Doxorubicin is a major substrate of cytochrome P450 CYP3A4 and CYP2D6 and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4, CYP2D6 and/or P-gp (e.g., verapamil) resulting in increased concentration and clinical effect of doxorubicin. Inducers of CYP3A4 (e.g., phenobarbital, phenytoin, St. John's Wort) and P-gp inducers may decrease the concentration of doxorubicin.
Doxorubicin is mainly used in combination with other cytotoxic agents. Additive toxicity may occur, especially with regard to bone marrow/haematologic and gastrointestinal effects (see Precautions).
Adjuvant Chemotherapy Involving Doxorubicin: It is not recommended that doxorubicin be used routinely as adjuvant chemotherapy in any tumour category. The activity of doxorubicin in combination with other drugs is affected not only by the nature of the drug itself, but also by the schedule of administration. It is strongly recommended that in situations where doxorubicin is intended for use as adjuvant chemotherapy, higher authorities as well as the Hospital Ethical Committee be consulted.
Cyclophosphamide: Concurrent cyclophosphamide treatment sensitises the heart to the cardiotoxic effects of doxorubicin (see Precautions). Doxorubicin may exacerbate cyclophosphamide cystitis.
Cyclosporin: The addition of cyclosporin to doxorubicin may result in increases in area under the concentration-time curve (AUC) for both doxorubicin and doxorubicinol, possibly due to a decrease in clearance of the parent drug and a decrease in metabolism of doxorubicinol. Literature reports suggest that adding cyclosporin to doxorubicin results in more profound and prolonged hematologic toxicity than that observed with doxorubicin alone. Coma and seizures have also been described with concomitant administration of cyclosporin and doxorubicin.
Heparin: Doxorubicin should not be mixed with heparin since it has been reported that these drugs are incompatible to the extent that a precipitate may form.
Mediastinal Radiotherapy: Concurrent mediastinal radiotherapy and doxorubicin may be associated with enhanced myocardial toxicity of doxorubicin (see Precautions).
Paclitaxel: Paclitaxel can cause increased plasma concentration of doxorubicin and/or its metabolites when given prior to doxorubicin. Certain data indicate that this effect is minor when anthracycline is administered prior to paclitaxel.
Propranolol: In view of the finding that doxorubicin and propranolol have both been shown to inhibit cardiac mitochondrial CoQ10 enzymes it is possible that such a drug interaction may result in an additive cardiotoxic effect.
Radiotherapy: Concurrent radiotherapy and doxorubicin treatment may be associated with increased radiation toxicity, i.e., skin reactions and mucositis.
Sorafenib: Both increases (21% - 47%) and no change in the AUC of doxorubicin were observed with concomitant treatment with sorafenib 400 mg twice daily. The clinical significance of these findings is unknown.