Cyclophosphamide interactions

Levesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest 2003 111(2) 187-196. 

The following drug classes may have a potential drug interaction with nevirapine Antiarrhythmics, anticonvulsants, antifungals, calcium channel blockers, cancer chemotherapy (cyclophosphamide), ergot alkaloids, immunosuppressants, motility agents, opiate agonists. 

Amifostine (Elhyol) [Antineoplastic/Thiophosphate Cytoprotective] Uses Xerostomia prophylaxis during RT (head, neck, ovarian, NSCLQ -I- renal tox w/ rqjeated cisplatin Action Prodrug, dqjhosphorylated by alkaline phosphatase to active thiol metabohte Dose 910 mg/mVd 15-min IV inf 30 min prior to chemo Caution [C, +/—] CV Dz Disp Inj SE Transient X BP (>60%), NA, flushing w/ hot or cold chills, dizziness, X Ca % somnolence, sneezing Notes Does not -1- effectiveness of cyclophosphamide + cisplatin chemo Interactions T Effects W/ antih5 pertensives EMS Monitor BP for hypotension OD Severe hypotension treat w/IV fluids... 

Trastuzumab (Herceptin) [Antineeplastic/Monoover express the HERlIneu. protein breast CA adjuvant, w/ doxorubicin, cyclophosphamide, and paclitaxel if pt HER2/neu(+) Action MoAb binds human EGF receptor 2 protein HER2) mediates cellular cytotox Dose Per protocol, typical 2 mg/kg/IV/wk Caution [B, ] CV dysfxn, alla-gy/inf Rxns Contra Live vaccines Disp Inj SE Anemia, cardiomyopathy, nephrotic synd, pneumonitis Interactions t Risk of cardiac dysfxn W/ anthracycline, cyclophosphamide, doxorubicin, epirubicin EMS Cardiomyopathy, ventricular dysfxn and pulm tox have been reported monitor for Sxs of reduced cardiac Fxn OD Sxs unknown... 

Astragalus Astragalus membranaceus) Uses Rx of resp infxns, enhancement of immune system, HF Action Root saponins t diuresis, -1- BP anti-inflammatory action related to the stimulation of macrophages, t antibody formation t T-lymphocyte proliferation Available forms Caps/tabs 1-4 g tid, PO Liq ext 4-8 mL/d (1 2 ratio) dry ext 250 mg (1 8 ratio) tid, PO Notes E Immunosuppression w/ doses >28 g Interactions t Effect OF acyclovir, anticoagulants, antihypertensives, antithrombotics, antipits, intCTleukin 2, intCTferon X effect OF cyclophosphamide EMS t Risk of bleeding... 

Herceptin with cisplatin, doxorubicin or epirubicin plus cyclophosphamide, or paclitaxel. A comparison of serum levels of trastuzumab given in combination with various chemotherapeutic agents did not suggest the possibility of any pharmacokinetic interactions except in combination with paclitaxel. Although not statistically signihcant, mean serum trough concentrations of trastuzumab were consistently elevated, about 1.5-fold, when Herceptin was administered in combination with paclitaxel. However, trastuzumab and paclitaxel were used concurrently in clinical trials with positive outcome results. The concurrent administration of anthracyclines, cyclophosphamide, and trastuzumab increased the incidence and severity of cardiac dysfunction during clinical trials. 

Hicks, R.M., Wakefield, S.J., and Chowaniec, J. (1975). Evaluation of a new model to detect bladder carcinogens or co-carcinogens results obtained with saccheirine, cyclamate and cyclophosphamide, Chem.-Biol. Interactions 11,224. 

Senthilkumar, S., Yogeeta, S. K., Subashini, R., and Devaki, T. (2006). Attenuation of cyclophosphamide induced toxicity by squalene in experimental rats. Chem. Biol. Interact. 160, 252-260. 

Incompatibilities of metoclopramide depend on drug concentration, pH, and temperature. It is incompatible with cephalosporins, chloramphenicol, sodium bicarbonate, doxorubicin, cisplatin, and cyclophosphamide. Caution should be exercised with simultaneous administration of metoclopramide with lithium, sym-pathomimetics, antidepressants, bromocriptine, and carbamazepine. Omperazole interacts with tolbutamide, clarithromycin, and phenytoin. Coadministration of rantidine and cisapride increases the plasma concentration of rantidine. Abuse of senna laxative has been reported and may cause hepatitis.176-178... 

Reynolds T, Baughman S, Schofield C, Palazzolo M, Dalgard D, Thomas DA. A 3-week interaction study of rhuMAb HER2 with doxorubicin, cyclophosphamide and paclitaxel in rhesus monkeys. Toxicologist 1996 30(1) 36. 

