Pharmacy Blog – Dr Vibore

Methotrexate causes a modest reduction in theophylline clearance. Theophylline may reduce methotrexate-induced neurotoxicity, but there is possibility that it may also reducemethotrexate efficacy.

The apparent clearance of theophylline (given as oral aminophylline,choline theophyllinate or theophylline) was reduced by 19 % in 8 patients with severe, steroid-dependent asthma after 6 weeks of treatment with intramuscular methotrexate 15mg weekly. Three patients complained of nausea and theophylline dosage was reduced in one of them as theophylline level was more than 20 micrograms/mL (See reference number 1).

Four of 6 patients aged 3 to 16 years with acute lymphoblastic leukaemia and high-dose methotrexate-induced neurotoxicity had a complete resolution of their symptoms when they were given a 2.5-mg/kg aminophylline infusion over 1 hour. The other 2 had some improvement in symptoms. One patient also had symptom relief with rapid-release theophylline (See reference number 2). Similar results were reported for another child who developed neurotoxicity after receiving high-dose methotrexate. In this case,aminophylline was reported not to alter methotrexate levels (See reference number 3). A patient with methotrexate-induced leukoencephalopathy recovered after being given a combination of intravenous folinic acid with intravenous aminophylline 145mg daily for 7days (See reference number 4).

Theophylline is a competitive antagonist for adenosine receptors at serum concentrations within therapeutic range used in respiratory disease (See reference number 2)

The clinical importance of small reduction in theophylline clearance is uncertain, although it may be worth bearing this in mind in patients maintained at higher end of therapeutic levels for theophylline, as they may be more likely to develop toxicity. Aminophylline may reduce methotrexate-induced neurotoxicity, and, although there is some evidence that theophylline does not alter cytotoxic effects of methotrexate, this requires confirmation.(See reference number 2) One UK manufacturer of methotrexate (licenced for rheumatoid arthritis) recommends avoiding excessive consumption of caffeine and theophylline-containing drinks, however this recommendation appears to be based on studies and surveys which looked at effects of caffeine intake in patients taking low-dose, weekly methotrexate for rheumatoid arthritis or psoriasis,(See reference number 5,6) see Methotrexate + Caffeine interaction.

Glynn-Barnhart AM,Erzurum SC, Leff JA, Martin RJ, Cochran JE, Cott GR, Szefler SJ. Effectof low-dose methotrexate on the disposition of glucocorticoids and theophylline. J Allergy Clin Immunol (1991) 88, 180–6.

Bernini JC,Fort DW, Griener JC, Kane BJ, Chappell WB, Kamen BA. Aminophylline formethotrexate-induced neurotoxicity. Lancet (1995) 345, 544–7.

Peyriere H,Poiree M, Cociglio M, Margueritte G, Hansel S, Hillaire-Buys D. Reversal of neurologic disturbances related to high-dose methotrexate by aminophylline. Med Pediatr Oncol (2001) 36, 662–4.

Jaksic W,Veljkovic D, Pozza C, Lewis I. Methotrexate-induced leukoencephalopathy reversed by aminophylline and high-dose folinic acid. Acta Haematol (Basel) (2004) 111, 230–2.

Metoject (Methotrexate). Medac GmbH. UK Summary of product characteristics,July 2006.

Medac UK. Personal Communication,March 2007.

Methotrexate-induced stomatitis and other toxic effects may beincreased by use of nitrous oxide

Clinical evidence,mechanism, importance and management

A study in which intravenous methotrexate,cyclophosphamide and fluorouracil (CMF) were used within 36 hrs of mastectomy suggested that stomatitis may be caused by a toxic interaction between methotrexate and nitrous oxide used during anaesthesia. Stomatitis was much more common in those receiving CMF within 6 hrs of surgery (See reference number 1-3). A possible reason is that effects of methotrexate on tetrahydrofolate metabolism are increased by nitrous oxide, and this has been confirmed in animals (See reference number 4). It was found that incidence of stomatitis, severe leucopenia, thrombocytopenia, and of severe systemic and local infections could be reduced by giving calcium folinate (leucovorin) and intravenous hydration (See reference number 2,3). Alternatively, use of nitrous oxide shortly before methotrexate administration should be avoided (See reference number 4).

Ludwig Breast Cancer Study Group. Toxic effects of early adjuvant chemotherapy for breast cancer. Lancet (1983) ii,542–4.

Goldhirsch A,Gelber RD, Tattersall MNH, Rudenstam C-M, Cavalli F. Methotrexate/nitrousoxide toxic interaction in perioperative chemotherapy for early breast cancer. Lancet (1987) ii,

151.

