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Varivax

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Varivax

CLINICAL PHARMACOLOGY

Varicella is a highly communicable disease in children, adolescents, and adults caused by the varicella-zoster virus (VZV). The disease usually consists of 300 to 500 maculopapular and/or vesicular lesions accompanied by a fever (oral temperature ≥ 100°F) in up to 70% of individuals.1,2 Approximately 3.5 million cases of varicella occurred annually from 1980-1994 in the United States with the peak incidence occurring in children five to nine years of age.3 The incidence rate of chickenpox in the total population was 8.3-9.1% per year in children 1-9 years of age before licensure of VARIVAX (varicella virus vaccine live) .4,6 The attack rate of natural varicella following household exposure among healthy susceptible children was shown to be 87% in unvaccinated populations.2 Although it is generally a benign, self-limiting disease, varicella may be associated with serious complications (e.g., bacterial superinfection, pneumonia, encephalitis, Reye's Syndrome), and/or death.

Evaluation of Clinical Efficacy Afforded by VARIVAX (varicella virus vaccine live)

The following section presents clinical efficacy data on a 1-dose regimen and a 2-dose regimen in children, and a 2-dose regimen in adolescents and adults.

Clinical Data in Children

One-Dose Regimen in Children

In combined clinical trials5 of VARIVAX (varicella virus vaccine live) at doses ranging from 1000-17,000 PFU, the majority of subjects who received VARIVAX (varicella virus vaccine live) and were exposed to wild-type virus were either completely protected from chickenpox or developed a milder form (for clinical description see below) of the disease. The protective efficacy of VARIVAX (varicella virus vaccine live) was evaluated in three different ways: 1) by comparing chickenpox rates in vaccinees versus historical controls, 2) by assessment of protection from disease following household exposure, and 3) by a placebo-controlled, double-blind clinical trial.

In early clinical trials,5 a total of 4240 children 1 to 12 years of age received 1000-1625 PFU of attenuated virus per dose of VARIVAX (varicella virus vaccine live) and have been followed for up to nine years post single-dose vaccination. In this group there was considerable variation in chickenpox rates among studies and study sites, and much of the reported data was acquired by passive follow-up. It was observed that 0.3%-3.8% of vaccinees per year reported chickenpox (called breakthrough cases). This represents an approximate 83% (95% confidence interval [CI], 82%, 84%) decrease from the age-adjusted expected incidence rates in susceptible subjects over this same period.19 In those who developed breakthrough chickenpox postvaccination, the majority experienced mild disease (median of the maximum number of lesions < 50). In one study, a total of 47% (27/58) of breakthrough cases had < 50 lesions compared with 8% (7/92) in unvaccinated individuals, and 7% (4/58) of breakthrough cases had > 300 lesions compared with 50% (46/92) in unvaccinated individuals.7

Among a subset of vaccinees who were actively followed in these early trials for up to nine years postvaccination, 179 individuals had household exposure to chickenpox. There were no reports of breakthrough chickenpox in 84% (150/179) of exposed children, while 16% (29/179) reported a mild form of chickenpox (38% [11/29] of the cases with a maximum total number of < 50 lesions; no individuals with > 300 lesions). This represents an 81% reduction in the expected number of varicella cases utilizing the historical attack rate of 87% following household exposure to chickenpox in unvaccinated individuals in the calculation of efficacy.

In later clinical trials5 with the current vaccine, a total of 1114 children 1 to 12 years of age received 2900-9000 PFU of attenuated virus per dose of VARIVAX (varicella virus vaccine live) and have been actively followed for up to 10 years post single-dose vaccination. It was observed that 0.2%-2.3% of vaccinees per year reported breakthrough chickenpox for up to 10 years post single-dose vaccination. This represents an estimated efficacy of 94% (95% CI, 93%, 96%), compared with the age-adjusted expected incidence rates in susceptible subjects over the same period.4,6,19 In those who developed breakthrough chickenpox postvaccination, the majority experienced mild disease, with the median of the maximum total number of lesions < 50. The severity of reported breakthrough chickenpox, as measured by number of lesions and maximum temperature, appeared not to increase with time since vaccination.

