FDA Approves Proquad Combination Vaccine

WHITEHOUSE STATION, N.J., September 6, 2005 - Merck & Co., Inc. today announced that the U.S. Food and Drug Administration has approved the Company’s combination vaccine Proquad (Measles, Mumps, Rubella and Varicella (Oka/Merck) Virus Vaccine Live) for simultaneous vaccination against measles, mumps, rubella (German measles) and varicella (chickenpox) in children 12 months to 12 years of age. Proquad is the first and only vaccine approved in the United States to help protect against these four diseases in a single shot. Proquad is also approved for use in children 12 months to 12 years of age if a second dose of measles, mumps, and rubella vaccine is to be administered.

Proquad, which reflects more than 20 years of Merck research, combines two well-established Merck vaccines - M-M-R II (Measles, Mumps and Rubella Virus Vaccine Live) and Varivax (Varicella Virus Vaccine Live (Oka/Merck)). Vaccination with M-M-R II has contributed to a greater than 99 percent reduction in the United States in the incidence of measles, mumps and rubella -- diseases that have been associated with serious complications and once claimed tens of thousands of lives each year in this country alone. Since its licensure in 1995, Varivax has contributed to a significant reduction in the number of chickenpox cases in the United States. Chickenpox-related hospitalizations and deaths have also declined over the past decade in the United States. Proquad builds on the tradition of these Merck vaccines in helping to protect children against these four potentially serious diseases.

"Until now, a young child had to undergo two separate vaccinations against these diseases. The approval of Proquad makes it more likely that more children can gain protection against these four diseases because fewer shots can potentially mean better compliance," said Henry Shinefield, M.D., clinical professor of pediatrics and dermatology, University of California School of Medicine at San Francisco, clinical investigator for Proquad and author of more than 150 published articles related to vaccination. "By allowing vaccination against chickenpox to occur simultaneously with vaccination against measles, mumps and rubella, Proquad can help increase the number of children vaccinated against chickenpox at the earliest recommended time -- upon a baby’s first birthday."

Preference for Combination Vaccines

Leading U.S. authorities on vaccination -- such as the American Academy of Pediatrics (AAP), American Academy of Family Physicians (AAFP) and the Center for Disease Control and Prevention’s (CDC’s) Advisory Committee on Immunization Practices (ACIP) -- recommend routine vaccination against measles, mumps, rubella and varicella. As a combination vaccine indicated for simultaneous vaccination against all four of these diseases in children 12 months to 12 years of age, Proquad can help physicians meet these vaccination recommendations. Moreover, according to the report "Combination Vaccines for Childhood Immunization," issued by the ACIP in 1999, "the use of licensed combination vaccines is preferred over separate injection of their equivalent component vaccines."

Potential advantages of combination vaccines include reducing multiple injections, improving timely vaccination coverage, reducing the costs of stocking and administration of separate vaccines for health care providers and reducing health care costs for extra health visits, according to the report.

"Based on the public health benefits realized following the introduction of other combination vaccines, such as M-M-R II, we expect Proquad to become a primary option for prevention of measles, mumps, rubella and chickenpox," said Mark Feinberg, M.D., Ph.D., vice president of policy, public health and medical affairs, Merck Vaccine Division. "Proquad can help reduce the gap that exists in the United States between vaccination rates for chickenpox -- which were an estimated 87.5 percent in 2004 -- and rates for measles, mumps and rubella -- which were an estimated 93 percent in 2004. The main goal for any vaccine is to help eliminate disease and this is possible when very high vaccination rates are achieved in the community."

Proquad Provided Immunogenicity Similar to its Component Vaccines

Merck’s Biologics License Application for Proquad included results from studies that evaluated the immunogenicity, antibody persistence and safety of Proquad compared to its component vaccines.

Immunogenicity was studied in 5,835 healthy children 12 months to six years of age with a negative clinical history of measles, mumps, rubella and varicella who participated in five randomized trials. In these trials, the immunogenicity of Proquad was similar to that of its individual component vaccines, M-M-R II and Varivax.

In four randomized trials in which 5,446 healthy children aged 12 to 23 months received Proquad, vaccine response rates for Proquad were similar to the rates induced by the concomitant administration of single doses of M-M-R II and Varivax at separate injection sites in 2,038 children. Results showed that following a single dose of Proquad, the immune response rates were 97.4 percent for measles, 95.8 to 98.8 percent for mumps, 98.5 percent for rubella and 91.2 percent for chickenpox. The duration of protection from measles, mumps, rubella and chickenpox infections after vaccination with Proquad is unknown.

In two of the four trials, 1,035 of the 5,446 children administered a single dose of Proquad received a second dose of Proquad approximately three months after the first dose. The proportion of initially seronegative vaccinees with positive serological responses following two doses were 99.4 percent for measles, 99.9 percent for mumps, 98.3 percent for rubella and 99.4 percent for chickenpox. The rates of adverse experiences after the second dose were generally similar to, or lower than, those seen with the first dose. The fever rate was lower after the second dose of Proquad than after the first dose.

