Pediatric Pharmacotheraphy - December 2005
Pediatric Pharmacotheraphy - December 2005
On September 6, 2005, the Food and Drug Administration (FDA) approved a new combination measles, mumps, rubella, and varicella (MMRV) vaccine for children 12 months to 12 years of age.1 It combines Merck's measles, mumps, and rubella live virus vaccine (M-M-R-II) and varicella live virus vaccine (Varivax).
According to the 2004 National Immunization Survey, the estimated vaccination coverage rate among children 19 to 35 months of age was 93.0% for the measles, mumps, rubella vaccine, but only 87.5% for the varicella vaccine. The MMRV vaccine was developed to reduce the number of injections required in the routine childhood immunization schedule and increase the percentage of children immunized against varicella within the first two years of life. Like other combination vaccine products, it is anticipated that MMRV will reduce patient discomfort and increase clinic efficiency as well. The inclusion of MMRV into the Recommended Childhood and Adolescent Immunization Schedule is pending review by the Advisory Committee on Immunization Practices. This issue of Pediatric Pharmacotherapy will describe the new MMRV combination vaccine and review the documents supporting its efficacy and safety in children.
The MMRV vaccine has been in development for nearly a decade. Early attempts to produce a combination vaccine resulted in effective coverage against measles, mumps, and rubella, but produced inadequate antibody titers to varicella. Reformulation of the product has now resulted in a combination vaccine that produces levels of antibody response similar to those created when the vaccines are given separately.
In the August issue of The Pediatric Infectious Diseases Journal, Shinefield and colleagues published the results of two clinical trials of MMRV. In the first study, 480 children between 12 and 23 months of age were randomized to receive either MMRV or M-M-RII and Varivax given concomitantly at separate sites. The children were then randomized to receive a subsequent dose of either MMRV or placebo 90 days after the first immunization. Immunogenicity was evaluated 6 weeks after each immunization. Response rates were > 90% to all components of the vaccines in both groups. After the first dose, geometric mean titers to measles and mumps were significantly higher in the patients given MMRV. The second dose of MMRV produced small increases in measles, mumps, and rubella antibody titers, but a significant increase in varicella titers. Based on the information obtained in earlier studies, the authors hypothesize that the increase in varicella titers produced by MMRV may be beneficial in preventing future varicella-zoster virus breakthrough.
The response to the varicella component of the vaccine was further evaluated in a study comparing three different lots of the MMRV vaccine with differing levels of varicella-zoster virus to the vaccines given separately. The authors enrolled 1,559 children between 12 and 23 months of age and randomized them to receive one of the three lots of MMRV or the measles, mumps, and rubella vaccine and varicella vaccines given concomitantly. Patients who were given MMRV were given a second dose 90 days later. The highest potency MMRV produced similar antibody response rates to varicella administered separately. The antibody response to measles, mumps, and rubella were similar between the MMRV groups and the patients given separate vaccines. The second dose produced a significant boost in varicella antibody titers, similar to that observed in the previous study.
In addition to those studies, the immunogenicity of MMRV has been evaluated by the manufacturer in a total of 5,835 children between 12 months and 6 years of age, as part of five randomized controlled clinical trials. Four of the trials were conducted in previously unimmunized children between the ages of 12 to 23 months. The antibody response in 5,446 children given MMRV was compared to that achieved in 2,038 children vaccinated with the measles, mumps, and rubella vaccine and the varicella vaccine given concomitantly at two separate sites. After a single dose of MMRV, positive seroconversion occurred in 95.8% of children for measles, in 98.5-98.9% for mumps, 98.5% for rubella, and 91.2% for varicella. The results were similar to the response rates with the use of separate vaccines.
A subgroup of 1,035 children from the single-dose study was selected to receive a second dose of MMRV approximately 3 months after the first dose. In those who had remained seronegative after the first dose, 99.4% had a positive serologic response to measles after the second dose, 99.9% had a response to mumps, 98.3% to rubella, and 99.4% to varicella.