Among a subset of vaccinees who were actively followed in these later trials for up to 10 years postvaccination, 95 individuals were exposed to an unvaccinated individual with wild-type chickenpox in a household setting. There were no reports of breakthrough chickenpox in 92% (87/95) of exposed children, while 8% (8/95) reported a mild form of chickenpox (maximum total number of lesions < 50; observed range, 10 to 34). This represents an estimated efficacy of 90% (95% CI, 82%, 96%) based on the historical attack rate of 87% following household exposure to chickenpox in unvaccinated individuals in the calculation of efficacy.

Although no placebo-controlled trial was carried out with VARIVAX (varicella virus vaccine live) using the current vaccine, a placebo-controlled trial was conducted using a formulation containing 17,000 PFU per dose.4,8 In this trial, a single dose of VARIVAX (varicella virus vaccine live) protected 96-100% of children against chickenpox over a two-year period. The study enrolled healthy individuals 1 to 14 years of age (n=491 vaccine, n=465 placebo). In the first year, 8.5% of placebo recipients contracted chickenpox, while no vaccine recipient did, for a calculated protection rate of 100% during the first varicella season. In the second year, when only a subset of individuals agreed to remain in the blinded study (n=163 vaccine, n=161 placebo), 96% protective efficacy was calculated for the vaccine group as compared to placebo.

There are insufficient data to assess the rate of protection against the complications of chickenpox (e.g., encephalitis, hepatitis, pneumonia) in children.

Two-Dose Regimen in Children

In a clinical trial, a total of 2216 children 12 months to 12 years of age with a negative history of varicella were randomized to receive either 1 dose of VARIVAX (varicella virus vaccine live) (n=1114) or 2 doses of VARIVAX (varicella virus vaccine live) (n=1102) given 3 months apart. Subjects were actively followed for varicella, any varicella-like illness, or herpes zoster and any exposures to varicella or herpes zoster on an annual basis for 10 years after vaccination. Persistence of VZV antibody was measured annually for 9 years. Most cases of varicella reported in recipients of 1 dose or 2 doses of vaccine were mild.26 The estimated vaccine efficacy for the 10-year observation period was 94% for 1 dose and 98% for 2 doses (p < 0.001). This translates to a 3.4-fold lower risk of developing varicella > 42 days postvaccination during the 10-year observation period in children who received 2 doses than in those who received 1 dose (2.2% vs. 7.5%, respectively).

Clinical Data in Adolescents and Adults

Two-Dose Regimen in Adolescents and Adults

In early clinical trials, a total of 796 adolescents and adults received 905-1230 PFU of attenuated virus per dose of VARIVAX (varicella virus vaccine live) and have been followed for up to six years following 2-dose vaccination. A total of 50 clinical varicella cases were reported > 42 days following 2-dose vaccination. Based on passive follow-up, the annual chickenpox breakthrough event rate ranged from < 0.1% to 1.9%. The median of the maximum total number of lesions ranged from 15 to 42 per year.

Although no placebo-controlled trial was carried out in adolescents and adults, the protective efficacy of VARIVAX (varicella virus vaccine live) was determined by evaluation of protection when vaccinees received 2 doses of VARIVAX (varicella virus vaccine live) 4 or 8 weeks apart and were subsequently exposed to chickenpox in a household setting.5 Among the subset of vaccinees who were actively followed in these early trials for up to six years, 76 individuals had household exposure to chickenpox. There were no reports of breakthrough chickenpox in 83% (63/76) of exposed vaccinees, while 17% (13/76) reported a mild form of chickenpox. Among 13 vaccinated individuals who developed breakthrough chickenpox after a household exposure, 62% (8/13) of the cases reported maximum total number of lesions < 50, while no individual reported > 75 lesions. The attack rate of unvaccinated adults exposed to a single contact in a household has not been previously studied. Utilizing the previously reported historical attack rate of 87% for natural varicella following household exposure to chickenpox among unvaccinated children in the calculation of efficacy, this represents an approximate 80% reduction in the expected number of cases in the household setting.

In later clinical trials, a total of 220 adolescents and adults received 3315-9000 PFU of attenuated virus per dose of VARIVAX (varicella virus vaccine live) and have been actively followed for up to six years following 2-dose vaccination. A total of 3 clinical varicella cases were reported > 42 days following 2-dose vaccination. Two cases reported < 50 lesions and none reported > 75. The annual chickenpox breakthrough event rate ranged from 0% to 1.2%. Among the subset of vaccinees who were actively followed in these later trials for up to five years, 16 individuals were exposed to an unvaccinated individual with wild-type chickenpox in a household setting. There were no reports of breakthrough chickenpox among the exposed vaccinees.

