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1 1 ZOSTAVAX ® [Zoster Vaccine Live (Oka/Merck)] Approved by the Food and Drug Administration on May 25, 2006 2 2 Description • Lyophilized preparation of the Oka/Merck strain of live, attenuated VZV. • Each 0.65-mL dose contains a minimum of 19,400 plaque- forming units (PFU). • Each dose also contains sucrose, hydrolyzed porcine gelatin, sodium chloride, monosodium L-glutamate, sodium phosphate dibasic, potassium phosphate monobasic, and potassium chloride; residual components of MRC-5 cells, including DNA and protein, and trace quantities of neomycin and bovine calf serum. • Contains no preservatives. Description • ZOSTAVAX ® [Zoster Vaccine Live (Oka/Merck)] is a lyophilized preparation of the Oka/Merck strain of live, attenuated VZV. • Each 0.65-mL dose of the vaccine contains a minimum of 19,400 plaque-forming units (PFU) of attenuated virus. • Each dose also contains sucrose, hydrolyzed porcine gelatin, sodium chloride, monosodium L-glutamate, sodium phosphate dibasic, potassium phosphate monobasic, and potassium chloride; residual components of MRC-5 cells, including DNA and protein, and trace quantities of neomycin and bovine calf serum. • The product does not contain preservatives. 3 3 Indications and Usage • ZOSTAVAX is indicated for the prevention of herpes zoster (shingles) in individuals 60 years of age and older. • ZOSTAVAX is not indicated for the treatment of zoster or postherpetic neuralgia. Indications and Usage • ZOSTAVAX ® [Zoster Vaccine Live (Oka/Merck)] is indicated for the prevention of herpes zoster (or shingles) in individuals 60 years of age and older. • ZOSTAVAX is not indicated for the treatment of zoster or postherpetic neuralgia. 4 4 Contraindications • ZOSTAVAX should not be administered to individuals: – With a history of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other component of the vaccine (see WARNINGS). – With a history of primary or acquired immunodeficiency states including leukemia; lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system; or AIDS or other clinical manifestations of infection with human immunodeficiency viruses (see WARNINGS). – On immunosuppressive therapy, including high-dose corticosteroids. – With active untreated tuberculosis. – Who are or may be pregnant (see PRECAUTIONS, Pregnancy). Contraindications ZOSTAVAX ® [Zoster Vaccine Live (Oka/Merck)] is contraindicated in individuals who: • Have a history of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other component of the vaccine (see WARNINGS). • Have a history of primary or acquired immunodeficiency states including leukemia; lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system; or AIDS or other clinical manifestations of infection with human immunodeficiency viruses (see WARNINGS). • Are on immunosuppressive therapy, including high-dose corticosteroids. • Have active untreated tuberculosis. • Are or may be pregnant. (Please refer to PRECAUTIONS, Pregnancy in the Prescribing Information.) 5 5 Clinical Pharmacology: The Shingles Prevention Study Design Oxman MN, Levin MJ, Johnson GR, et al. N Engl J Med. 2005;352:2271–2284. Subjects Enrolled N=38,546 Age 60 to 69 years n=20,747 Age ≥70 years n=17,799 Zoster vaccine n=10,378 Placebo n=10,369 Zoster vaccine n=8,892 Placebo n=8,907 Adverse Event (AE) Substudy n=6,616 Immunogenicity Substudy n=1,395 Clinical Pharmacology: The Shingles Prevention Study Design • The Shingles Prevention Study was a placebo-controlled, randomized, double-blind study. 1 • The study enrolled a total of 38,546 subjects who were 60 years of age or older. 1 • Randomization was stratified by age 1 : – 60 to 69 years of age – ≥70 years of age • Subjects were randomized to receive either a single dose of zoster vaccine (n=19,270) or placebo (n=19,276). 