t tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer.
J Clin Oncol 1996; 14: 2731-2737

*Mitomycin C
Concomitant use of mitomycin C and tamoxifen resulted in a higher incidence of anaemia, thrombocytopenia and increased risk of haemolytic uraemic syndrome.

References
Montes A et al
A toxic interaction between mitomycin C and tamoxifen causing the haemolytic uraemic syndrome.
Eur J Cancer 1993; 13: 1854-1857

*Mitoxantrone
A synergistic effect in drug sensitive and multidrug resistant cells, possibly due to an inhibition of mitoxantrone efflux from the cells, could be observed between mitoxantrone and tamoxifen.

References
Desai PB et al
Effect of tamoxifen on mitoxantrone cytotoxicity in drug-sensitive and multidrug-resistant MCF-7 cells.
Cancer Chemother Pharmacol 1995; 36(5): 368-372

*Phenobarbital
A lower steady-state serum level of tamoxifen was observed in one patient treated with concomitant phenobarbital (26 ng/ml vs. 122 ng/ml).

References
Product Information Nolvadex 1999

*Theophylline
Oral administration of tamoxifen increased the clearance of theophylline by 39% in Sprague-Dawley rats. 

References
Poisson D et al
Effect of tamoxifen on the pharmacokinetics of theophylline in rats.
J Pharm Pharmacol 1997; 49(1): 40-42

*Vinblastine
In a study 63 patients with renal cell carcinoma were treated with vinblastine (1.2 - 1.5 mg/mē/day for 4 - 5 days) or with vinblastine plus high dose tamoxifen (300 mg/mē/day). Tamoxifen was not able to modulate resistance.

References
Samuels BL et al
Modulation of vinblastine resistance in metastatic renal cell carcinoma with cyclosporin A or tamoxifen : A Cancer and Leukemia Group B study.
Clin Cancer Res 1997; 3: 1977-1984

*Warfarin
A potentially fatal interaction of tamoxifen with warfarin is documented in several publications (Tenni et al; Lalich and Tenni; Lodwick et al). The anticoagulant effect of warfarin is markedly increased by tamoxifen. The reason for this severe interaction may be the inhibition of the cytochrome P-450 system by tamoxifen.

References
Lalich DL, Tenni PC
Tamoxifen and warfarin - A previously undocumented drug interaction.
Aust J Hosp Pharm 1988; 18: 83

Lodwick R et al
Life threatening interaction between tamoxifen and warfarin.
Br Med J Clin Res 1987; 295: 1141

Tenni P et al
Life threatening interaction between tamoxifen and warfarin.
Br Med J 1989; 298: 93






Tauromustine
________________________________________________________________

*Fluorouracil
Simultaneous administration or 24 hours pretreatment with fluorouracil alters the pharmacokinetic profile of tauromustine in mice. 5-FU may interact with the specific tauromustine carrier mechanism to reduce the rate of uptake and thus lower circulating levels.

References
Hill SR et al
Combination with 5-fluorouracil alters the pharmacokinetics of the nitrosurea tauromustine in NMRI mice.
Br J Cancer 1993; 67: 62





Tegafur
________________________________________________________________

*Remark
Tegafur is a masked prodrug, which is converted into fluorouracil. For possible interactions, therefore, see also fluorouracil.

*Fadrazole 
From experiments using human hepatic microsomes in vitro, it was concluded that the biotransformation of tegafur was not influenced by fadrazole. The inhibition constant (Ki) value of fadrazole, when administered alone, was 1.14 (M, but 0.05 (M when coadministered with tegafur.

References
Nagayama S et al
Drug-drug-interaction between tegafur and fadrazole.
Proc Amer Assoc Cancer Res 2000; 41: 700-701

*Sorivudine
Eighteen patients have died in Japan because of an interaction of sorivudine with oral 5-fluorouracil prodrugs resulting in marked decreases in leukocytes and thrombocytes, marked atrophy of the intestinal mucosa, diarrhea with bloody flux and severe anorexia. To investigate the underlying toxicokinetic mechanism in greater detail a study was performed in rats. Both drugs were orally administered simultaneously once daily. All rats died within 10 days, whereas rats on sorivudine or tegafur alone showed no change over 20 days compared with controls. Extreme enhancement of the tissue 5-fluorouracil levels as a result of retarded 5-FU catabolism was the cause of the observed toxicity.

References
Okuda H et al
A possible mechanism of eighteen patient deaths caused by interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs.
J Pharmacol Exp Ther 1998; 287(2): 791-799


Temozolomide
________________________________________________________________

*Food
Rate and extent of absorption were found to be decreased when temozolomide was administered with food (peak plasma concentration: -32%, AUC: -9%). The time to maximum concentration was also increased from 1.1 hours to 2.25 hours when temozolomide was given with a high-fat meal. Consistency of temozolomide administration with respect to meals is recommended.