There are insufficient data to assess the rate of protection of VARIVAX (varicella virus vaccine live) against the serious complications of chickenpox in adults (e.g., encephalitis, hepatitis, pneumonitis) and during pregnancy (congenital varicella syndrome).

Immunogenicity of VARIVAX (varicella virus vaccine live)

The following section presents immunogenicity data on a 1-dose regimen and a 2-dose regimen in children, and a 2-dose regimen in adolescents and adults.

One-Dose Regimen in Children

Clinical trials with several formulations of the vaccine containing attenuated virus ranging from 1000 to 17,000 PFU per dose have demonstrated that VARIVAX (varicella virus vaccine live) induces detectable immune responses in a high proportion of individuals and is generally well tolerated in healthy individuals ranging from 12 months to 55 years of age.4,5,9-15

Seroconversion is defined by the acquisition of any detectable VZV antibodies, based on an optical density (OD) cutoff, corresponding approximately to a lower limit of 0.6 glycoprotein enzyme-linked immunosorbent assay (gpELISA) units/mL.

The gpELISA is a highly sensitive assay that is not commercially available. Seroconversion was observed in 97% of vaccinees at approximately 4-6 weeks postvaccination in 6889 susceptible children 12 months to 12 years of age. Rates of breakthrough disease were significantly lower among children with VZV antibody titers ≥ 5 gpELISA units/mL compared with children with titers < 5 gpELISA units/mL. Titers ≥ 5 gpELISA units/mL were induced in approximately 76% of children vaccinated with a single dose of vaccine at 1000-17,000 PFU per dose.

VARIVAX (varicella virus vaccine live) also induces cell-mediated immune responses in vaccinees. The relative contributions of humoral immunity and cell-mediated immunity to protection from chickenpox are unknown.

Two-Dose Regimen in Children

In a multicenter study, healthy children 12 months to 12 years of age received either 1 dose of VARIVAX (varicella virus vaccine live) or 2 doses administered 3 months apart. The immunogenicity results are shown in the following table.

  VARIVAX VARIVAX
  1-Dose Regimen
(N = 1114)
2-Dose Regimen
(N = 1102)
6 Weeks Post vaccination 6 Weeks Post dose 1 6 Weeks Post dose 2
Seroconversion Rate 98.9% (882/892) 99.5% (847/851) 99.9% (768/769)
Percent with VZV Antibody Titer ≥ 5 gpELISA units/mL 84.9% (757/892) 87.3% (743/851) 99.5% (765/769)
Geometric mean titers (gpELISA units/mL) 12.0 12.8 141.5

The results from this study and other studies in which a second dose of vaccine was administered 3 to 6 years after the initial dose demonstrate significant boosting of the VZV antibody response with a second dose. VZV antibody levels after 2 doses given 3 to 6 years apart are comparable to those obtained when the 2 doses are given 3 months apart.

Two-Dose Regimen in Adolescents and Adults

In a multicenter study involving susceptible adolescents and adults 13 years of age and older, 2 doses of VARIVAX (varicella virus vaccine live) administered 4 to 8 weeks apart induced a seroconversion rate of approximately 75% in 539 individuals 4 weeks after the first dose and of 99% in 479 individuals 4 weeks after the second dose. The average antibody response in vaccinees who received the second dose 8 weeks after the first dose was higher than that in vaccinees who received the second dose 4 weeks after the first dose. In another multicenter study involving adolescents and adults, 2 doses of VARIVAX (varicella virus vaccine live) administered 8 weeks apart induced a seroconversion rate of 94% in 142 individuals 6 weeks after the first dose and 99% in 122 individuals 6 weeks after the second dose.

Persistence of Immune Response

The following section presents immune persistence data on a 1-dose regimen and a 2-dose regimen in children, and a 2-dose regimen in adolescents and adults.

One-Dose Regimen in Children

In clinical studies involving healthy children who received 1 dose of vaccine, detectable VZV antibodies were present in 99.0% (3886/3926) at 1 year, 99.3% (1555/1566) at 2 years, 98.6% (1106/1122) at 3 years, and 99.4% (1168/1175) at 4 years, 99.2% (737/743) at 5 years, 100% (142/142) at 6 years, 97.4% (38/39) at 7 years, 100% (34/34) at 8 years, and 100% (16/16) at 10 years postvaccination.