In an additional clinical trial, the manufacturer assessed the immunogenicity of MMRV as a booster dose in children who had previously received the M-M-R-II and Varivax vaccines separately. In a study of 79 children 4 to 6 years of age, 399 received MMRV and placebo while another 195 were given the two vaccines separately. In the patients given MMRV, rates of seropositive response were 99.2% for measles, 99.5% for mumps, 100% for rubella, and 98.9% for varicella. The rates of seroconversion and the rise in antibody titers with MMRV were similar to those seen in the patients who received the two vaccines separately.
The persistence of antibody to the components of MMRV was assessed in a sample of 2,107 children enrolled in premarketing clinical trials. One year after immunization, antibody to measles was demonstrated in 98.9% of patients, with antibody to mumps found in 96.7%, to rubella in 99.6%, and to varicella in 97.5%. Although long-term experience with MMRV is not yet available, measurable antibody titers have been demonstrated up to 10 years after immunization with M-M-R-II and Varivax vaccines.
The use of MMRV is contraindicated in patients with a known hypersensitivity to any component of the vaccine, including neomycin and gelatin, and in patients with a history of a severe reaction to either of the two component vaccines. Administration is also contraindicated in patients with blood dyscrasias, leukemia, lymphomas, or any other malignancies of the bone marrow or lymphatic system, patients with primary or acquired immunodeficiency states, and those with a family history of congenital or hereditary immunodeficiency. The use of MMRV is also contraindicated in individuals on immunosuppressive therapy, those with untreated tuberculosis or an acute febrile illness with fever greater than 101.3º F, and in pregnancy.
Caution should be used when administering MMRV to children with a history of cerebral injury, a history (or family history) of seizures, or any condition in which fever should be avoided. Patients with an egg allergy are at low risk for anaphylactic reactions to MMRV, but should be closely monitored, as it is not possible to predict the potential for an anaphylactic response. In addition, the MMRV product contains albumin, so standard precautions regarding the administration of a blood-derived product apply.
Because MMRV contains live attenuated viruses, small amounts of rubella and varicella may be shed for up to a month after immunization. It is recommended that vaccine recipients attempt to avoid close contact with immunocompromised or unvaccinated individuals for 6 weeks following immunization.
Administration of immune globulins concomitantly with MMRV may lessen antibody response. It is recommended that vaccination with MMRV be postponed for 3 months after a patient has received blood products or immune globulins. After administration of MMRV, immune globulins, including varicella immune globulin, should not be administered for 1 month, unless the benefit clearly outweighs the risk of reduced antibody response.
Because of the association with salicylate administration during varicella infection and Reye's syndrome, it is recommended that patients immunized with MMRV not receive salicylates for a period of 6 weeks after immunization. Patients being treated with topical or low-dose corticosteroids may be immunized with MMRV.
Information on adverse reactions has been collected from a sample of 4,497 children between 12 and 23 months of age enrolled in premarketing clinical trials. Overall, the rate of adverse effects post-immunization was similar between children receiving MMRV and those given the component vaccines separately. The only significant differences were a higher incidence of fever greater than or equal to 102º F (21.5% versus 14.9%, respectively) and rash (3% versus 2.1%). Pain at the injection site was significantly lower in patients given MMRV (22.0% compared to 25.5% in patients given the two vaccines separately).
Other reactions occurring in greater than 1% of children given MMRV included erythema (14.4%), swelling (8.4%), and bruising at the injection site (1.5%). In addition to fever and a measles-like rash, the other systemic adverse reactions with MMRV included: irritability (6.7%), varicella-like rash (2.1%), unspecified rash (1.6%), upper respiratory infection (1.3%), viral exanthema (1.2%), and diarrhea (1.2%).
Similar results were observed in the trial by Shinefield, with the most common reactions being fever (in 27.7% of the patients given MMRV compared to 18.7% of the patients given separate vaccines) and rash (5.9% versus 1.9%). The incidence of other adverse effects was similar between the groups. One patient in each group had a febrile seizure possibly related to administration of the vaccine. No other serious adverse events were reported in either group.