1 • The median follow-up of the study was 3.1 years (range 31 days to 4.9 years). • The study excluded people who were immunocompromised or using corticosteroids on a regular basis, anyone with a previous history of HZ, and those with conditions that might interfere with study evaluations, including people with cognitive impairment, severe hearing loss, those who were non-ambulatory and those whose survival was not considered to be at least 5 years. • The clinical trial included 2 substudies 1 : – The Adverse Event (AE) Monitoring Substudy, which comprised 6,616 subjects. – An immunogenicity substudy, which comprised 1,395 subjects. • Zoster cases were confirmed by polymerase chain reaction (93%), viral culture (1%), or in the absence of viral detection, by the Clinical Evaluation Committee (6%). • Individuals in both vaccination groups who developed zoster were given famciclovir and, as necessary, pain medications. 1 Reference: 1. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271–2284. 6 6 Patient Demographics in the Shingles Prevention Study 227 (1.2)217 (1.1)Other or unknown 248 (1.3)265 (1.4)Hispanic 420 (2.2)395 (2.0)Black 18,381 (95.4)18,393 (95.4)White Race n (%) 7,919 (41.1)7,867 (40.8)Female 11,357 (58.9)11,403 (59.2)Male Gender n (%) 8,907 (46.2)8,892 (46.1) ≥70 years 10,369 (53.8)10,378 (53.9)60 to 69 years Age n (%) Placebo Group N=19,276 Vaccine Group N=19,270Characteristic Oxman MN, Levin MJ, Johnson GR, et al. N Engl J Med. 2005;352:2271–2284. Patient Demographics in the Shingles Prevention Study • Baseline patient characteristics were similar in both vaccination groups in the Shingles Prevention Study. 1 – The age distribution of enrolled patients was 59 to 99 years in both groups. – The gender distribution was 59% male and 41% female. 1 – The racial distribution of white (95%), black (2%), Hispanic (1%), and other (1%) was also similar in both groups. 1 Reference: 1. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271–2284. 7 7 Prevention of Herpes Zoster Number of zoster cases Age (years) –64% (95% CI: 56%, 71%) –41% (95% CI: 28%, 52%) –18% (95% CI: –29%, 48%) 315 122 156 47 261 334 642 37 0 100 200 300 400 500 600 700 Overall 60–69 70–79 ≥80 Placebo ZOSTAVAX –51% (95% CI: 44%, 58%) Incidence rate of zoster per 1,000 person-years 11.1 10.8 11.4 12.25.4 3.9 6.7 9.9 Prevention of Herpes Zoster • ZOSTAVAX ® [Zoster Vaccine Live (Oka/Merck)] significantly reduced the risk of developing zoster compared with placebo*: 315/19,254 cases (5.4 cases per 1,000 person-years) vs 642/19,247 cases [11.1 cases per 1,000 person-years]). The protective efficacy was 51% (95% CI: 44%, 58%). 1 – Vaccine efficacy for the prevention of zoster was highest for those subjects 60 to 69 years of age and declined with increasing age. – ZOSTAVAX reduced the incidence of zoster by 64% in individuals 60 to 69 years of age (ZOSTAVAX, n=10,370; placebo, n=10,356); by 41% in individuals 70 to 79 years of age (ZOSTAVAX, n=7,621; placebo, n=7,559); and by 18% in individuals 80 years of age or older (ZOSTAVAX, n=1,263; placebo, n=1,332). • As with any vaccine, vaccination with ZOSTAVAX may not result in protection of all vaccine recipients. • The duration of protection after vaccination with ZOSTAVAX is unknown. In the Shingles Prevention Study, protection from zoster was demonstrated through 4 years of follow-up. The need for revaccination has not been defined. *Primary analysis was performed on the modified intent-to-treat (MITT) population that included all randomized patients who were followed for at least 30 days postvaccination and did not develop an evaluable case of zoster within the first 30 days postvaccination. Reference: 1. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271–2284. 8 8 Postherpetic Neuralgia* in the Shingles Prevention Study *Zoster-associated pain rated as ≥3 on a 10-pt scale and occurring or persisting at least 90 days after rash onset. **Age-adjusted estimate based on the age strata (60–69 and ≥70 years of age) at randomization. 