References 
Product Information Temodar(, 1999

Brada M et al
Phase I dose-escalation and pharmacokinetic study of temozolomide 
(SCH 52365) for refractory or relapsing malignancies.
Br J Cancer 1999; 81: 1022-1030

*Ranitidine
No alterations of the maximum concentration or the area under the concentration-time curve values for temozolomide were found in a multiple-dose study after coadministration with ranitidine.

References 
Product Information Temodar(, 1999

*Valproate
Population analysis indicates that valproic acid decreases the clearance of temozolomide by approximately 5%. The clinical significance of that interaction is uncertain.

References 
Product Information Temodar(, 1999




Teniposide
________________________________________________________________

*Anticonvulsants
The systemic clearance of teniposide consistently increased by a factor of 2-3 by concomitant therapy with phenobarbital or phenytoin (Baker et al).
Most anticonvulsant drugs (phenytoin, phenobarbital, carbamazepine) induce drug metabolising enzymes and thereby increase the clearance of anticancer drugs when given at the same time. When the efficacy of antileukaemic therapy was compared in 40 children who received anticonvulsant therapy and in 676 children who did not, a significantly worse event-free survival with a higher rate of haematological and CNS relapses was found for patients with B-cell ALL receiving anticonvulsants. An increased systemic clearance was found for teniposide and methotrexate, but not for cytarabine (Relling et al).

References
Baker DK et al
Increased teniposide clearance with concomitant anticonvulsant therapy.
J Clin Oncol 1992; 10: 311-315

Relling MV et al
Chronic anticonvulsant therapy reduces the efficacy of chemotherapy for childhood acute lymphoblastic leukemia (ALL).
Blood 1999; 94(10): abstr 1294

*Cyclosporin
Patients with refractory metastatic renal cell carcinoma were concomitantly treated with teniposide and cyclosporin. AUC of teniposide was significantly higher and terminal half-life was increased (1.72-fold) after cyclosporin administration. Systemic clearance was decreased by 1.4-fold.

References
Toffoli G et al
Cyclosporin A as a multidrug-resistant modulator in patients with renal cell carcinoma treated with teniposide.
Br J Cancer 1997; 75(5): 715-721

*Cytarabine 
Prior exposure to teniposide (and etoposide, but not to amsacrine, mitoxantrone, anthracyclines and asparaginase) decreased the intracellular cytarabine triphosphate formation and thus should not immediately precede cytarabine administration in clinical trials.

References
Ehninger G et al
Interaction of cytosine arabinoside uptake and cytosine arabinoside triphosphate with various cytotoxic drugs.
Ann Hematol 1991; 62: A30 (abstr 95)

*Methotrexate
In 50 patients treated with cyclophosphamide, methotrexate, and etoposide 12 cases (24%) of interstitial pneumonitis were seen. This unusually high incidence of pulmonary toxicity appears to represent the clinical manifestation of a known in vitro drug interaction between methotrexate and etoposide, which may exists for teniposide as well.

References
Zimmermann MS et al
Chemotherapy induced interstitial pneumonitis during treatment of small cell anaplastic lung cancer.
J Clin Oncol 1984; 2: 396-405

*Vincristine
In a study with 9 patients with non-Hodgkin's lymphoma vincristine neuropathy was enhanced by administration of teniposide, doxorubicin, cyclophosphamide and methotrexate. Vincristine (maximum dose 2mg) was given on day 8, 15 and 22. Symmetrical paresthesia was observed in 8 patients. The time of onset of neuropathy was variable, but occurred as early as the second week of therapy. Symptoms slowly resolved over 2-9 months.

References
Griffiths JD et al
Vincristine neurotoxicity enhanced in combination chemotherapy including both teniposide and vincristine.
Cancer Treat Rep 1986; 70: 519-521





Thalidomide
________________________________________________________________

*Contraceptives
In two crossover studies, thalidomide did not alter the pharmacokinetics of ethinyl estradiol or norethindrone. The efficacy of oral contraceptives containing ethinyl estradiol or norethindrone, therefore, should not be affected by concomitant thalidomide therapy.