Two-Dose Regimen in Children

In recipients of 1 dose of VARIVAX (varicella virus vaccine live) over 9 years of follow-up, the geometric mean titer (GMT) and the percent of subjects with VZV antibody titers ≥ 5 gpELISA units/mL generally increased. The GMTs and percent of subjects with VZV antibody titers ≥ 5 gpELISA units/mL in the 2-dose recipients were higher than those in the 1-dose recipients for the first year of follow-up and generally comparable thereafter. The cumulative rate of VZV antibody persistence with both regimens remained very high at year 9 (99.0% for the 1-dose group and 98.8% for the 2-dose group).

Two-Dose Regimen in Adolescents and Adults

In clinical studies involving healthy adolescents and adults who received 2 doses of vaccine, detectable VZV antibodies were present in 97.9% (568/580) at 1 year, 97.1% (34/35) at 2 years, 100% (144/144) at 3 years, 97.0% (98/101) at 4 years, 97.4% (76/78) at 5 years, and 100% (34/34) at 6 years postvaccination.

A boost in antibody levels has been observed in vaccinees following exposure to natural varicella which could account for the apparent long-term persistence of antibody levels after vaccination in these studies. The duration of protection from varicella obtained using VARIVAX (varicella virus vaccine live) in the absence of wild-type boosting is unknown. VARIVAX (varicella virus vaccine live) also induces cell-mediated immune responses in vaccinees. The relative contributions of humoral immunity and cell-mediated immunity to protection from chickenpox are unknown.

Transmission

In the placebo-controlled trial, transmission of vaccine virus was assessed in household settings (during the 8-week postvaccination period) in 416 susceptible placebo recipients who were household contacts of 445 vaccine recipients. Of the 416 placebo recipients, three developed chickenpox and seroconverted, nine reported a varicella-like rash and did not seroconvert, and six had no rash but seroconverted. If vaccine virus transmission occurred, it did so at a very low rate and possibly without recognizable clinical disease in contacts. These cases may represent either natural varicella from community contacts or a low incidence of transmission of vaccine virus from vaccinated contacts (see PRECAUTIONS, Transmission).4,16 Post-marketing experience suggests that transmission of vaccine virus may occur rarely between healthy vaccinees who develop a varicella-like rash and healthy susceptible contacts. Transmission of vaccine virus from vaccinees without a varicella-like rash has been reported but has not been confirmed.

Herpes Zoster

Overall, 9454 healthy children (12 months to 12 years of age) and 1648 adolescents and adults (13 years of age and older) have been vaccinated with Oka/Merck live attenuated varicella vaccine in clinical trials. Eight cases of herpes zoster have been reported in children during 42,556 person years of follow-up in clinical trials, resulting in a calculated incidence of at least 18.8 cases per 100,000 person years. The completeness of this reporting has not been determined. One case of herpes zoster has been reported in the adolescent and adult age group during 5410 person years of follow-up in clinical trials resulting in a calculated incidence of 18.5 cases per 100,000 person years.5

All nine cases were mild and without sequelae. Two cultures (one child and one adult) obtained from vesicles were positive for wild-type VZV as confirmed by restriction endonuclease analysis.5,17 The long-term effect of VARIVAX (varicella virus vaccine live) on the incidence of herpes zoster, particularly in those vaccinees exposed to natural varicella, is unknown at present.

In children, the reported rate of herpes zoster in vaccine recipients appears not to exceed that previously determined in a population-based study of healthy children who had experienced natural varicella.5,18,19 The incidence of herpes zoster in adults who have had natural varicella infection is higher than that in children.20

Reye's Syndrome

Reye's Syndrome has occurred in children and adolescents following natural varicella infection, the majority of whom had received salicylates.21 In clinical studies in healthy children and adolescents in the United States, physicians advised varicella vaccine recipients not to use salicylates for six weeks after vaccination. There were no reports of Reye's Syndrome in varicella vaccine recipients during these studies.

