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DRUG INTERACTIONS CORNER Daniel
S. Streetman, Section Advisor
New data published on Vinca alkaloid drug interactions
Key point: Three recently published papers highlight
drug interactions between vincristine and azole antifungals, including
posaconazole (Noxafil—Schering-Plough), and between vinorelbine
and clarithromycin. These interactions result in increased
chemotherapy-associated toxicities and are believed to be mediated by
inhibition of cytochrome P450 (CYP)3A4 and/or P-glycoprotein.
Finer points: Eiden and colleagues described a case
report of vincristine neurotoxicity exacerbated by coadministration of
posaconazole. A 9-year-old girl with an acute lymphoblastic leukemia
relapse was treated with posaconazole 50 mg three times daily, started 5
days before chemotherapy as an antifungal prophylactic agent.
Vincristine 1.5 mg/m2 was given on days 1 and 6 in addition
to other chemotherapeutic agents. Six days after the second dose of
vincristine, the patient experienced grade 3 lower extremities
peripheral neuropathy and gastrointestinal (GI) distress. After a week,
symptoms progressed to impaired consciousness, confusion, agitation, and
seizures. Once posaconazole was discontinued, all symptoms resolved
within 7 days. The investigators attributed this interaction to
inhibition of CYP3A4 by posaconazole, which is the enzyme responsible
for vincristine metabolism. In addition, they theorized that
posaconazole may also inhibit P-glycoprotein–mediated vincristine
efflux, thereby increasing intracellular vincristine levels. They
concluded that, although causality cannot be proven with this single
case report, clinicians need to be aware of the risks associated with
the coadministration of these agents.
Harnicar and colleagues conducted a retrospective study to assess if
vincristine dosing is being modified when given concurrently with an
azole antifungal (fluconazole, voriconazole [Vfend—Pfizer], or
posaconazole) and if patients on concurrent therapy (n = 29) had
increased GI adverse events compared with those on vincristine alone (n
= 21). The investigators reported that more patients on combination
therapy had a vincristine dosage modification, which included dose
reductions, dose delays, or therapy discontinuation, compared with those
not receiving an azole antifungal (58.6% vs. 23.8%, P = 0.02).
In addition, symptoms of decreased peristalsis, occurring primarily
after the second vincristine dose, were more common in patients on
combination therapy (65.5% vs. 28.6%, P =0.003). Patients on
combination therapy were also less likely to complete their full course
of vincristine therapy (48.3% vs. 9.5%, P = 0.005).
Yano and colleagues conducted a retrospective study to evaluate the
risk of vinorelbine-induced neutropenia when given with clarithromycin,
a CYP3A4 and P-glycoprotein inhibitor. Of 59 vinorelbine chemotherapy
courses, 19 were administered with clarithromycin and 40 were not. The
investigators reported that more episodes of grade 3 or 4 neutropenia
occurred among patients who were given clarithromycin (63.2% vs. 27.5%,
P = 0.012) and that the incidence of grade 4 neutropenia was
significantly higher in this group (31.6% vs. 2.5%, P =
0.0033).
What you need to know: These recent data highlight
the importance of being vigilant for potential drug interactions between
Vinca alkaloids and inhibitors of CYP3A4 and/or P-glycoprotein such as
azole antifungals and clarithromycin. If patients receiving vincristine
or vinorelbine require CYP3A4/P-glycoprotein inhibitors, steps should be
taken to reduce the dose of the Vinca alkaloid or delay therapy if
necessary. Institutional guidelines should be developed to standardize
the care of patients receiving Vinca alkaloids with azole antifungals
because these antifungal agents are commonly used in oncology patients.
Further research is needed to fully characterize the interaction between
vinorelbine and clarithromycin; however, caution should be exercised if
this combination is coadministered.
What your patients need to know: Patients receiving
Vinca alkaloids as part of their chemotherapeutic regimen should be
counseled on the potential for drug interactions. Tell patients to
report all medications and any adverse events they may be experiencing
to their health care providers.
Sources:
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