuralgia) can be primarily attributed to the vaccine’s effect on the prevention of shingles. Vaccination with ZOSTAVAX reduced the incidence of long-term nerve pain from shingles in individuals 70 years of age and older who were vaccinated with ZOSTAVAX but went on to develop shingles. Following completion of the SPS, a separate analysis was conducted to evaluate the reduction in postherpetic neuralgia in the group of individuals who had been vaccinated with ZOSTAVAX but who had developed shingles. In the analysis, ZOSTAVAX reduced the overall incidence of postherpetic neuralgia by a statistically significant 39 percent compared to the placebo group. A statistically significant reduction in postherpetic neuralgia was seen in individuals aged 70 to 79 (55 percent) and a nonstatistically significant reduction in postherpetic neuralgia was seen in those aged 60 to 69 (5 percent) and 80 and older (26 percent) in the analysis.
Safety Profile of ZOSTAVAX
In the Adverse Event Monitoring Study (AEMS), which included a subgroup of individuals from the SPS, vaccine-related injection site and systemic adverse events seen in the first 42 days after vaccination in 1 percent or greater of the individuals 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.
In the overall study population in the SPS, 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) in the first 42 days after vaccination. 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).
In the entire SPS study population, the rates of overall cardiovascular events (0.4 percent) including coronary artery disease related conditions (0.2 percent) were similar in subjects vaccinated with ZOSTAVAX or placebo. In the AEMS of the SPS, in the first 42 days after vaccination, the rate of overall cardiovascular events was higher after ZOSTAVAX (0.6 percent) than after placebo (0.4 percent), including the rate of coronary artery disease-related conditions (ZOSTAVAX, 0.3 percent; placebo, 0.2 percent).
Selected Important Information about ZOSTAVAX
ZOSTAVAX is indicated for prevention of herpes zoster (shingles) in individuals 60 years of age and older. ZOSTAVAX is not a treatment for shingles or postherpetic neuralgia. As with any vaccine, vaccination with ZOSTAVAX may not result in protection of all vaccine recipients.
Patients should be informed of the theoretical risk of transmitting the vaccine virus to close contacts (including household contacts) who may be pregnant and have not had chickenpox or been vaccinated against chickenpox, or contacts who have problems with their immune system. The risk of transmitting the attenuated vaccine virus to a susceptible individual should be weighed against the risk of developing natural shingles that could be transmitted to a susceptible individual.
The duration of protection after vaccination with ZOSTAVAX is unknown. In the SPS, protection with ZOSTAVAX was demonstrated through four years of follow-up. The need for revaccination has not been defined. ZOSTAVAX is not a substitute for VARIVAX(R) (Varicella Virus Vaccine Live (Oka/Merck)) and ZOSTAVAX should not be used in children.
Concurrent administration of ZOSTAVAX and antiviral medications known to be effective against the varicella zoster virus has not been evaluated. Concurrent administration of ZOSTAVAX and other vaccines has not been evaluated.
Merck Commitment to Vaccines
“Merck is pleased to introduce the first and only shingles vaccine – the result of nearly two decades of Merck vaccine research,” said Mark Feinberg, M.D., Ph.D., vice president of policy, public health and medical affairs, Merck Vaccines. “The Company is also very pleased to announce that we will make ZOSTAVAX and all of Merck’s other adult vaccines available free of charge through a new patient assistance program for vaccines for low-income individuals for whom the vaccines are medically appropriate.”
Through this new program, Merck will provide free vaccines to adults who are uninsured and who are unable to afford vaccines. Merck’s vaccines will become available through this program in the third quarter of 2006.
Outside the United States, ZOSTAVAX was approved for licensure in the European Union and in Australia earlier this month, and Merck has filed regulatory applications for ZOSTAVAX in other world markets. Merck will begin to commercialize ZOSTAVAX outside of the U.S. in 2007. In addition, the FDA and other regulatory agencies around the world are now reviewing applications for GARDASIL(R) (quadrivalent human papillomavirus types 6, 11, 16, 18, recombinant vaccine), Merck’s investigational HPV and cervical cancer vaccine. In February, the FDA approved ROTATEQ(R) (rotavirus vaccine, live, oral pentavalent), Merck’s rotavirus vaccine.