Ludwig Breast Cancer Study Group. On the safety of perioperative adjuvant chemotherapywith cyclophosphamide,methotrexate and 5-fluorouracil in breast cancer. Eur J Cancer Clin Oncol (1988) 24, 1305–8.

Ermens AAM,Schoester M, Spijkers LJM, Lindemans J, Abels J. Toxicity of methotrexate inrats preexposed to nitrous oxide. Cancer Res (1989) 49, 6337–41.

When 2 patients with osteosarcoma, treated with high-dose methotrexate 12 g/m(See reference number 2) per course, were given ciprofloxacin 500mg twice daily, either during or 2 days before start of methotrexate course, methotrexate elimination was delayed, resulting in raised serum levels, severe cutaneous toxicity and renal impairment. The first patient also had hepatic injury and haematological toxicity. Following increased folinic acid rescue,methotrexate levels normalised after several days. In earlier courses without ciprofloxacin in first patient and subsequent courses without ciprofloxacin in second patient, methotrexate elimination was normal (See reference number 1). This preliminary report(See reference number 1) has subsequently been published in full (See reference number 2,3).

Information appears to be limited to one report,but it would seem prudent to monitor for raised methotrexate levels if concurrent use is necessary. More study is needed.

Dalle JH,Auvrignon A, Vassal G, Leverger G. Possible ciprofloxacin-methotrexate interaction: a report of 2 cases. Intersci Conf Antimicrob Agents Chemother (2000) 40, 477.

Dalle JH,Auvrignon A, Vassal G, Leverger G, Kalifa C. Interaction méthotrexate–ciprofloxacine: à propos de deux cas d’intoxication sévère. Arch Pediatr (2001) 8, 1078–81.

Dalle J-H,Auvrignon A, Vassal G, Leverger G. Interaction between methotrexate and ciprofloxacin. J Pediatr Hematol Oncol (2002) 24, 321–2.

Clinical evidence,mechanism, importance and management

A study in 10 patients with multiple myeloma showed that half-life of oral melphalan 5 mg/m(See reference number 2) was unaffected when it was taken with a standardised breakfast, but AUC was reduced by 39%. In one patient, no melphalan was detectable in plasma when it was given with food. In 8 of patients who had also been given intravenous melphalan at same dose, bioavailability of oral melphalan was calculated to be 85 % (range 26 % to 96%) when fasting and 58 % (7% to 99%) when given with food. The authors recommend that melphalan should not be taken with food (See reference number 1). The manufacturer notes that absorption after oral administration is highly variable, and that dosage should be adjusted based on frequent monitoring of blood counts. They make no specific recommendations about intake in relation to food (See reference number 2,3).

1. Reece PA,Kotasek D, Morris RG, Dale BM, Sage RE. The effect of food on oral melphalanabsorption. Cancer Chemother Pharmacol (1986) 16, 194–7.

Alkeran Tablets (Melphalan). GlaxoSmithKline UK. UK Summary of product characteristics,July 2007.

Alkeran (Melphalan). GlaxoSmithKline. US Prescribing information,November 2004.

Retrospective data suggests that tobacco smoking might increasethe clearance of irinotecan and reduce its toxicity,and presumably therefore, its efficacy.

In a retrospective analysis, pharmacokinetics of irinotecan were compared between 49 patients who were smokers and 141 who were nonsmokers, and who had received intravenous irinotecan 175 to 350 mg/m(See reference number 2)(or a fixed dose of 600 mg) once every 3 weeks. Clearance of irinotecan was 18 % faster in group of patients who smoked, and these patients also showed more extensive conversion of active metabolite SN-38 to inactive glucuronide (SN-38G). Smokers experienced significantly less haematological toxicity than non-smokers (grade 3 to 4 neutropenia 6 % versus 38%), possibly as a result of increased rate of clearance (See reference number 1).

Irinotecan is metabolised by cytochrome P450 CYP3A isoenzymes, which, although not most commonly implicated isoenzyme in interactions involving tobacco smoking, may be induced by some of components of tobacco smoke, resulting in increased clearance of irinotecan. In addition,smoking might induce glucuronyltransferases (which are responsible for glucuronidation) (See reference number 1).

The findings of this retrospective analysis suggest that smoking might reduce efficacy of irinotecan. However, evidence is insufficient to make recommendations regarding smoking cessation or an increased irinotecan dose (See reference number 1). Further study is required.

1. van der Bol JM,Mathijssen RHJ, Loos WJ, Friberg LE, van Schaik RHN, de Jonge MJA,Planting AST, Verweij J, Sparreboom A, de Jong FA. Cigarette smoking and irinotecan treatment: pharmacokinetic interaction and effects on neutropenia. J Clin Oncol (2007) 25. Published ahead of print at http://jco.ascopubs.org/cgi/reprint/JCO.2006.09.6115v1.

