rtant serious adverse reactions reported included one case each of PML, Stevens-Johnson syndrome and tumor lysis syndrome.
Dose modifications
Adverse reactions that led to dose delays in more than 5% of patients were neutropenia (14%) and peripheral sensory neuropathy (11%) [see Dose Modification (2.2)].
Discontinuations
Adverse reactions led to treatment discontinuation in 21% of patients. Adverse reactions that led to treatment discontinuation in 2 or more patients with HL or sALCL were peripheral sensory neuropathy (8%) and peripheral motor neuropathy (3%).
6.2 Immunogenicity
Patients with HL and sALCL in the phase 2 trials [see Clinical Studies (14.1)] were tested for antibodies to brentuximab vedotin every 3 weeks using a sensitive electrochemiluminescent immunoassay. Approximately 7% of patients in these trials developed persistently positive antibodies (positive test at more than 2 timepoints) and 30% developed transiently positive antibodies (positive in 1 or 2 post-baseline timepoints). The anti-brentuximab antibodies were directed against the antibody component of brentuximab vedotin in all patients with transiently or persistently positive antibodies. Two of the patients (1%) with persistently positive antibodies experienced adverse reactions consistent with infusion reactions that led to discontinuation of treatment. Overall, a higher incidence of infusion related reactions was observed in patients who developed persistently positive antibodies.
A total of 58 patient samples that were either transiently or persistently positive for anti-brentuximab vedotin antibodies were tested for the presence of neutralizing antibodies. Sixty-two percent of these patients had at least one sample that was positive for the presence of neutralizing antibodies. The effect of anti-brentuximab vedotin antibodies on safety and efficacy is not known.
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ADCETRIS with the incidence of antibodies to other products may be misleading.
7 DRUG INTERACTIONS
In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.
7.1 Effect of Other Drugs on ADCETRIS
CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A [see Clinical Pharmacology (12.3)]. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.
7.2 Effect of ADCETRIS on Other Drugs
Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations [see Clinical Pharmacology (12.3)]. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.7)].
There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mec |