References 
Scheffler MR et al
Thalidomide does not alter estrogen-progesterone hormone single-dose pharmacokinetics.
Clin Pharmacol Ther 1999; 65: 483-490

Trapnell CB et al
Thalidomide does not alter the pharmacokinetics of ethinyl estradiol and norethindrone.
Clin Pharmacol Ther 1998; 64: 597-602

*Dexamethasone
A possible interaction of thalidomide with concomitant dexamethasone leading to toxic epidermal necrolysis was seen in a 64-year-old myeloma patient. The authors recommend that until a safe dose schedule has been determined, dexamethasone (or other corticosteroids) should not be used in combination with thalidomide for the treatment of newly diagnosed myeloma, except in closely monitored trials.

References 
Rajkumar SV et al
Life-threatening toxic epidermal necrolysis with thalidomide therapy for myeloma.
N Engl J Med 2000; 343: 972-973



Thioguanine
________________________________________________________________

*Remark
Azathioprine, mercaptopurine and thioguanine are metabolized by thiopurine methyltransferase (TPMTase), forming thioguanine nucleotides as terminal metabolites. Toxicity may be apparent in subjects with low TPMTase activity phenotype.

References
Escousse A et al
6-Mercaptopurine pharmakokinetics after use of azathioprine in renal transplant recipients with intermediate or high thiopurine methyl transferase activity phenotype.
J Pharm Pharmacol 1998; 50(11) :1261-1266

*Busulfan
In patients with continuous busulfan and thioguanine therapy nodular regenerative hyperplasia of the liver, oesophageal varices, and portal hypertension were observed.

References
Key NS et al
Oesophageal varices associated with busulfan-thioguanine combination therapy for chronic myeloid leukemia.
Lancet 1987; 2: 1050-1052

*Daunorubicin
In 13 patients with acute non-lymphocytic leukaemia treated with daunorubicin, the combined use of cytarabine, thioguanine, and pyrimethamine increased the expected plasma concentration of daunorubicin. Probably the increased plasma levels of daunorubicin will be accompanied by increased toxicity.

References
Riggs CE et al
Alteration of plasma daunorubicin pharmacokinetics by combination chemotherapy.
Clin Res 1980; 28: 242A





Thiotepa
________________________________________________________________

*Acyclovir
No inhibition of the metabolism of thioTEPA to form TEPA was observed for acyclovir.

References 
Van Maanen MJ et al
Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate.
Anticancer Res 2000; 20: 1711-1716

*Amphotericin
No inhibition of the metabolism of thioTEPA to form TEPA was observed for amphotericin B, whereas the conversion to monoglutathionyl thioTEPA was inhibited with an IC50 value of 55 mM (which is far higher than therapeutic drug levels).

References 
Van Maanen MJ et al
Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate.
Anticancer Res 2000; 20: 1711-1716

*Carboplatin 
No inhibition of the metabolism of thioTEPA to form TEPA was observed for carboplatin.

References 
Van Maanen MJ et al
Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate.
Anticancer Res 2000; 20: 1711-1716

*Ciproflocaxin
No inhibition of the metabolism of thioTEPA to form TEPA was observed for ciproflocaxin.

References 
Van Maanen MJ et al
Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate.
Anticancer Res 2000; 20: 1711-1716

*Cyclophosphamide
A strong inhibition of cyclophosphamide bioactivation by thiotepa in high-dose chemotherapy regimens was reported by at least two working groups (Anderson et al; Chen et al; Huitema et al). Administration of thiotepa one hour prior to cyclophosphamide resulted in decreased Cmax (-62%) and AUC (-26%) values of 4-hydroxycyclophosphamide compared to those of the reverse sequence of administration. No change in the pharmacokinetics of thiotepa (Ackland et al) or in the inhibition of the formation of TEPA by cyclophosphamide (Huitema et al; van Maanen et al) was observed. Based on their experience Huitema and colleagues seriously question the practice of simultaneous continuous infusion of cyclophosphamide and thiotepa and suggest that the sequencing and scheduling of these two agents in high-dose chemotherapy regimens may be of critical importance.

References
Ackland SP et al
Human plasma pharmacokinetics of thiotepa following administration of high-dose thiotepa and cyclophosphamide.
J Clin Oncol 1988; 6: 1192-1196

Anderson LW et al
Cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide kinetics in patients receiving high-dose cyclophosphamide chemotherapy.
Clin Cancer Res 1996; 2: 1481-1487

Chen T-L et al
Nonlinear pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide/ aldophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation.
Drug Metab Dispos 1997; 25: 544-551

Huitema ADR et al
Reduction of cyclophosphamide bioactivation by thioTEPA: critical sequence-dependency in high-dose chemotherapy regimens.
Cancer Chemother Pharmacol 2000; 46: 119-127

Van Maanen MJ et al
Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate.
Anticancer Res 2000; 20: 1711-1716

*Dexamethasone 
No inhibition of the metabolism of thioTEPA to form TEPA was observed for dexamethasone.