Because of the lack of long-term safety data with MMRV, the manufacturer will be conducting three additional postmarketing studies enrolling over 3,000 children. In addition, the FDA has required Merck to conduct a postmarketing surveillance study in a minimum of 25,000 patients. One of the primary outcome measurements of this study will be to evaluate the risk for febrile seizures after MMRV administration. It is anticipated that the results of this study will be available by June 2008.
The MMRV vaccine is available as ProQuad . It is available in 0.5 ml single-dose vials of lyophilized powder, supplied with vials of sterile water diluent The vaccine must be maintained in a frozen state at a temperature of -4º F or colder. It has a shelf-life of 18 month when kept frozen. The diluent may be stored at room temperature or refrigerated. Reconstituted vaccine should be discarded if it is not used within 30 minutes.
The dose should be administered by subcutaneous administration, preferably into the outer aspect of the deltoid or in the higher anterolateral area of the thigh. If MMRV is administered after a dose of the measles, mumps, rubella vaccine or varicella vaccine, at least a month should elapse between the administration of the two doses. In patients requiring a second dose of MMRV, a minimum period of 3 months should elapse between doses.
The MMRV vaccine is indicated for administration at the 12 to 15 month visit. It may also be used for the booster dose at 4 to 6 years of age. The MMRV vaccine may be administered concomitantly with Haemophilus influenzae type b conjugate vaccine or hepatitis B vaccine. Concurrent administration with other vaccines has not been adequately studied at this time to ensure efficacy and safety.
The average wholesale price (AWP) for ProQuad is $153.31 per dose. While this is higher than the cost of the two products given separately, $49.90 for M-M-R-II and $83.34 for Varivax , many health care institutions are able to purchase the vaccine at a reduced cost.
The MMRV vaccine provides a new option for reducing the number of injections required for the routine childhood immunization schedule. By combining two well established products, the manufacturer has created a new product that maintains a high level of seroconversion and is well tolerated. Additional data are needed, however, to confirm the clinical efficacy and safety of the MMRV vaccine.
On September 6, 2005, the Food and Drug Administration (FDA) approved a new combination measles, mumps, rubella, and varicella (MMRV) vaccine for children 12 months to 12 years of age.1 It combines Merck's measles, mumps, and rubella live virus vaccine (M-M-R-II) and varicella live virus vaccine (Varivax).
According to the 2004 National Immunization Survey, the estimated vaccination coverage rate among children 19 to 35 months of age was 93.0% for the measles, mumps, rubella vaccine, but only 87.5% for the varicella vaccine. The MMRV vaccine was developed to reduce the number of injections required in the routine childhood immunization schedule and increase the percentage of children immunized against varicella within the first two years of life. Like other combination vaccine products, it is anticipated that MMRV will reduce patient discomfort and increase clinic efficiency as well. The inclusion of MMRV into the Recommended Childhood and Adolescent Immunization Schedule is pending review by the Advisory Committee on Immunization Practices. This issue of Pediatric Pharmacotherapy will describe the new MMRV combination vaccine and review the documents supporting its efficacy and safety in children.
The MMRV vaccine has been in development for nearly a decade. Early attempts to produce a combination vaccine resulted in effective coverage against measles, mumps, and rubella, but produced inadequate antibody titers to varicella. Reformulation of the product has now resulted in a combination vaccine that produces levels of antibody response similar to those created when the vaccines are given separately.
In the August issue of The Pediatric Infectious Diseases Journal, Shinefield and colleagues published the results of two clinical trials of MMRV. In the first study, 480 children between 12 and 23 months of age were randomized to receive either MMRV or M-M-RII and Varivax given concomitantly at separate sites. The children were then randomized to receive a subsequent dose of either MMRV or placebo 90 days after the first immunization. Immunogenicity was evaluated 6 weeks after each immunization. Response rates were > 90% to all components of the vaccines in both groups. After the first dose, geometric mean titers to measles and mumps were significantly higher in the patients given MMRV. The second dose of MMRV produced small increases in measles, mumps, and rubella antibody titers, but a significant increase in varicella titers. Based on the information obtained in earlier studies, the authors hypothesize that the increase in varicella titers produced by MMRV may be beneficial in preventing future varicella-zoster virus breakthrough.
