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.

ADJUST DOSING INTERVAL: Reactivity to diagnostic skin test antigens may be temporarily depressed in patients who have recently been vaccinated with live, attenuated viral or bacterial vaccines, potentially resulting in a false negative reaction. The mechanism of this interaction is not well described, but may involve live vaccine-mediated suppression of the immune system, possibly via inhibition of the lymphocyte mitotic response. Clinical data are limited. In one study, 26 tuberculin-positive children were vaccinated with the live, attenuated mumps virus vaccine. A tuberculin skin test was administered on day 1 and then every 7 days for 4 doses, with the magnitude of induration measured 48 hours after each skin test. The mumps vaccination was given on day 3 of the study. A significant decrease in the tuberculin reaction was observed in 17 of the 26 children. Delayed hypersensitivity to the tuberculoprotein virtually disappeared within 2 weeks of the live, attenuated mumps vaccine for many of these children and for some the depression of delayed hypersensitivity persisted through the 4-week observational period. A similar response was also reported in a separate study of 15 children with tuberculosis who developed mild cases of measles following vaccination with the live measles vaccine, with or without gamma globulin. The tuberculin skin test was documented as negative often during the measles incubation period and frequently observed to be negative during the first week of measles symptoms in these children. While this reaction has only been reported clinically in patients receiving the tuberculin skin test with certain live, attenuated viral vaccines, it may also apply to other skin tests and live, attenuated bacterial vaccines as well.

MANAGEMENT: Clinicians should be aware of the potential for falsely insignificant or false-negative results when performing delayed-hypersensitivity skin testing on patients who have recently received live, attenuated viral or bacterial vaccines. In general, tuberculin skin tests can be administered before a live vaccine, given simultaneously with the live vaccine at separate sites (preferred option), or the tuberculin skin test should be postponed for at least 4 weeks after immunization. For the live, non-replicating smallpox and monkeypox vaccine, some authorities recommend following the same guidelines that are recommended for other live vaccines with the tuberculin skin test; however, if a delay in the tuberculin skin test would cause a substantial burden for the patient, they state that any sequence of vaccination and tuberculin skin test is acceptable. Although not addressed in the labeling for other diagnostic skin tests, these recommendations should be considered when evaluating skin testing and administration of live vaccines. Local vaccination guidelines and prescribing information for both the vaccine(s) and individual skin test(s) should be consulted for further guidance.

ADJUST DOSING INTERVAL: Reactivity to diagnostic skin test antigens may be temporarily depressed in patients who have recently been vaccinated with live, attenuated viral or bacterial vaccines, potentially resulting in a false negative reaction. The mechanism of this interaction is not well described, but may involve live vaccine-mediated suppression of the immune system, possibly via inhibition of the lymphocyte mitotic response. Clinical data are limited. In one study, 26 tuberculin-positive children were vaccinated with the live, attenuated mumps virus vaccine. A tuberculin skin test was administered on day 1 and then every 7 days for 4 doses, with the magnitude of induration measured 48 hours after each skin test. The mumps vaccination was given on day 3 of the study. A significant decrease in the tuberculin reaction was observed in 17 of the 26 children. Delayed hypersensitivity to the tuberculoprotein virtually disappeared within 2 weeks of the live, attenuated mumps vaccine for many of these children and for some the depression of delayed hypersensitivity persisted through the 4-week observational period. A similar response was also reported in a separate study of 15 children with tuberculosis who developed mild cases of measles following vaccination with the live measles vaccine, with or without gamma globulin. The tuberculin skin test was documented as negative often during the measles incubation period and frequently observed to be negative during the first week of measles symptoms in these children. While this reaction has only been reported clinically in patients receiving the tuberculin skin test with certain live, attenuated viral vaccines, it may also apply to other skin tests and live, attenuated bacterial vaccines as well.

MANAGEMENT: Clinicians should be aware of the potential for falsely insignificant or false-negative results when performing delayed-hypersensitivity skin testing on patients who have recently received live, attenuated viral or bacterial vaccines. In general, tuberculin skin tests can be administered before a live vaccine, given simultaneously with the live vaccine at separate sites (preferred option), or the tuberculin skin test should be postponed for at least 4 weeks after immunization. For the live, non-replicating smallpox and monkeypox vaccine, some authorities recommend following the same guidelines that are recommended for other live vaccines with the tuberculin skin test; however, if a delay in the tuberculin skin test would cause a substantial burden for the patient, they state that any sequence of vaccination and tuberculin skin test is acceptable. Although not addressed in the labeling for other diagnostic skin tests, these recommendations should be considered when evaluating skin testing and administration of live vaccines. Local vaccination guidelines and prescribing information for both the vaccine(s) and individual skin test(s) should be consulted for further guidance.