References 
Van Maanen MJ et al
Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate.
Anticancer Res 2000; 20: 1711-1716

*Fluconazol
No inhibition of the metabolism of thioTEPA to form TEPA was observed for fluconazol.

References 
Van Maanen MJ et al
Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate.
Anticancer Res 2000; 20: 1711-1716

*Granisetron
No inhibition of the metabolism of thioTEPA to form TEPA was observed for granisetron.

References 
Van Maanen MJ et al
Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate.
Anticancer Res 2000; 20: 1711-1716

*Itraconazol
No inhibition of the metabolism of thioTEPA to form TEPA was observed for itraconazol. The conversion to monoglutathionyl-thioTEPA was inhibited with an IC50 value of 256 mM (which is far higher than therapeutic drug levels).

References 
Van Maanen MJ et al
Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate
Anticancer Res 2000; 20: 1711-1716

*Lorazepam
No inhibition of the metabolism of thioTEPA to form TEPA was observed for lorazepam.

References 
Van Maanen MJ et al
Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate.
Anticancer Res 2000; 20: 1711-1716

*Ondansetron
No inhibition of the metabolism of thioTEPA to form TEPA was observed for ondansetron. The conversion to monoglutathionyl-thioTEPA was inhibited with an IC50 value of 40 mM (which is far higher than therapeutic drug levels).

References 
Van Maanen MJ et al
Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate.
Anticancer Res 2000; 20: 1711-1716

*Ranitidine
No inhibition of the metabolism of thioTEPA to form TEPA was observed for ranitidine. 

References 
Van Maanen MJ et al
Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate.
Anticancer Res 2000; 20: 1711-1716

*Succinylcholine
Alkylating agents may inhibit plasma pseudocholinesterase resulting in reduced metabolism of succinylcholine. A prolonged action of succinylcholine is observed.

References
Viby-Morgensen J
Interaction of other drugs with muscle relaxants.
Semin Anesth 1985; 4: 52-64





Tirapazamine
________________________________________________________________

*Carboplatin 
Preclinical studies with an in vivo/in vitro clonogenic assay (RIF-1 murine tumour transplanted into C3H mice) were performed to examine the interaction of tirapazamine with chemotherapeutic agents, including carboplatin, cyclophosphamide, doxorubicin, etoposide, fluorouracil, paclitaxel, and vinorelbine. The greatest enhancement of antitumour activity was with carboplatin, with the maximum effectiveness when tirapazamine was given 2-3 hours before carboplatin.

References 
Dorie MJ, Brown JM
Modification of the antitumor activity of chemotherapeutic drugs by the hypoxic cytotoxic agent tirapazamine.
Cancer Chemother Pharmacol 1997; 39: 361-366

*Cisplatin
In preclinical studies as well as in phase II and III clinical trials tirapazamine has been shown to potentiate the antitumour efficacy of cisplatin without increasing its systemic toxicity. This cisplatin potentiation depends on tirapazamine exposure being at oxygen concentrations below 1%, which are typical of many cells in tumours but not in normal tissues. The mechanism of the interaction at the cellular level appears to be through a potentiation of cisplatin-induced DNA interstrand cross-links, possibly as a result of a diminished or delayed repair of these lesions.

References 
Kovacs MS et al
Cisplatin anti-tumour potentiation by tirapazamine results from a hypoxia-dependent cellular sensitization to cisplatin.
Br J Cancer 1999; 80: 1245-1251

Wouters BG et al
Tirapazamine: a new drug producing tumor specific enhancement of platinum-based chemotherapy in non-small cell lung cancer. 
Ann Oncol 1999; 10 (Suppl 5): 29-33

*Cyclophosphamide 
Additive tumour cell killing was observed in preclinical studies when tirapazamine was combined with cyclophosphamide. The activity of cyclophosphamide was most enhanced when tirapazamine was given 24 hours in advance (Dorie and Brown). No pharmacokinetic interactions between cyclophosphamide and tirapazamine were found in a second investigation (Gatzemeier et al).

References 
Dorie MJ, Brown M
Modification of the antitumor activity of chemotherapeutic drugs by the hypoxic cytotoxic agent tirapazamine. 
Cancer Chemother Pharmacol 1997; 39: 361-366

Gatzemeier U et al
Tirapazamine-cisplatin: the synergy (review).
Br J Cancer 1998; 77 (Suppl 4): 15-17

*Fluorouracil 
Preclinical studies with an in vivo/in vitro clonogenic assay (RIF-1 murine tumour transplanted into C3H mice) were performed to examine the interaction of tirapazamine with chemotherapeutic agents, including carboplatin, cyclophosphamide, doxorubicin, etoposide, fluorouracil, paclitaxel and vinorelbine. As with the other drugs at least an additive tumour cell killing was observed when tirapazamine was combined with fluorouracil, unfortunately, the systemic toxicity of fluorouracil was enhanced at the same time, indicating no potential clinical benefit for that combination.