Studies with Other Vaccines

In combined clinical studies involving 1080 children 12 to 36 months of age, 653 received VARIVAX (varicella virus vaccine live) and M-M-R* II (Measles, Mumps, and Rubella Virus Vaccine Live) concomitantly at separate sites and 427 received the vaccines six weeks apart. Seroconversion rates and antibody levels were comparable between the two groups at approximately six weeks post-vaccination to each of the virus vaccine components. No differences were noted in adverse reactions reported in those who received VARIVAX (varicella virus vaccine live) concomitantly with M-M-R II at separate sites and those who received VARIVAX (varicella virus vaccine live) and M-M-R II at different times (see PRECAUTIONS: DRUG INTERACTIONS, Use with Other Vaccines).5

In a clinical study involving 318 children 12 months to 42 months of age, 160 received an investigational vaccine (a formulation combining measles, mumps, rubella, and varicella in one syringe) concomitantly with booster doses of DTaP (diphtheria, tetanus, acellular pertussis) and OPV (oral poliovirus vaccine) while 144 received M-M-R II concomitantly with booster doses of DTaP and OPV followed by VARIVAX (varicella virus vaccine live) 6 weeks later. At six weeks postvaccination, seroconversion rates for measles, mumps, rubella, and VZV and the percentage of vaccinees whose titers were boosted for diphtheria, tetanus, pertussis, and polio were comparable between the two groups, but anti-VZV levels were decreased when the investigational vaccine containing varicella was administered concomitantly with DTaP. No clinically significant differences were noted in adverse reactions between the two groups.5

In another clinical study involving 307 children 12 to 18 months of age, 150 received an investigational vaccine (a formulation combining measles, mumps, rubella, and varicella in one syringe) concomitantly with a booster dose of PedvaxHIB* [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] while 130 received M-M-R II concomitantly with a booster dose of PedvaxHIB followed by VARIVAX (varicella virus vaccine live) 6 weeks later. At six weeks postvaccination, seroconversion rates for measles, mumps, rubella, and VZV, and geometric mean titers for PedvaxHIB were comparable between the two groups, but anti-VZV levels were decreased when the investigational vaccine containing varicella was administered concomitantly with PedvaxHIB. No clinically significant differences in adverse reactions were seen between the two groups.5

In a clinica[study involving 609 children 12 to 23 months of age, 305 received VARIVAX (varicella virus vaccine live) , M-M-R II, and TETRAMUNE** (Haemophilus influenzae type b, diphtheria, tetanus, and pertussis vaccines) concomitantly at separate sites, and 304 received M-M-R II and TETRAMUNE concomitantly at separate sites, followed by VARIVAX (varicella virus vaccine live) 6 weeks later. At six weeks postvaccination, seroconversion rates for measles, mumps, rubella and VZV were similar between the two groups. Postvaccination GMTs for all antigens were similar in both treatment groups except for VZV, which was lower when VARIVAX (varicella virus vaccine live) was administered concomitantly with M-M-R II and TETRAMUNE, but within the range of GMTs seen in previous clinical experience when VARIVAX (varicella virus vaccine live) was administered alone. At 1 year postvaccination, GMTs for measles, mumps, rubella, VZV and Haemophilus influenzae type b were similar between the two groups. All three vaccines were well tolerated regardless of whether they were administered concomitantly at separate sites or 6 weeks apart. There were no clinically important differences in reaction rates when the three vaccines were administered concomitantly versus 6 weeks apart.

In a clinical study involving 822 children 12 to 15 months of age, 410 received COMVAX* [Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) vaccine], M-M-R II, and VARIVAX (varicella virus vaccine live) concomitantly at separate sites, and 412 received COMVAX followed by M-M-R II and VARIVAX (varicella virus vaccine live) given concomitantly at separate sites, 6 weeks later. At six weeks postvaccination, the immune responses for the subjects who received the concomitant doses of COMVAX, M-M-R II, and VARIVAX (varicella virus vaccine live) were similar to those of the subjects who received COMVAX followed 6 weeks later by M-M-R II and VARIVAX (varicella virus vaccine live) with respect to all antigens administered. All three vaccines were generally well tolerated regardless of whether they were administered concomitantly at separate sites or 6 weeks apart. There were no clinically important differences in reaction rates when the three vaccines were administered concomitantly versus 6 weeks apart.

VARIVAX (varicella virus vaccine live) is recommended for subcutaneous administration. However, during clinical trials, some children received VARIVAX (varicella virus vaccine live) intramuscularly resulting in seroconversion rates similar to those in children who received the vaccine by the subcutaneous route.22 Persistence of antibody and efficacy in those receiving intramuscular doses have not been defined.

REFERENCES

1. Balfour, H.H.; et al.: Acyclovir Treatment of Varicella in Otherwise Healthy Children, Pediatrics., 116: 633-639, 1990.

