Drug Interaction Report

ADJUST DOSING INTERVAL: If multiple live, attenuated parenteral viral or bacterial vaccines are not given on the same day, but are administered within 28 days of each other, the immune response to the second live parenteral vaccine may be diminished by the immune response to the first. The exact mechanism of this interaction is unknown, but may involve competition for cellular receptors, competition for molecular substrates required for replication, and/or induction of inhibitory host proteins like interferon. Clinical data are limited and sometimes conflicting. One randomized clinical trial in Brazil was conducted in 12-month-old children (n=1769) receiving routine vaccinations. Volunteers were randomized to receive simultaneous yellow fever (YF) and measles, mumps, rubella (MMR) vaccines or to receive YF 30 days after the MMR vaccine. Subjects who received both vaccines simultaneously had lower seroconversion rates for rubella, YF, and mumps than those vaccinated 30 days apart (90% vs. 97%, 70% vs. 87%, and 62% vs. 71%, respectively). Seroconversion rates for measles were unaffected (>98% in both groups). Geometric mean titers (GMT) for rubella and YF were approximately three times higher in those who were vaccinated 30 days apart. However, a different randomized, non-inferiority trial in healthy one-year-old children in Argentina (n=738), which evaluated coadministration of MMR and YF vaccines compared to MMR followed by the YF vaccine 28 to 35 days later, or YF followed by the MMR vaccine 28 to 35 days later, reported that effective seroconversion was achieved when the two vaccines were administered concurrently. This study did note that antibody levels for rubella and YF were significantly lower following co-administration. A separate study conducted in two U.S. health maintenance organizations found that the risk for varicella vaccine failure (defined as varicella disease in a vaccinated individual) was three times higher in those who received the varicella vaccine within 28 days of the MMR vaccine, when compared to those who received the varicella vaccine more than 28 days after MMR vaccination. Clinical data are not available for all possible live vaccine combinations in all age groups.

MANAGEMENT: The U.S. Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices generally recommends that doses of live, attenuated parenteral viral or bacterial vaccines that are not administered simultaneously (using different injection sites and separate needles and syringes for injectable products not formulated as combinations) should be separated by an interval of at least 28 days. If the live vaccines involved are separated by less than 4 weeks, the second vaccine administered should not be counted and the dose should be repeated at least 4 weeks later. Oral vaccines (e.g., Ty21a typhoid vaccine and rotavirus) can be administered simultaneously with or at any interval before or after other live vaccines if indicated. The United Kingdom's Green Book recommends always separating the YF and MMR vaccines by at least 4 weeks, unless rapid protection is required in which case they advise considering an additional dose of the MMR vaccine. Additionally, the Canadian Immunization Guide recommends avoiding simultaneous administration of a first-generation smallpox vaccine with a varicella-containing vaccine; suggesting that if both are needed, the varicella-containing vaccine should be given at least 4 weeks before or after the first-generation smallpox vaccine. Current local immunization guidelines and prescribing information for individual vaccines should be consulted for specific recommendations.

GENERALLY AVOID: The administration of live, attenuated virus or bacterial vaccines during corticosteroid therapy may be associated with a risk of disseminated infection due to enhanced replication of vaccine virus or bacteria in the presence of diminished immune competence. Patients may be immunosuppressed if they have recently received or are receiving high dosages of corticosteroids or adrenocorticotropic agents (e.g., greater than or equal to 2 mg/kg/day or 20 mg/day of prednisone or equivalent for 14 consecutive days or more), or long-term topical or inhaled corticosteroids. Such patients may also have increased adverse reactions and decreased or suboptimal immunologic response to vaccines. With respect to chronic corticosteroid inhalation therapy, a study was conducted to examine immune responsiveness to varicella vaccine in pediatric asthma patients ages 12 months to 8 years treated with budesonide inhalation suspension 0.25 mg to 1 mg daily. Compared to patients on noncorticosteroid asthma therapy, there was no significant difference in the percentage of budesonide patients who developed a seroprotective antibody titer following vaccination (85% vs. 90% for noncorticosteroid). In addition, no patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination.

MANAGEMENT: In general, live attenuated vaccines should not be used in patients receiving immunosuppressive corticosteroid therapy. Vaccination should be deferred until after such therapy is discontinued and immune function has been restored. The interval depends on the dosage and duration of corticosteroid therapy administered, but may be at least 3 months in most cases. Current local immunization guidelines should be consulted for recommendations. In patients who have recently been vaccinated, high-dose corticosteroid therapy should not be initiated for at least 2 weeks. Vaccines may generally be administered to patients receiving corticosteroids as replacement therapy (e.g., for Addison's disease).

GENERALLY AVOID: The administration of live, attenuated virus or bacterial vaccines during corticosteroid therapy may be associated with a risk of disseminated infection due to enhanced replication of vaccine virus or bacteria in the presence of diminished immune competence. Patients may be immunosuppressed if they have recently received or are receiving high dosages of corticosteroids or adrenocorticotropic agents (e.g., greater than or equal to 2 mg/kg/day or 20 mg/day of prednisone or equivalent for 14 consecutive days or more), or long-term topical or inhaled corticosteroids. Such patients may also have increased adverse reactions and decreased or suboptimal immunologic response to vaccines. With respect to chronic corticosteroid inhalation therapy, a study was conducted to examine immune responsiveness to varicella vaccine in pediatric asthma patients ages 12 months to 8 years treated with budesonide inhalation suspension 0.25 mg to 1 mg daily. Compared to patients on noncorticosteroid asthma therapy, there was no significant difference in the percentage of budesonide patients who developed a seroprotective antibody titer following vaccination (85% vs. 90% for noncorticosteroid). In addition, no patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination.

MANAGEMENT: In general, live attenuated vaccines should not be used in patients receiving immunosuppressive corticosteroid therapy. Vaccination should be deferred until after such therapy is discontinued and immune function has been restored. The interval depends on the dosage and duration of corticosteroid therapy administered, but may be at least 3 months in most cases. Current local immunization guidelines should be consulted for recommendations. In patients who have recently been vaccinated, high-dose corticosteroid therapy should not be initiated for at least 2 weeks. Vaccines may generally be administered to patients receiving corticosteroids as replacement therapy (e.g., for Addison's disease).