References 
Dorie MJ, Brown JM
Modification of the antitumor activity of chemotherapeutic drugs by the hypoxic cytotoxic agent tirapazamine. 
Cancer Chemother Pharmacol 1997; 39: 361-366





Topotecan
________________________________________________________________

*Cisplatin
Severe or fatal myelosuppression was observed during concomitant use of topotecan (1.25 mg/mē/day for 5 days) and cisplatin (50 mg/mē).
Administration of cisplatin before topotecan resulted in worse thrombocytopenia and neutropenia than topotecan preceding cisplatin (Rowinsky et al).

References
Product Information Hycamtin 1996

Rowinsky EK et al
Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence.
J Clin Oncol 1996; 14: 3074-3084

*Corticosteroids
No change of pharmakokinetics were observed during concomitant use of topotecan and corticosteroids.

References
Product Information Hycamtin 1997

*Cyclosporin
Topotecan treatment caused cyclosporin overdosage in a liver transplant patient. Topotecan may act as a Cytochrome P 450 3A inhibitor. A 3-fold increase of Cmax of cyclosporin was observed.

References
Goldwasser F et al
Topotecan is a P450-3A inhibitor: clinical and pharmacological evidence.
Proc Amer Assoc Cancer Res 1999; 40 (90 Meet): 40

*Docetaxel
Twenty-two patients were treated with docetaxel and topotecan. On cycle 1 docetaxel was administered (60-80mg/m2) on day 1 and topotecan (0.75mg/m2) on days 1 to 4. On cycle 2 topotecan was administered on days 1 to 4 and docetaxel on day 4. When docetaxel was given on day 4 an approximately 50% decrease in docetaxel clearance and increased neutropenia was observed. 

References
Zamboni WC et al
Pharmacokinetic and pharmacodynamic study of the combination of docetaxel and topotecan in patients with solid tumors.
J Clin Oncol 2000; 18: 3288-3294

*Filgrastim
Combined use of topotecan with filgrastim resulted in prolonged duration of neutropenia. Filgrastim should be given after completion of topotecan therapy.

References
Product Information Hycamtin 1996

*Granisetron, Ondansetron
Kinetics of topotecan were not altered by concomitant use of granisetron or ondansetron.

References
Product Information Hycamtin 1997

*Morphine
No change of pharmakokinetics were observed during concomitant use of topotecan and morphine.

References
Product Information Hycamtin 1997

*Phenytoin
Phenytoin coadministration increased topotecan clearance and plasma AUC of the active metabolite N-desmethyl topotecan.

References
Zamboni WC et al
Phenytoin alters the disposition of topotecan and N-desmethyl topotecan in a patient with medulloblastoma.
Clin Cancer Res 1998; 4(3): 783-789

*Quercetin
Drug resistance is a common problem in antineoplastic therapy. In a fibrosarcoma cell line with an overexpression of heat shock proteins, which are known as mediatiors of drug resistance, cells showed a marked elevation of cell survival. Quercetin, which is a known inhibitor of heat shock transcription factor, could be used to enhance cytotoxic activity of topotecan.

References
Sliutz G et al
Drug resistance against gemcitabine and topotecan mediated by constitutive hsp70 overexpression in vitro: implication of quercetin as sensitizer in chemotherapy.
Br J Cancer 1996; 74: 172-7

*Ranitidine
In a randomized, 2-period crossover trial of 18 cancer patients the prior administration of ranitidine had no influence on any of the plasma pharmacokinetic parameters for either the active lactone or total topotecan. No dosage adjustment of p.o. topotecan, therefore, seems to be necessary in patients who are pretreated with an H2 antagonist such as p.o. ranitidine.

References
Akhtar S et al
Pretreatment with ranitidine does not reduce the bioavailability of orally administered topotecan.
Cancer Chemother Pharmacol 2000; 46: 204-210

*Vincristine 
Topotecan and vincristine had no effect on each other's AUC, half-life and clearance in non-tumour-bearing mice.

References 
Ma MK et al
Topotecan disposition is not altered in combination with vincristine in a murine model.
Pharmacother 1999; 19: 1230-1231


Toremifene
________________________________________________________________

*Remark
Because of similarities between tamoxifen and toremifene, those interactions known for tamoxifen also may be expected for toremifene.