Pricing and CPT Code for ZOSTAVAX
ZOSTAVAX, a frozen vaccine, is available for ordering by physicians and Merck expects to begin shipping the vaccine soon. The catalog price of ZOSTAVAX is $145.35 purchased as a 10-pack of single-dose vials of lyophilized vaccine with sterile diluent and $152.50 purchased as a single-dose vial of vaccine with sterile diluent.
The American Medical Association has established the Current Procedural Terminology (CPT*)(R) code “CPT 90736 Zoster (shingles) vaccine, live, for subcutaneous use” for ZOSTAVAX. CPT codes allow for the identification and potential reimbursement of existing common procedures, services and products, new and emerging technologies as well as the collection of data to facilitate performance issues.
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.
Merck 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 cautionary statements in Item 1 of Merck’s Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.
* Current Procedural Terminology (CPT) is a registered trademark of the American Medical Association.
Prescribing information and patient product information for ZOSTAVAX is attached.
For more information on ZOSTAVAX, visit www.ZOSTAVAX.com
9703300 ZOSTAVAX(R) (Zoster Vaccine Live (Oka/Merck)) DESCRIPTION ZOSTAVAX* is a lyophilized preparation of the Oka/Merck strain of live, attenuated varicella-zoster virus (VZV). The virus was initially obtained from a child with naturally-occurring varicella, then introduced into human embryonic lung cell cultures, adapted to and propagated in embryonic guinea pig cell cultures and finally propagated in human diploid cell cultures (WI-38). Further passage of the virus was performed at Merck Research Laboratories (MRL) in human diploid cell cultures (MRC-5). The cells, virus seeds, virus bulks and bovine serum used in the manufacturing are all tested to provide assurance that the final product is free of adventitious agents. ZOSTAVAX, when reconstituted as directed, is a sterile preparation 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 also 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. CLINICAL PHARMACOLOGY Background 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. Although the rash is the most distinctive feature of zoster, the most frequently debilitating symptom is pain. Pain associated with zoster may occur during the prodrome, the acute eruptive phase, and the postherpetic phase of the infection. This later phase is most commonly referred to as postherpetic neuralgia (PHN). Serious complications, such as scarring, bacterial superinfection, allodynia, cranial and motor neuron palsies, pneumonia, encephalitis, visual impairment, hearing loss, and death can occur as the result of zoster. 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 Immunogenicity.) Clinical Studies Efficacy of ZOSTAVAX was evaluated in the Shingles Prevention Study (SPS),(1)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 Greater Than or Equal to70 years of age. 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 1). Vaccine efficacy for the prevention of HZ was highest for those subjects 60-69 years of age and declined with increasing age. Table 1 Efficacy of ZOSTAVAX on HZ Incidence Compared with Placebo in the Shingles Prevention Study* ZOSTAVAX Placebo ------------------------------------------------ Age # # HZ Incidence # # HZ Incidence Vaccine group** subjects cases rate of subjects cases rate of Efficacy (yrs.) HZ per HZ per (95% CI) 1000 1000 person- person- yrs. 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%) ---------------------------------------------------------------------- Greater Than or Equal to 80 1263 37 9.9 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 Greater Than or Equal to70 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 2 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 2 Postherpetic Neuralgia (PHN)* in the Shingles Prevention Study** ZOSTAVAX ------------------------------------ Age group (yrs.) + # # HZ # PHN Incidence% HZ 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% ---------------------------------------------------------------------- Greater Than or Equal to 80 1263 37 7 1.9 18.9% ---------------------------------------------------------------------- Placebo ------------------------------------ Age group (yrs.) + # # HZ # PHN Incidence% HZ Vaccine efficacy subjects cases cases rate of cases against PHN in PHN per with subjects who 1,000 PHN develop HZ person- postvaccination yrs. (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%) ---------------------------------------------------------------------- Greater Than or 26% Equal to80 1332 47 12 3.1 25.5% (-69%, 68%) ---------------------------------------------------------------------- *PHN was defined as HZ-associated pain rated as Greater Than or Equal to3 (on a 0-10 scale), persisting or appearing more than 90 days after onset of HZ rash using Zoster Brief Pain Inventory (ZBPI)(2). ** 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 Greater Than or Equal to70 years of age. ++ Age-adjusted estimate based on the age strata (60-69 and Greater Than or Equal to70 years of age) at randomization. The median duration of clinically significant pain (Greater Than or Equal to3 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 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 3). Table 3 Specific complications* of zoster among HZ cases in the Shingles Prevention Study Complication ZOSTAVAX Placebo (N = 19,270) (N = 19,276) ---------------------------------------------------------------------- (n = 321) % Among (n = 659) % Zoster Among Cases 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 Greater Than or Equal to1% 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. Immunogenicity 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. INDICATIONS AND USAGE ZOSTAVAX is 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. 