The immunogenicity of Proquad was also evaluated in a clinical trial of 799 healthy children four to six years of age who had received M-M-R II and Varivax as primary vaccination against measles, mumps, rubella and chickenpox at least one month prior to study entry. In this study, 399 children received Proquad and placebo, 205 received M-M-R II and placebo concomitantly at separate injection sites and 195 children received M-M-R II and Varivax concomitantly at separate injection sites. Following the dose of Proquad, seropositivity rates were 99.2 percent for measles, 99.5 percent for mumps, 100 percent for rubella and 98.9 for varicella. The rates of adverse experiences, including the most commonly reported adverse experiences of injection site reactions, nasopharyngitis and cough, were generally similar among the three treatment groups.

Formal studies to evaluate the clinical efficacy of Proquad have not been performed. Efficacy of the measles, mumps, rubella and chickenpox components of Proquad was previously established in a series of clinical studies with the monovalent vaccines. A high degree of protection from infection was demonstrated in these studies.

Proquad had a Safety Profile Similar to its Components

In clinical trials, the safety of Proquad was compared with the safety of M-M-R II and Varivax given concomitantly at separate injection sites. Proquad was administered to 4,497 children 12 to 23 months of age without concomitant administration with other vaccines. Children in these studies were monitored for up to 42 days post-vaccination. The safety profile for Proquad was similar to the component vaccines. Injection-site adverse experiences reported in greater than or equal to 1 percent of children 12 to 23 months of age who received one dose of Proquad were: pain/tenderness/soreness (22 percent); erythema (abnormal redness of the skin) (14.4 percent); swelling (8.4 percent); ecchymosis (bruising) (1.5 percent); and rash (2.3 percent). Pain/tenderness/soreness at the injection site was reported at a statistically lower rate in individuals who received Proquad than in individuals who received M-M-R II and Varivax concomitantly at separate injection sites.

Systemic vaccine-related adverse experiences reported in greater than or equal to 1 percent of children 12 to 23 months of age who received one dose of Proquad were fever greater than or equal to 102 degrees F (21.5 percent), irritability (6.7 percent), measles-like rash (3 percent), varicella-like rash (2.1 percent), rash not otherwise specified (1.6 percent), upper respiratory infection (1.3 percent), viral exanthema (1.2 percent) and diarrhea (1.2 percent). The only systemic vaccine-related adverse experiences reported at a significantly greater rate in individuals who received Proquad than individuals who received M-M-R II and Varivax concomitantly at separate injection sites were fever (greater than or equal to 102 degrees F) and measles-like rash. Both fever and measles-like rash usually occurred within 5 to 12 days following vaccination, were of short duration and resolved with no long-term issues.

Proquad Demonstrated Antibody Persistence at One Year

The persistence of antibody at one year after vaccination was evaluated in 2,107 children enrolled in clinical trials. Antibody persistence rates one year after a single dose of Proquad were 98.9 percent against measles; 96.7 percent against mumps; 99.6 percent against rubella and 97.5 percent against chickenpox. These persistence rates are similar to those observed at one year with the individual component vaccines, M-M-R II and Varivax. The duration of protection from measles, mumps, rubella and chickenpox (varicella) infections after vaccination with Proquad is unknown.

Selected Important Information about Proquad

Proquad is a combined attenuated live virus vaccine indicated for simultaneous vaccination against measles, mumps, rubella and chickenpox in children 12 months to 12 years of age. No clinical data are available on the safety, immunogenicity and efficacy of Proquad in children less than 12 months of age. Proquad may be used in children 12 months to 12 years of age if a second dose of measles, mumps and rubella vaccine is to be administered. At least one month should elapse between a dose of a measles-containing vaccine, such as M-M-R II, and a dose of Proquad. If for any reason a second dose of varicella-containing vaccine is required, at least three months should elapse between administration of the two doses. Proquad should not be administered to individuals with a history of anaphylactic reactions to neomycin. Proquad should not be administered to individuals with a history of hypersensitivity to any component of the vaccine, including gelatin.

Proquad should not be administered to individuals with certain medical conditions, including blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system, or individuals with any immunodeficient condition or receiving immunosuppressive therapy. Proquad also should not be used in individuals with active untreated tuberculosis or active febrile illness with fever (> 101.3 degrees F) or those who are pregnant. Proquad may be used in individuals who are receiving topical corticosteroids or low-dose corticosteroids for asthma prophylaxis or replacement therapy (e.g., for Addison’s disease), but should not be given to individuals receiving immunosuppressive doses of corticosteroids.

Vaccination with Proquad may not offer 100 percent protection from measles, mumps, rubella and chickenpox (varicella) infection. Caution should be exercised in administering Proquad to persons with a history of cerebral injury, individual or family history of convulsions, or any other condition in which stress due to fever should be avoided. The vaccination history of a prospective vaccine recipient should be obtained to determine whether the individual had any previous reactions to any vaccine including Proquad, Varivax or any measles, mumps or rubella containing vaccines.

Source: Merck & Co., Inc.

Posted: September 2005


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