*Doxorubicin 
Doxorubicin at a dose of 60 mg/mē was administered to 11 patients in the absence of toremifene to establish baseline doxorubicin pharmacokinetics. Six of these patients then received 600 mg/day toremifene for 5 days with doxorubicin on day 5. No significant change in the doxorubicin elimination kinetics with or without toremifene therapy was observed, suggesting that toremifene does not appear to interfere with the elimination kinetics of doxorubicin.

References 
Wurz GT et al
Pharmacokinetic analysis of high-dose toremifene in combination with doxorubicin. 
Cancer Chemother Pharmacol 1998; 42: 363-366

*Food
The pharmacokinetics of oral toremifene (60mg) was tested in a cross-over trial with 12 healthy male subjects, once after a 14-hour fast, and once following a high-fat meal. Although maximum blood level was delayed after high-fat meal no changes in Cmax, AUC or t1/2 were observed. As the drug has a relatively long half-life, toremifene can be taken equally well in fasted conditions or with meals.

References
Antilla M
Effect of food on the pharmacokinetics of toremifene.
Eur J Cancer 1997; 33 (Suppl 8): abstr 1144 (ECCO 9)

*Melphalan
An antagonism between melphalan and toremifene was proven in an animal tumour model.

References
Osborne CK
Interactions of tamoxifen with cytotoxic chemotherapy for breast cancer.
In Jordan VC: Long-term tamoxifen treatment for breast cancer 1994; 181-198

*Mitoxantrone
A synergistic effect in drug sensitive and multidrug resistant cells possibly due to an inhibition of mitoxantrone efflux from the cells could be observed.

References
Bhardwaj R et al
Activity of mitoxantrone in combination with toremifene against drug-sensitive and multidrug resistant MCF-7 cells in vitro.
Proc Amer Assoc Cancer Res 1993; abstr 1779

*Warfarin
A potentially fatal interaction of tamoxifen with warfarin is documented in several publications (Tenni et al; Lalich and Tenni; Lodwick et al). The reason for this severe interaction may be the inhibition of cytochrome P-450 system by tamoxifen. It is possible that such an interaction exists for toremifene as well (Product Info Fareston). However, the binding of toremifene as well as of warfarin to serum proteins was not affected in vitro when both drugs were given together in therapeutic concentrations (Laakso and Anttila).

References
Laakso S, Anttila M
Binding of toremifene to human serum proteins: Study on potential interactions between toremifene and other highly protein-bound drugs in vitro.
Eur J Cancer 1997; 33 (Suppl 8): abstr 1137 (ECCO 9)

Lalich DL, Tenni PC
Tamoxifen and warfarin - A previously undocumented drug interaction.
Aust J Hosp Pharm 1988; 18: 83

Lodwick R et al
Life threatening interaction between tamoxifen and warfarin.
Br Med J Clin Res 1987; 295: 1141

Product Information Fareston 1997

Tenni P et al
Life threatening interaction between tamoxifen and warfarin.
Br Med J 1989; 298: 93




Trastuzumab (Herceptin)
________________________________________________________________

*Anthracyclines
Trastuzumab can cause acute heart failure when used concomitantly with anthracyclines (especially doxorubicin and epirubicin). It also appears to cause heart failure when used after anthracyclines. Patients who are receiving or who have received anthracyclines, particularly in the recent past, should be carefully monitored during trastuzumab therapy and should always have a baseline ejection fraction determined to detect underlying asymptomatic left ventricular dysfunction. Alternative therapy should be considered and/or the patient closely monitored in case of significant cardiac dysfunction.

References 
Keefe DL
Cardiovascular emergencies in the cancer patient.
Semin Oncol 2000; 27: 244-255

*Cyclophosphamide 
The cardiotoxic effects of trastuzumab can be enhanced by the concurrent administration of cyclophosphamide.

References 
Product Information Herceptin(, 1998

*Paclitaxel 
The serum trough concentrations of trastuzumab were found to be elevated approximately 1.5 fold when administered in combination with paclitaxel.

References 
Product Information Herceptin(, 1998

*Warfarin
Two patients with breast cancer who were receiving warfarin anticoagulation developed coagulation and bleeding disorders within 2 months of starting treatment with trastuzumab. Theoretically, trastuzumab might displace warfarin from its binding to albumin, however, other mechanisms may be involved. Patients who are taking both trastuzumab and warfarin, should be monitored closely for an elevated International Normalized Ratio (INR) with warfarin dosage adjustment as required.

References 
Niessenblatt MJ, Karp GI
Bleeding risk with trastuzumab (Herceptin) treatment.
J Am Med Assoc 1999; 282: 2299-2300



Treosulfan
________________________________________________________________

*Chloroquine
Concurrent use of treosulfan and chloroquine decreased pharmacological efficacy of chloroquine.