The response to the varicella component of the vaccine was further evaluated in a study comparing three different lots of the MMRV vaccine with differing levels of varicella-zoster virus to the vaccines given separately. The authors enrolled 1,559 children between 12 and 23 months of age and randomized them to receive one of the three lots of MMRV or the measles, mumps, and rubella vaccine and varicella vaccines given concomitantly. Patients who were given MMRV were given a second dose 90 days later. The highest potency MMRV produced similar antibody response rates to varicella administered separately. The antibody response to measles, mumps, and rubella were similar between the MMRV groups and the patients given separate vaccines. The second dose produced a significant boost in varicella antibody titers, similar to that observed in the previous study.
In addition to those studies, the immunogenicity of MMRV has been evaluated by the manufacturer in a total of 5,835 children between 12 months and 6 years of age, as part of five randomized controlled clinical trials. Four of the trials were conducted in previously unimmunized children between the ages of 12 to 23 months. The antibody response in 5,446 children given MMRV was compared to that achieved in 2,038 children vaccinated with the measles, mumps, and rubella vaccine and the varicella vaccine given concomitantly at two separate sites. After a single dose of MMRV, positive seroconversion occurred in 95.8% of children for measles, in 98.5-98.9% for mumps, 98.5% for rubella, and 91.2% for varicella. The results were similar to the response rates with the use of separate vaccines.
A subgroup of 1,035 children from the single-dose study was selected to receive a second dose of MMRV approximately 3 months after the first dose. In those who had remained seronegative after the first dose, 99.4% had a positive serologic response to measles after the second dose, 99.9% had a response to mumps, 98.3% to rubella, and 99.4% to varicella.
In an additional clinical trial, the manufacturer assessed the immunogenicity of MMRV as a booster dose in children who had previously received the M-M-R-II and Varivax vaccines separately. In a study of 79 children 4 to 6 years of age, 399 received MMRV and placebo while another 195 were given the two vaccines separately. In the patients given MMRV, rates of seropositive response were 99.2% for measles, 99.5% for mumps, 100% for rubella, and 98.9% for varicella. The rates of seroconversion and the rise in antibody titers with MMRV were similar to those seen in the patients who received the two vaccines separately.
The persistence of antibody to the components of MMRV was assessed in a sample of 2,107 children enrolled in premarketing clinical trials. One year after immunization, antibody to measles was demonstrated in 98.9% of patients, with antibody to mumps found in 96.7%, to rubella in 99.6%, and to varicella in 97.5%. Although long-term experience with MMRV is not yet available, measurable antibody titers have been demonstrated up to 10 years after immunization with M-M-R-II and Varivax vaccines.
The use of MMRV is contraindicated in patients with a known hypersensitivity to any component of the vaccine, including neomycin and gelatin, and in patients with a history of a severe reaction to either of the two component vaccines. Administration is also contraindicated in patients with blood dyscrasias, leukemia, lymphomas, or any other malignancies of the bone marrow or lymphatic system, patients with primary or acquired immunodeficiency states, and those with a family history of congenital or hereditary immunodeficiency. The use of MMRV is also contraindicated in individuals on immunosuppressive therapy, those with untreated tuberculosis or an acute febrile illness with fever greater than 101.3º F, and in pregnancy.
Caution should be used when administering MMRV to children with a history of cerebral injury, a history (or family history) of seizures, or any condition in which fever should be avoided. Patients with an egg allergy are at low risk for anaphylactic reactions to MMRV, but should be closely monitored, as it is not possible to predict the potential for an anaphylactic response. In addition, the MMRV product contains albumin, so standard precautions regarding the administration of a blood-derived product apply.
