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.

MONITOR: The administration of live, attenuated vaccines to patients receiving therapy with leniolisib has not been studied but may be associated with diminished or suboptimal immunologic response. Patients with activated phosphoinositide 3-kinase delta (APDS) are reported to have reduced humoral and cellular immunity. A retrospective cohort study of the clinical and laboratory features of eight patients with activated phosphoinositide 3-kinase delta (APDS) reported that all patients received vaccination with both attenuated live and subunit vaccines with no adverse effects, with some displaying an impaired vaccination response. However, the clinical trial evaluating the efficacy of leniolisib in patients with APDS-associated genetic PI3K-delta mutation with a documented variant in either PIK3CD or PIK3R1 excluded patients who had received live vaccines (including attenuated live vaccines) in the 6-week period prior to study entry and for up to 7 days after receiving the last dose of leniolisib. Data concerning administration of inactivated, killed, or otherwise noninfectious vaccines are not available.

MANAGEMENT: Due to the potential for a diminished or suboptimal immunologic response, caution is recommended with the administration of live, attenuated vaccines in patients receiving therapy with leniolisib. Specific recommendations concerning the administration time of live, attenuated vaccines in relation to leniolisib therapy are not available. Although there is no data concerning the use of inactivated, killed, or otherwise noninfectious vaccines, caution is also advised. Local immunization guidelines and prescribing information for individual vaccines and leniolisib should be consulted for further guidance.

MONITOR: The administration of live, attenuated vaccines to patients receiving therapy with leniolisib has not been studied but may be associated with diminished or suboptimal immunologic response. Patients with activated phosphoinositide 3-kinase delta (APDS) are reported to have reduced humoral and cellular immunity. A retrospective cohort study of the clinical and laboratory features of eight patients with activated phosphoinositide 3-kinase delta (APDS) reported that all patients received vaccination with both attenuated live and subunit vaccines with no adverse effects, with some displaying an impaired vaccination response. However, the clinical trial evaluating the efficacy of leniolisib in patients with APDS-associated genetic PI3K-delta mutation with a documented variant in either PIK3CD or PIK3R1 excluded patients who had received live vaccines (including attenuated live vaccines) in the 6-week period prior to study entry and for up to 7 days after receiving the last dose of leniolisib. Data concerning administration of inactivated, killed, or otherwise noninfectious vaccines are not available.

MANAGEMENT: Due to the potential for a diminished or suboptimal immunologic response, caution is recommended with the administration of live, attenuated vaccines in patients receiving therapy with leniolisib. Specific recommendations concerning the administration time of live, attenuated vaccines in relation to leniolisib therapy are not available. Although there is no data concerning the use of inactivated, killed, or otherwise noninfectious vaccines, caution is also advised. Local immunization guidelines and prescribing information for individual vaccines and leniolisib should be consulted for further guidance.

MONITOR: Coadministration with inhibitors of CYP450 3A4 including grapefruit or grapefruit juice may increase the plasma concentrations of leniolisib, which undergoes extensive CYP450 3A4-mediated first-pass metabolism in the gut wall and liver. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of leniolisib. Some authorities recommend to avoid grapefruit products during leniolisib treatment (UK).