References
Product Information 1994

*Ibuprofen
Concurrent use of treosulfan and ibuprofen decreased pharmacological efficacy of ibuprofen.

References
Product Information 1994





Trimetrexate
________________________________________________________________

*Cimetidine
By an inhibition of the cytochrome P450 enzyme system cimetidine may increase trimetrexate plasma concentrations and its toxicity (myelosuppression, renal and hepatic dysfunction, gastrointestinal ulceration). As far as clinically possible, the concomitant administration of trimetrexate and cimetidine should be avoided.

References 
Product Information Neutrexin(, 1993

*Erythromycin
By an inhibition of the cytochrome P450 enzyme system erythromycin may increase trimetrexate plasma concentrations and its toxicity (myelosuppression, renal and hepatic dysfunction, gastrointestinal ulceration). As far as clinically possible, the concomitant administration of trimetrexate and erythromycin should be avoided.

References 
Product Information Neutrexin(, 1993

*Fluconazole
By an inhibition of the cytochrome P450 enzyme system fluconazole may increase trimetrexate plasma concentrations and its toxicity (myelosuppression, renal and hepatic dysfunction, gastrointestinal ulceration). As far as clinically possible, the concomitant administration of trimetrexate and fluconazole should be avoided.

References 
Product Information Neutrexin(, 1993

*Itraconazole
Itraconazole inhibits the cytochrome P450 3A4 isoenzyme which metabolizes trimetrexate. Coadministration of itraconazole and trimetrexate thus may lead to increased trimetrexate plasma levels and an increased risk of trimetrexate toxicity (myelosuppression, renal and hepatic dysfunction, gastrointestinal ulceration). As far as clinically possible, the concomitant administration of trimetrexate and itraconazole should be avoided.

References 
Product Information Sporanox(, 2000

*Ketoconazole
Inhibitors of the cytochrome P450 enzyme system, such as ketoconazole, may cause drug interactions that increase trimetrexate plasma concentrations. Trimetrexate toxicity (myelosuppression,renal and hepatic dysfunction, gastrointestinal ulceration) may be increased as well, and the concomitant administration of trimetrexate and ketoconazole should, therefore, be avoided, if clinically possible.

References 
Product Information Neutrexin(, 1993

*Rifampicin
Being an inducer of the cytochrome P450 enzyme system, rifampicin may cause drug interactions leading to decreased trimetrexate plasma concentrations and the risk of decreased trimetrexate efficacy.

References 
Product Information Neutrexin(, 1993



Trofosfamide 
________________________________________________________________

*Remark
Clinically relevant interactions of trofosfamide with other drugs have not been reported yet. Because of chemical similarity and comparable mechanisms of action, interactions like those with cyclophosphamide or ifosfamide should be considered.

*Ketoconazole
Ketoconazole, which is a selective inhibitor of cytochrome P450 CYP3A4, substantially inhibited microsomal 4-hydroxylation and N-dechloroethylation of trofosfamide in vitro.

References 
May-Manke A et al
Investigation of the major human hepatic cytochrome P450 involved in 4-hydroxylation and N-dechloroethylation of trofosfamide.
Cancer Chemother Pharmacol 1999; 44: 327-334





Tumour Necrosis Factor (TNF)
________________________________________________________________

*Melphalan
In rats with BN-175 soft tissue sarcomas tumour necrosis factor alpha increased the accumulation of melphalan into tumour tissue. The concentration of melphalan in the tumour was 6-fold higher when tumour necrosis factor was given. There was no effect on melphalan concentration in skin or muscle tissue.

References
De Wilt JHW et al
Tumour necrosis factor alpha increases melphalan concentration in tumour tissue after isolated limb perfusion.
Br J Cancer 2000; 82: 1000-1003

UFT
________________________________________________________________

*Remark
UFT is a mixture of tegafur with uracil at a molar ratio of 1:4 (100 mg tegafur + 224 mg uracil). Interactions described for tegafur, therefore, should also be relevant for UFT.

*Phenytoin
Two patients with malignant brain tumour received phenytoin resulting in phenytoin levels of 5 micrograms/ml. Oral therapy with UFT, which is a mixture of uracil and tegafur (a masked compound of 5-FU), increased phenytoin levels to toxic values of 48.2 and 30.9 micrograms/ml, respectively.