Because MMRV contains live attenuated viruses, small amounts of rubella and varicella may be shed for up to a month after immunization. It is recommended that vaccine recipients attempt to avoid close contact with immunocompromised or unvaccinated individuals for 6 weeks following immunization.
Administration of immune globulins concomitantly with MMRV may lessen antibody response. It is recommended that vaccination with MMRV be postponed for 3 months after a patient has received blood products or immune globulins. After administration of MMRV, immune globulins, including varicella immune globulin, should not be administered for 1 month, unless the benefit clearly outweighs the risk of reduced antibody response.
Because of the association with salicylate administration during varicella infection and Reye's syndrome, it is recommended that patients immunized with MMRV not receive salicylates for a period of 6 weeks after immunization. Patients being treated with topical or low-dose corticosteroids may be immunized with MMRV.
Information on adverse reactions has been collected from a sample of 4,497 children between 12 and 23 months of age enrolled in premarketing clinical trials. Overall, the rate of adverse effects post-immunization was similar between children receiving MMRV and those given the component vaccines separately. The only significant differences were a higher incidence of fever greater than or equal to 102º F (21.5% versus 14.9%, respectively) and rash (3% versus 2.1%). Pain at the injection site was significantly lower in patients given MMRV (22.0% compared to 25.5% in patients given the two vaccines separately).
Other reactions occurring in greater than 1% of children given MMRV included erythema (14.4%), swelling (8.4%), and bruising at the injection site (1.5%). In addition to fever and a measles-like rash, the other systemic adverse reactions with MMRV included: irritability (6.7%), varicella-like rash (2.1%), unspecified rash (1.6%), upper respiratory infection (1.3%), viral exanthema (1.2%), and diarrhea (1.2%).
Similar results were observed in the trial by Shinefield, with the most common reactions being fever (in 27.7% of the patients given MMRV compared to 18.7% of the patients given separate vaccines) and rash (5.9% versus 1.9%). The incidence of other adverse effects was similar between the groups. One patient in each group had a febrile seizure possibly related to administration of the vaccine. No other serious adverse events were reported in either group.
Because of the lack of long-term safety data with MMRV, the manufacturer will be conducting three additional postmarketing studies enrolling over 3,000 children. In addition, the FDA has required Merck to conduct a postmarketing surveillance study in a minimum of 25,000 patients. One of the primary outcome measurements of this study will be to evaluate the risk for febrile seizures after MMRV administration. It is anticipated that the results of this study will be available by June 2008.
The MMRV vaccine is available as ProQuad . It is available in 0.5 ml single-dose vials of lyophilized powder, supplied with vials of sterile water diluent The vaccine must be maintained in a frozen state at a temperature of -4º F or colder. It has a shelf-life of 18 month when kept frozen. The diluent may be stored at room temperature or refrigerated. Reconstituted vaccine should be discarded if it is not used within 30 minutes.
The dose should be administered by subcutaneous administration, preferably into the outer aspect of the deltoid or in the higher anterolateral area of the thigh. If MMRV is administered after a dose of the measles, mumps, rubella vaccine or varicella vaccine, at least a month should elapse between the administration of the two doses. In patients requiring a second dose of MMRV, a minimum period of 3 months should elapse between doses.
The MMRV vaccine is indicated for administration at the 12 to 15 month visit. It may also be used for the booster dose at 4 to 6 years of age. The MMRV vaccine may be administered concomitantly with Haemophilus influenzae type b conjugate vaccine or hepatitis B vaccine. Concurrent administration with other vaccines has not been adequately studied at this time to ensure efficacy and safety.
The average wholesale price (AWP) for ProQuad is $153.31 per dose. While this is higher than the cost of the two products given separately, $49.90 for M-M-R-II and $83.34 for Varivax , many health care institutions are able to purchase the vaccine at a reduced cost.
The MMRV vaccine provides a new option for reducing the number of injections required for the routine childhood immunization schedule. By combining two well established products, the manufacturer has created a new product that maintains a high level of seroconversion and is well tolerated. Additional data are needed, however, to confirm the clinical efficacy and safety of the MMRV vaccine.