Fleer R, Brendel M. 1982. Toxicity, interstrand cross-links and DNA fragmentation induced by activated cyclophosphamide in yeast Comparative studies on 4-hydroxyperoxy-cyclophosphamide, its monofunctional analogue, acrolein, phosphoramide mustard, and nor-nitrogen mustard. Chem Biol Interact 39 1-15. 

Lindemann H. 1984. Interaction of cyclophosphamide with DNA in isolated rat liver cell nuclei. Anticancer Res 4 53-58. 

Wildenauer DB, Oehlmann CE. 1982. Interaction of cyclophosphamide metabolites with membrane proteins An in vitro study with rabbit liver microsomes and human red blood cells. Effect of thiols. Biochem Pharmacol 31 3535-3541. 

Fig. 3 Venn-diagram for selected compounds interacting with the key MDR-related ABC transporters. MDR-substrate anticancer agents. Abbreviations VCR vincristine, VP-16 etoposide, STER steroids, TAM tamoxiphen, TKI-INHIB tyrosin kinase inhibitors e.g. STI-571, DOX doxorubicine or adriamycin, DNR daunorubicin, EPIR epirubicin, MX mitoxantrone, TOPOT topotecan, iridotecan, BISANT bisanthrone, COLCH colchicin, ACT-D actinomycin D, MYTOM mytomycin, TX methotrexate, CPHAM cyclophosphamide, CHLB chlorambucil, CARM carmustine, LCV leucovorin, HUR hydroxy urea, CISPL cisplatin, TAXOL paclitaxel. (Reproduced from [4])...

The clinical significance of the aforementioned findings is unknown. A report by Khakoo et al. (62) did not demonstrate a pharmacokinetic interaction between IFNa2i) and ribavirin or an additive effect of the combination therapy on safety assessments. In another study, administration of IFNa prior to the administration of cyclophosphamide significantly impaired the metabolism of cyclophosphamide and 4 hydrox-ycyclophosphamide. In contrast, the administration of IFNa after cyclophosphamide resulted in higher 4-hydroxy cyclophosphamide concentrations and produced a significant decrease in leukocyte count (63). 

The calcium channel blocker mibefradil (Posicor ) was removed from the market in 1998. The headline for the Pink Sheets article describing this action was "Posicor Withdrawal Reflects Complexity of Interaction Profile" (59). Products identified as potentially dangerous in combination with mibefradil included cardiac drugs, such as amiodarone, flecainide, and propafenone oncologic products, such as tamoxifen, cyclophosphamide, etoposide, ifosfamide, and vinblastine and the immunosuppressant medications cyclosporine and tacrolimus. The sponsor s decision to withdraw mibefradil was based on the complexity of the drug interaction information that would have to be communicated to ensure safe usage. 

An interaction of doxorubicin with the anti-HER2 receptor humanized monoclonal antibody, trastuzumab (Herceptin), has been reported. Most patients who received trastuzumab in early trials had been pretreated with anthracyclines. Despite this, preliminary information suggested that reduced systolic cardiac function was an adverse effect of trastuzumab (119). More recently, this problem has been further highlighted in a study of women with metastatic breast cancer (120). Patients who had not received prior anthracycline-containing adjuvant chemotherapy were at greater risk of cardiotoxicity when they received trastuzumab in combination with doxorubicin or cyclophosphamide (27 and 75% respectively), compared with only 11% of patients who received trastuzumab in combination with pachtaxel (120,121). The risk of cardiac events in patients treated with doxorubicin, cyclophosphamide, and trastuzumab increased markedly after a cumulative doxorubicin dose of 360 mg/m. This suggests synergistic cardiotoxicity with trastuzumab and doxorubicin. Trastuzumab is therefore currently licensed only for use in conjunction with pacli-taxel or docetaxel and not with conventional doxorubicin. 

Cyclophosphamide is a prodrug that requires cjdochrome P450 -dependent hepatic activation to produce alkylating species and several inactive by-products. However, very few metabolic interactions involving cyclophosphamide have been reported. In a retrospective study of 22 children treated with cyclophosphamide for cancer or bone marrow transplantation, cyclophosphamide clearance was significantly lower in nine patients taking fluconazole compared with 13 patients not taking it (77). In vitro studies in human hver microsomes confirmed that the rate of 4-hydroxylation of cyclophosphamide was inhibited by fluconazole. 

Daily prednisolone significantly reduced the total clearance of cyclophosphamide and the peak concentration and AUC of 4-hydroxycyclophosphamide (78). It is not known whether this interaction has clinical consequences. 

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