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). WARNINGS Vaccination with a live attenuated vaccine, such as ZOSTAVAX, 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.(3) 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. PRECAUTIONS General 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, for example, in the presence of fever Greater Than 38.5(degree)C (Greater Than 101.3(degree)F). The duration of protection after vaccination with ZOSTAVAX is unknown. In the Shingles Prevention Study (SPS), 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 (see CLINICAL PHARMACOLOGY, Clinical Studies). Transmission In clinical trials with ZOSTAVAX, transmission of the vaccine virus has not been reported. However, post-marketing 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. Information for Patients The health care provider should question the vaccine recipient about reactions to previous vaccines (see CONTRAINDICATIONS). 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 Sheet at the end of this insert, and be given an opportunity to discuss any questions or concerns. Vaccinees should also be informed of the theoretical risk of transmitting the vaccine virus to varicella-susceptible individuals, including pregnant women who have not had chickenpox. Patients should also be told that pregnancy should be avoided for three months following vaccination. Patients should be instructed to report any adverse reactions to their health care provider. Drug Interactions Concurrent administration of ZOSTAVAX and antiviral medications known to be effective against VZV has not been evaluated. Concurrent administration of ZOSTAVAX and other vaccines has not been evaluated. Carcinogenesis, Mutagenesis, Impairment of Fertility ZOSTAVAX has not been evaluated for its carcinogenic or mutagenic potential, or its potential to impair fertility. 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. Therefore, ZOSTAVAX should not be administered to pregnant females; furthermore, pregnancy should be avoided for three months following vaccination (see CONTRAINDICATIONS). Vaccinees and health care providers are encouraged to report any exposure to ZOSTAVAX during pregnancy by calling (800) 986-8999. Nursing Mothers Some viruses are excreted in human milk; however, 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. Pediatric Use ZOSTAVAX should not be used in children. 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. ADVERSE REACTIONS 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 (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. Because clinical trials are conducted under conditions that may not be typical of those observed in clinical practice, the adverse reaction rates presented below may not be reflective of those observed in clinical practice. Serious Adverse Reactions In the overall study population, serious adverse experiences (SAEs) 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, from Day 0-42 postvaccination (Table 4). Table 4 Number of Subjects with Greater Than or Equal to 1 Serious Adverse Experience (0-42 Days Postvaccination) in the Shingles Prevention Study Cohort ZOSTAVAX Placebo Relative Risk n/N n/N (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) Greater Than or Equal to 80 27/1220 21/1289 1.36 years old 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) Greater Than or Equal to 80 11/217 4/173 2.19 years old 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 Table 5 displays selected cardiovascular SAEs occurring in the SPS within 42 days postvaccination. Table 5 Selected Serious Adverse Experiences (SAEs) Reported More Frequently After ZOSTAVAX than After Placebo Days 0-42 Postvaccination in the Shingles Prevention Study AE Monitoring Entire Study Substudy Cohort ZOSTAVAX Placebo ZOSTAVAX Placebo N = 3326 N = 3249 N = N = 18671 18717 n (%) n (%) n (%) n (%) ---------------------------------------------------------------------- Overall Cardiovascular events by body system 20 (0.6)12 (0.4)81 (0.4)72 (0.4) Coronary Artery Disease-related conditions* 10 (0.3) 5 (0.2)45 (0.2)35 (0.2) ---------------------------------------------------------------------- N=number of subjects with safety follow-up n=number of subjects reporting SAE within the category *CAD-related conditions: angina pectoris, coronary artery disease, coronary occlusion, cardiovascular disorder, myocardial ischemia, & myocardial infarction Rates of hospitalizations were similar among subjects who received ZOSTAVAX and subjects who received placebo in the AE Monitoring Substudy, throughout the entire study. 