Drug Interactions between Docefrez and Nuedexta

GENERALLY AVOID: Coadministration with potent CYP450 2D6 inhibitors (e.g., quinidine, terbinafine) may significantly increase the plasma concentrations of dextromethorphan in patients who are extensive metabolizers of this isoenzyme (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). The proposed mechanism is inhibition of the CYP450 2D6-mediated O-demethylation of dextromethorphan. Studies in humans have shown an increase in systemic exposure of dextromethorphan of up to 43-fold when given concurrently with quinidine. Increased plasma concentrations increase the risk of dextromethorphan-related adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome. However, this interaction has also been used clinically, with dextromethorphan in combination with quinidine indicated by some authorities for the treatment of pseudobulbar affect. Data evaluating the impact of this interaction in patients who are poor metabolizers of CYP450 2D6 are limited; most studies include extensive metabolizers of this isoenzyme. It is expected that poor metabolizers would have elevated dextromethorphan levels without concurrent quinidine

MANAGEMENT: The combination of dextromethorphan with potent CYP450 2D6 inhibitors should be generally avoided. Some manufacturers consider the concomitant use of dextromethorphan and selective serotonin reuptake inhibitors contraindicated. If use is considered necessary, the patient should be monitored for signs of dextromethorphan adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome, and advised to notify their health care professional if these adverse effects develop or worsen. Dose reduction of dextromethorphan may also be required.

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MONITOR: Coadministration with inhibitors of P-glycoprotein (P-gp) may increase the blood concentrations of the taxanes, docetaxel and paclitaxel, which have been shown to be substrates of the efflux transporter. The clinical significance has not been fully elucidated. However, use of dual CYP450 3A4 and P-gp inhibitors such as ketoconazole, amiodarone, and dronedarone have been shown to increase the systemic exposure of docetaxel and paclitaxel. In a case report involving a 77-year-old woman with HER2-positive invasive ductal breast cancer on long-term amiodarone therapy, 4 cycles of paclitaxel (80 mg/m2 weekly) and trastuzumab led to development of increasing abdominal discomfort and skin lesions. However, switching to reduced dose docetaxel (100 mg or 75 mg/m2 weekly) led to the development of severe skin and mucosal toxicity, requiring hospitalization 8 days after the first docetaxel dose was administered. Analysis of two blood samples taken 9 and 10 days after docetaxel administration showed an approximately fivefold increase in its AUC as well as the presence of paclitaxel in unquantifiable levels, 20 and 21 days after it was last administered. The authors of this case study propose that, in addition to CYP450 3A4 inhibition, P-gp inhibition due to amiodarone may have contributed to the interaction.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of paclitaxel or docetaxel therapy should be considered during coadministration with P-gp inhibitors, including adverse effects such as myelosuppression, stomatitis, neurotoxicity (e.g., paraesthesia, dysesthesia, pain), myalgia, asthenia, fluid retention, nausea, vomiting, and diarrhea. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever a P-gp inhibitor is added to or withdrawn from therapy.

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