References
Wakisaka S et al
Acute phenytoin intoxication associated with the antineoplastic agent UFT.
Fukuoka Igaku Zasshi 1990; 81: 192-196

*Warfarin
Oral UFT potentiates warfarin activity. A 62-year-old women received long-term treatment with warfarin. Her international normalised ratio (INR) was between 1.5 and 2.4. During her first cycle of UFT (300 mg/m2/day) her INR raised to 7.4. Dose adaptation was necessary. This interaction is also well documented for 5-fluorouracil.

References
Karwal MW et al
Presumed drug interaction between Orzel and warfarin.
Blood 1999; 94(Suppl 1): 106




Valspodar (PSC-833)
________________________________________________________________

*Doxorubicin
PSC-833 is a non-immunosuppressive analogue of cyclosporin A and is able to modify multidrug resistance mediated by P-glycoprotein. In an animal model with P388/doxorubicin-resistant leukaemia cells pretreatment with PSC-833 resulted in higher tissue levels of doxorubicin with a 7-fold increase of the area under the curve in the leukaemia cells. Although higher levels were achieved, PSC-833 was unable to reverse resistance (Colombo et al).
Valspodar may decrease clearance of doxorubicin and thus enhance its toxicity. During combined therapy dose reduction of doxorubicin of up to 75% was required (Sonneveld et al).
A dramatic increase in toxicity was also observed in mice. Made CD F1 mice were treated with intravenous doxorubicin and i.p. PSC-833. Doxorubicin levels were analysed by HPLC. In all tissues (serum, heart, intestine, liver, kidney, and adrenals) the area under the concentration-time curve (AUC) of doxorubicin was much higher when PSC-833 was given concurrently (Gonzales et al).

References
Colombo T et al
Distribution and activity of doxorubicin combined with SDZ PSC 833 in mice with P388 and P388/DOX leukemia.
Br J Cancer 1996; 73(7): 866-871

Gonzales O et al
Changes in doxorubicin distribution and toxicity in mice pretreated with cyclosporin analogue SDZ PSC-833.

Sonneveld P et al
Reversal of multidrug resistance by SDZ PSC-833 combined with VAD (vincristine, doxorubicin, dexamethasone) in refractory multiple myeloma. A phase I study.
Leukemia 1996; 10: 1741-1750

*Food
Valspodar given with a high-fat meal resulted in an increase of the area under the concentration-time curve (24%). Peak blood concentration was unchanged.

References
Mueller EA et al
Optimizing the absorption of valspodar, a p-glycoprotein modulator. Part I: selecting and oral formulation and exploring ist clinical pharmacokinetics/dynamics.
J Clin Pharmacol 1997; 37: 1001-1008

*Vincristine 
Valspodar may increase plasma levels of vincristine and thus enhance its toxicity. During combined therapy dose adaptation of vincristine can be necessary.

References
Fischer V et al
The multidrug resistance modulator valspodar (PSC833) is metabolized by human cytochrome P4503A. Implications for drug-drug interactions and pharmacological activity of the main metabolite.
Drug Metrption of acetyldigoxin, resulting in a 50% reduction of steady-state plasma levels of digoxin.

References
Rodin SM, Johnson BF
Pharmacokinetic interactions with digoxin.
Clin Pharmacokinet 1988; 15: 227-244

*Anticonvulsant drugs
Fifteen patients with brain tumours were treated with lomustine (110 mg/mē), vincristine (1.14 mg/mē, maximum 2 mg), and procarbazine (60 mg/mē). Nine of the patients also used either carbamazepine or phenytoin, which are inductors of cytochrome P450 3A. In this group systemic clearance of vincristine was 63% higher and the elimination half-life 35% shorter. The total AUC was 43% smaller. 

References
Villikka K et al
Cytochrome P450-inducing antiepileptics increase the clearance of vincristine in patients with brain tumors.
Clin Pharmacol Ther 1999; 66(6): 589-593 

*Asparaginase
The combination of potentially neurotoxic drugs with vinca alkaloids may increase the neurotoxicity of the latter. Severe paraesthesia, muscle weakness, and atrophy of nerve fibers were observed in one patient who received vincristine with asparaginase.

References
Hildebrand J et al
Vincristine neurotoxicity.
N Engl J Med 1972; 287: 517

*Carbamazepine
Carbamazepine induces cytochrome P450 3A4, thus interfering with vincristine biotransformation. Decreased vincristine efficacy may result.

References
Villikka K et al
Cytochrome P450-inducing antiepileptics increase the clearance of vincristine in patients with brain tumors.
Clin Pharmacol Ther 1999; 66: 589-593

*Cyclophosphamide 
An acute myocardial infarction occurred in a patient with no antecedent cardiac history who received both vincristine and conventional chemotherapeutic doses of cyclophosphamide for the treatment of chronic lymphocytic leukaemia.

References
Federma