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 overall incidence of death occurring Days 0 to 42 postvaccination was similar between vaccination groups 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 experiences reported at an incidence Greater Than or Equal to 1% are shown in Table 6. Most of these adverse experiences were reported as mild in intensity. The overall incidence of vaccine-related injection-site adverse experiences was significantly greater for subjects vaccinated with ZOSTAVAX versus subjects who received placebo (48% for ZOSTAVAX and 17% for placebo). Table 6 Injection-Site and Systemic Adverse Experiences Reported by Vaccine Report Card in Greater Than or Equal to1% of Adults Who Received ZOSTAVAX or Placebo (0-42 Days Postvaccination) in the AE Monitoring Substudy of the Shingles Prevention Study Adverse Experience ZOSTAVAX Placebo (N = 3345) (N = 3271) % % ---------------------------------------------------------------------- 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 (Greater Than or Equal to38.3(degree)C (Greater Than or Equal to101.0(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 Greater Than or Equal to1% 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%)). Adverse Events Occurring after Day 42 postvaccination AE Monitoring Substudy subjects in the Shingles Prevention Study were monitored for hospitalizations through monthly automated phone queries and the remainder of subjects were passively monitored for safety in this study from Day 43 postvaccination through study end. Over the course of the study (4.9 years), 51 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. Clinical Safety with High Potency ZOSTAVAX In an additional clinical study, high potency ZOSTAVAX (203,000 plaque-forming units (pfu)) administered to 461 subjects was compared to a lower potency ZOSTAVAX (57,000 pfu; similar to potencies studied in the Shingles Prevention Study) administered to 234 subjects. Moderate or severe injection-site reactions were more common in the recipients of the higher potency ZOSTAVAX (17%) as compared to the lower potency recipients (9%). Among recipients of the higher potency ZOSTAVAX, 4 subjects (0.9%) reported SAEs (1 case each of angina pectoris, coronary artery disease, depression and enteritis); 1 subject (0.4%) receiving the lower potency ZOSTAVAX reported an SAE (lung cancer). VZV rashes following vaccination 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 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 all other clinical trials in support 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 recipients and placebo recipients. Of the 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). 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.(4) DOSAGE AND ADMINISTRATION FOR SUBCUTANEOUS ADMINISTRATION. Do not inject intravascularly. ZOSTAVAX is administered as a single dose. Caution: 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. Reconstitute the vaccine using only the diluent supplied. The supplied diluent is free of preservatives or other antiviral substances which might inactivate the vaccine virus. Use a separate sterile needle and syringe for reconstituting and administration of ZOSTAVAX to prevent transfer of infectious diseases. 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. To reconstitute the vaccine: Withdraw the entire contents of the diluent vial into a syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ZOSTAVAX when reconstituted is a semi-hazy to translucent, off-white to pale yellow liquid. Inject all of the diluent in the syringe into the vial of lyophilized vaccine and gently agitate to mix thoroughly. Withdraw the entire contents into a syringe and inject the total volume of reconstituted vaccine subcutaneously; preferably in the upper arm. 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. HOW SUPPLIED 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 -20(degree)C (-4(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). REFERENCES 1. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, Weinberg A, Boardman KD, Williams HM, Zhang JH, Peduzzi PN, Beisel CE, Morrison VA, Guatelli JC, Brooks PA, Kauffman CA, Pachucki CT, Neuzil KM, Betts RF, Wright PF, Griffin MR, Brunell P, Soto NE, Marques AR, Keay SK, Goodman RP, Cotton DJ, Gnann JW Jr, Loutit J, Holodniy M, Keitel WA, Crawford GE, Yeh SS, Lobo Z, Toney JF, Greenberg RN, Keller PM, Harbecke R, Hayward AR, Irwin MR, Kyriakides TC, Chan CY, Chan IS, Wang WW, Annunziato PW, Silber JL. A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults. NEJM 2005;352:2271-84. 2. 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. 3. Reitschel RL, Bernier R. Neomycin sensitivity and the MMR vaccine. JAMA 1981;245(6):571. 4. 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. Manuf. and Dist. by: Merck & Co., Inc., Whitehouse Station, NJ, 08889, USA Issued May 2006 Printed in USA *Registered trademark of Merck & Co., Inc. Copyright (C) 2006 Merck & Co., Inc. Whitehouse Station, NJ, USA All rights reserved **Registered trademark of Merck & Co., Inc.