0 Overall 60–69 70–79 ≥80 Age (years) Number of PHN Cases 80 23 45 1227 8 12 7 25.5 8.6 6.6 7.7 18.9 17.2 6.9 12.5 10 20 30 40 50 % of HZ Cases With Postherpetic Neuralgia –5% (95% CI: –107%, 56%) –55% (95% CI: 18%, 76%) –26% (95% CI: –69%, 68%) –39%** (95% CI: 7%, 59%) Placebo ZOSTAVAX Number of HZ Cases 642 334 261 47315 122 156 37 Postherpetic Neuralgia in the Shingles Prevention Study • Postherpetic neuralgia was defined as zoster-associated pain (rated as ≥3 on a 10- point scale by the patient) occurring or persisting at least 90 days following the onset of rash in evaluable cases of zoster. • Overall, the benefit of ZOSTAVAX ® [Zoster Vaccine Live (Oka/Merck)] in the prevention of postherpetic neuralgia can be primarily attributed to the effect of the vaccine on the prevention of zoster. Vaccination with ZOSTAVAX reduced the incidence of postherpetic neuralgia in individuals 70 years of age and older who developed zoster postvaccination. • Following completion of the Shingles Prevention Study, a separate analysis was conducted to evaluate the reduction in PHN in the group of individuals who have been vaccinated with ZOSTAVAX, but who had developed zoster. In the analysis, the overall efficacy of ZOSTAVAX for reduction of postherpetic neuralgia in patients who developed zoster following vaccination was 39% (95% CI: 7%, 59%). This is an age-adjusted estimate calculated based on the age strata of 60 to 69 and 70 years of age and older at randomization. • The vaccine efficacy against postherpetic neuralgia in patients who developed zoster following vaccination was 5% (95% CI: –107%, 56%) in patients 60 to 69 years of age; 55% (95% CI: 18%, 76%) in patients 70 to 79 years of age: and 26% (95% CI: –69%, 68%) in patients 80 years of age and older. 9 9 12 57 9 12 69 9 11 7 310 (n = 659) % Among Zoster Cases % Among Zoster Cases ( n = 321) 7 24 2 5 35 2 5 3 135 1.40.6Impaired Vision 47.042.1Allodynia 1.10.9Bacterial Superinfection 1.71.6Dissemination 10.510.9Ophthalmic Zoster 1.81.6Peripheral Nerve Palsies (motor) 1.40.6Ptosis 8.67.5Scarring 1.82.2Sensory Loss Placebo (N = 19,276) ZOSTAVAX (N = 19,270) Complication 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 patients with zoster. Specific Complications* of Zoster Among HZ Cases in the Shingles Prevention Study Specific Complications of Zoster Among HZ Cases in the Shingles Prevention Study • The table shows the number of patients with specific complications of zoster among zoster cases that were reported in the Shingles Prevention Study at a frequency of ≥1% in at least one vaccination group among subjects with zoster. – The number of zoster cases included the cases that developed within 30 days after vaccination. • Prespecified zoster-related complications were reported less frequently in subjects who received ZOSTAVAX ® [Zoster Vaccine Live (Oka/Merck)] compared to subjects who received placebo. • Among HZ cases, zoster-related complications were reported at similar rates in both vaccination groups. • Visceral complications reported by fewer than 1% of subjects with zoster included 3 cases of pneumonitis and 1 case of hepatitis in the placebo group, and 1 case of meningoencephalitis in the vaccine group. 10 10 Immunogenicity Substudy *As measured by gpELISA=glycoprotein enzyme-linked immunosorbent assay. In the Shingles Prevention Study, ZOSTAVAX elicited higher VZV-specific antibody responses at 6 weeks after vaccination compared with placebo Fold increase in VZV antibody* 1.7 1.0 1.00 1.25 1.50 1.75 2.00 ZOSTAVAX Placebo (95% CI: 1.6, 1.8) n= 691 n= 704 Immunogenicity Substudy • Immune responses to vaccination were evaluated in a subset of 1,395 subjects enrolled in the Shingles Prevention Study. • The vaccine elicited higher VZV-specific antibody responses at 6 weeks after vaccination compared with placebo. – There was a 1.7-fold increase in VZV antibody geometric mean titers (GMT) as measured by gpELISA* (95% CI: 1.6, 1.8). – The specific antibody level that correlates with protection from zoster has not been established. *gpELISA = glycoprotein enzyme-linked immunosorbent assay. [...]