Hot Flushes from Clozapine and Endoxifen Combination
The combination of clozapine and endoxifen does not cause hot flushes; rather, endoxifen itself (as the active metabolite of tamoxifen) is the primary cause of hot flushes, occurring in approximately 81% of patients taking tamoxifen. 1
Understanding the Source of Hot Flushes
The question conflates two separate clinical issues:
Endoxifen causes hot flushes independently: Hot flushes are a well-established adverse effect of tamoxifen and its active metabolite endoxifen due to their anti-estrogenic effects. 2, 1
Clozapine does not contribute to hot flushes: The available evidence on clozapine safety profiles does not identify hot flushes as an adverse effect of clozapine therapy, even when combined with other medications. 3
The Critical Drug Interaction to Consider
The clinically significant interaction between these agents involves certain antidepressants that inhibit CYP2D6, not clozapine causing or exacerbating hot flushes. 2
CYP2D6 Inhibition and Endoxifen Levels
Potent CYP2D6 inhibitors (paroxetine, fluoxetine) decrease plasma endoxifen levels by interfering with the enzymatic conversion of tamoxifen to endoxifen. 2
This interaction reduces tamoxifen efficacy, not hot flush incidence. 4
Switching from potent to weak CYP2D6 inhibitors increases endoxifen exposure approximately 3-fold, which could theoretically increase hot flushes as a marker of drug bioavailability. 4
Clinical Implications
If a patient on tamoxifen (producing endoxifen) experiences hot flushes, this is expected and may actually indicate adequate drug metabolism and therapeutic effect. 2
Management Approach
Hot flushes from endoxifen/tamoxifen can be managed with:
Avoid paroxetine and fluoxetine in patients taking tamoxifen, as they interfere with tamoxifen metabolism through CYP2D6 inhibition. 1
Important Caveat
Clozapine has no documented interaction with tamoxifen metabolism or endoxifen formation, and there is no evidence that combining these medications increases hot flush incidence beyond what would be expected from endoxifen alone. 3