9703300
Patient Information about
ZOSTAVAX(R) (pronounced “ZOS tah vax”)
Generic name: (Zoster Vaccine Live (Oka/Merck))
You should read this summary of information about ZOSTAVAX* 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 works by helping your immune system protect you from getting shingles and the associated pain and other serious complications. 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.
As with any vaccine, ZOSTAVAX may not protect everyone who receives the vaccine.
ZOSTAVAX cannot be used to treat shingles once you have it. If you do get shingles, see your health care provider within the first few days of getting the rash.
What do I need to know about shingles and the virus that causes it?
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.
People who have problems with their immune system may have a greater risk of getting more widespread rashes and longer-lasting pain.
Shingles is caused by the same virus that causes chickenpox. Once a person has had chickenpox, the virus can live, but remain inactive, in one or more nerve roots in your body for many years. For reasons that are not fully understood, the virus may become active again. Age and problems with the immune system may increase your risk of getting shingles.
Can I get ZOSTAVAX?
You can receive ZOSTAVAX if you are 60 years of age or older, but only your health care provider can decide if ZOSTAVAX is right for you.
Who should not receive ZOSTAVAX?
You should not receive ZOSTAVAX if you:
— are allergic to any of its ingredients. This includes
allergies to gelatin or neomycin.
— have a disease or condition that causes a weakened immune
system such as an immune deficiency, including leukemia,
lymphoma, HIV/AIDS or are taking high doses of steroids by
injection or by mouth.
— have active TB (tuberculosis) that is not being treated.
— are pregnant or may be pregnant.
*Registered trademark of Merck & Co., Inc.
Copyright (C) 2006 Merck & Co., Inc.
Whitehouse Station, NJ, USA
All rights reserved
What should I tell my health care provider before I receive ZOSTAVAX?
You should tell your health care provider if you:
— have or have had any medical problems.
— are taking any medications, including those that might weaken
your immune system.
— have any allergies, including allergies to neomycin or have
had an allergic reaction to another vaccine.
— become pregnant within 3 months of getting the vaccine.
Vaccine recipients are encouraged to report any exposure to
ZOSTAVAX during pregnancy by calling (800) 986-8999.
— are breast-feeding.
— have had shingles in the past.
— may be in close contact (including household contact) with
someone who may be pregnant and has not had chickenpox or been
vaccinated against chickenpox, or someone who has problems
with their immune system.
How is ZOSTAVAX given?
ZOSTAVAX is given as a single dose by injection under the skin.
What are the possible side effects of ZOSTAVAX?
Redness, pain, swelling, itching, warmth, and bruising at the site where the injection was given, and headache were the most common side effects that people in the clinical studies reported after receiving the vaccine. Talk to your health care provider about other possible side effects.
Call your health care provider right away if any medical condition you have gets worse or you develop any new or unusual symptoms after you receive ZOSTAVAX.
What are the ingredients in 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?
This leaflet summarizes information about ZOSTAVAX. If you would like more information, talk to your health care provider or visit the website: www.ZOSTAVAX.com.
Rx Only
Issued May 2006
Manuf. and Dist. by:
Merck & Co., Inc., Whitehouse Station, NJ 08889, USA
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