2. Ross, A.H.: Modification of Chickenpox in Family Contacts by Administration of Gamma Globulin, N Engl J Med. 267: 369-376, 1962.

3. Preblud, S.R.: Varicella: Complications and Costs, Pediatrics, 78(4 Pt 2): 728-735, 1986.

4. Weibel, R.E.; et al.: Live Attenuated Varicella Virus Vaccine, N Engl J Med. 370(22): 1409-1415, 1984.

5. Unpublished data; files of Merck Research Laboratories.

6. Wharton, M.; et al.: Health Impact of Varicella in the 1980's. Thirtieth Interscience Conference on Antimicrobial Agents and Chemotherapy, (Abstract #1138), 1990.

7. Bernstein, H.H.; et al.: Clinical Survey of Natural Varicella Compared with Breakthrough Varicella After Immunization with Live Attenuated Oka/Merck Varicella Vaccine. Pediatrics 92: 833-837, 1993.

8. Kuter, B.J.; et al.: Oka/Merck Varicella Vaccine in Healthy Children: Final Report of a 2-Year Efficacy Study and 7-Year Follow-up Studies, Vaccine, 9: 643-647, 1991.

9. Arbeter, A.M.; et al.: Varicella Vaccine Trials in Healthy Children, A Summary of Comparative and Follow-up Studies, AJDC 138: 434-438, 1984.

10. Weibel, R.E.; et al.: Live Oka/Merck Varicella Vaccine in Healthy Children, JAMA 254(17): 2435-2439, 1985.

11. Chartrand, D.M.; et al.: New Varicella Vaccine Production Lots in Healthy Children and Adolescents, Abstracts of the 1988 Inter-Science Conference Antimicrobial Agents and Chemotherapy: 237(Abstract #731).

12. Johnson, C.E.; et al.: Live Attenuated Vaccine in Healthy 12 to 24 month old Children, Pediatrics 81: 512-518, 1988.

13. Gershon, A.A.; et al.: Immunization of Healthy Adults with Live Attenuated Varicella Vaccine, J Infect Dis, 158(1): 132-137, 1988.

14. Gershon, A.A.; et al.: Live Attenuated Varicella Vaccine: Protection in Healthy Adults Compared with Leukemic Children, J Infect Dis, 161: 661-666, 1990.

15. White, C.J.; et al.: Varicella Vaccine (VARIVAX (varicella virus vaccine live) ) in Healthy Children and Adolescents: Results From Clinical Trials, 1987 to 1989, Pediatrics, 87(5): 604-610, 1991.

16. Asano, Y.; et al.: Contact Infection from Live Varicella Vaccine Recipients, Lancet 1(7966): 965, 1976.

17. Hammerschlag, M.R.; et al.: Herpes Zoster in an Adult Recipient of Live Attenuated Varicella Vaccine, J Infect Dis 160(3): 535-537, 1989.

18. White, C.J.: Letters to the Editor, Pediatrics 318: 354, 1992.

19. Guess, H.A.; et al.: Population-Based Studies of Varicella Complications, Pediatrics 78(4 Pt 2): 723-727, 1986.

20. Ragozzino, M.; et al.: Population-Based Study of Herpes Zoster and Its Sequelae, Medicine 61(5): 310-316, 1982.

21. Morbidity and Mortality Weekly Report 34(1): 13-16, Jan. 11, 1985.

22. Dennehy, P.H.; et al.: Immunogenicity of Subcutaneous Versus Intramuscular Oka/Merck Varicella Vaccination in Healthy Children, Pediatrics 88(3): 604-607, 1991.

23. Center for Disease Control: Immunization of Children Infected with Human T-Lymphotropic Virus Type III/Lymphadenopathy — Associated Virus, Ann Intern Med, 106: 75-78, 1987.

24. Recommendations of the Advisory Committee on Immunization Practices (ACIP); General Recommendations on Immunization, MMWR 43(No. RR-1): 15-18, Jan. 28, 1994.

25. Vaccine Adverse Event Reporting System — United States, MMWR 39(41): 730-733, 1990.

26. Kuter, B.J.; et al.: Ten Year Follow-up of Healthy Children who Received One or Two Injections of Varicella Vaccine, Pediatr Infect Dis J, 23:132-37, 2004.

Last reviewed on RxList: 10/16/2008
This monograph has been modified to include the generic and brand name in many instances.

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