... temperature (20°C to 25°C, 68°F to 77°F) or in refrigerator (2°C to 8°C, 36°F to 46°F) 22 Before administering ZOSTAVAX, please read the Prescribing Information by clicking the link below Click here to access the Prescribing Information and Patient Product Information www.MerckVaccines.com www .ZOSTAVAX. com ZOSTAVAX is a registered trademark of Merck & Co., Inc 20651999(1)-08/07-ZOS 23 23 ... Adverse Reactions • ZOSTAVAX was evaluated for safety in approximately 21,000 adults • Shingles Prevention Study – Routine safety monitoring • ZOSTAVAX: n=15,925; placebo: n=16,005 • Patients were actively followed for safety outcomes through Day 42 postvaccination • Subjects were followed passively for safety after Day 42 postvaccination to the end of the study – AE Monitoring Substudy • ZOSTAVAX: n=3,345;... administration of ZOSTAVAX and other vaccines has not been evaluated • ZOSTAVAX should not be administered to pregnant females; furthermore, pregnancy should be avoided for 3 months following vaccination • Some viruses are excreted in human milk; however, it is not known whether VZV is secreted in human milk Therefore, caution should be exercised if ZOSTAVAX is administered to a nursing woman • ZOSTAVAX should... not freeze the reconstituted vaccine 21 Conditions for Storage • ZOSTAVAX – STORE FROZEN at an average temperature of –15°C (+5°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°C or colder is acceptable for storing ZOSTAVAX • Diluent – Store diluent separately at room... 36°F to 46°F) 22 Conditions for Storage • ZOSTAVAX [Zoster Vaccine Live (Oka/Merck)] should be stored frozen at an average temperature of –15ºC (+5ºF) 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 –15ºC or colder is acceptable for storing ZOSTAVAX The diluent should be... • Pregnancy (Category C) – ZOSTAVAX should not be administered to pregnant females; furthermore, pregnancy should be avoided for 3 months following vaccination • Nursing Mothers – Caution should be exercised if ZOSTAVAX is administered to a nursing woman • Pediatric Use – ZOSTAVAX should not be used in children 14 Selected Precautions (cont) • Concurrent administration of ZOSTAVAX [Zoster Vaccine Live... 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 12 Selected Precautions • As with any vaccine, adequate treatment provisions, including epinephrine injection (1:1000), should be available for immediate... record AEs for 42 days postvaccination • Monthly surveillance for hospitalization 2 to 5 years postvaccination 15 Adverse Reactions • Overall, ZOSTAVAX [Zoster Vaccine Live (Oka/Merck)] has been evaluated in approximately 21,000 adults • In the Shingles Prevention Study, patients were given either a single dose of the zoster vaccine (n=19,270) or placebo (n=19,276) • 15,925 subjects who received ZOSTAVAX. .. actively followed for safety outcomes through Day 42 postvaccination Patients were followed passively for safety after Day 42 postvaccination to the end of the study • Patients enrolled in the AE Monitoring substudy (3,345 who received ZOSTAVAX and 3,271 who received placebo) used vaccination report cards to record AEs during the 42-day postvaccination period Monthly surveillance for hospitalization... higher after ZOSTAVAX (0.6%) than after placebo (0.4%), including the rate of coronary artery disease-related conditions postvaccination (ZOSTAVAX 0.3%, placebo 0.2%) 17 Injection-Site and Systemic Adverse Experiences Reported by vaccine report card in ≥1% of adults who received ZOSTAVAX or placebo (0 to 42 days postvaccination) in the AE monitoring substudy of the Shingles Prevention Study ZOSTAVAX Placebo . Usage • ZOSTAVAX is indicated for the prevention of herpes zoster (shingles) in individuals 60 years of age and older. • ZOSTAVAX is not indicated for the. exercised if ZOSTAVAX is administered to a nursing woman. • ZOSTAVAX should not be used in children. 15 15 Adverse Reactions • ZOSTAVAX was evaluated for safety