A retrospective analysis of studies in a total of 250 patients givenfluorouracil for treatment of gastrointestinal cancer foundthat chlorprothixene, cinnarizine, prochlorperazine, sodiumpentobarbital, thiethylperazine, trimethobenzamide (in antiemetic doses) did not significantly increase toxicity or decrease therapeutic effects, when compared with a placebo.(See reference number 1)

1. Moertel CG,Reitemeier RJ, Hahn RG. Effect of concomitant drug treatment on toxic and therapeutic activity of 5-fluorouracil (5-FU; NSC-19893). Cancer Chemother Rep (1972) 56, 245–

7.

One study suggested that intravenous dipyridamole may reducethe steady-state plasma levels of fluorouracil,whereas othersfound that oral dipyridamole caused no important changes influorouracil pharmacokinetics.

Clinical evidence,mechanism, importance and management

Numerous preclinical studies found that dipyridamole enhanced activity of fluorouracil, leading to its investigation as a biomodulator (See reference number 1). However, unexpectedly, in one phase I study of combination, use of dipyridamole was associated with lower steady state plasma level of fluorouracil, suggesting an approximately 30 % increase in total body clearance or volume of distribution of fluorouracil (See reference number 2). In this study,47 patients with advanced cancer were given fluorouracil in escalating doses ranging from 185 mg/m(See reference number 2) daily to 3600 mg/m(See reference number 2) daily with or without dipyridamole as a continuous infusion of 7.7 mg/kg per day for 72 hrs (See reference number 2). In contrast, in a later randomised study, oral dipyridamole 75mg three times daily for 5 days did not significantly alter pharmacokinetics of fluorouracil, except for prolonging half-life and slightly increasing dose-intensity: over 5 cycles average dose of fluorouracil was 479 mg/m(See reference number 2) alone, compared with 533 mg/m(See reference number 2)in presence of dipyridamole. In this study, oral dipyridamole did not improve antineoplastic activity of fluorouracil and folinic acid (See reference number 3). Similarly, another clinical study found that oral dipyridamole did not significantly alter pharmacokinetics of fluorouracil (See reference number 4). Thus, despite promise of preclinical studies, benefits of combining dipyridamole with fluorouracil have not been realised clinically.

Grem JL. Biochemical modulation of fluorouracil by dipyridamole: preclinical and clinical experience. Semin Oncol (1992) 19 (Suppl 3),56–65.

Trump DL,Egorin MJ, Forrest A, Willson JKV, Remick S, Tutsch KD. Pharmacokinetic andpharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole. J Clin Oncol (1991) 9, 2027–35.

Köhne C-H,Hiddemann W, Schüller J, Weiss J, Lohrmann H-P, Schmitz-Hüber U, Bodenstein H, Schöber C, Wilke H, Grem J, Schmoll H-J. Failure of orally administered dipyridamole toenhance the antineoplastic activity of fluorouracil in combination with leucovorin in patientswith advanced colorectal cancer: a prospective randomized trial. J Clin Oncol (1995) 13, 1201–8.

Czejka MJ,Jäger W, Schüller J, Fogl U, Weiss C, Schernthaner G. Clinical pharmacokineticsof fluorouracil: influence of the biomodulating agents interferon, dipyridamole and folinic acidalone and in combination. Arzneimittelforschung (1993) 43, 387–90.

Doxorubicin and cyclophosphamide have no clinically relevanteffects on pharmacokinetics of oral or intravenous etoposide.Methotrexate and procarbazine do not affect pharmacokinetics of oral etoposide

Clinical evidence,mechanism, importance and management

A pharmacokinetic study in 7 patients with small-cell lung cancer (SCLC) treated with cyclophosphamide 800 mg/m(See reference number 2), doxorubicin 40 mg/m(See reference number 2) and etoposide 100 mg/m(See reference number 2) (all given intravenously) found that protein binding, metabolism and renal clearance of etoposide were unaffected by other antineoplastics (See reference number 1). Similarly, another study found only modest changes in pharmacokinetics of intravenous etoposide when it was given with cyclophosphamide and doxorubicin, compared with use alone, and these changes were considered unlikely to be clinically relevant. Specifically, AUC of etoposide was 9 % higher and clearance was 10 % lower on day 1 of CAE cycle (cyclophosphamide, doxorubicin, and etoposide) compared with days 2 and 3 (etoposide alone) (See reference number 2). This is a commonly used regimen,and these data suggest there is no pharmacokinetic interaction.

Similarly,no changes in etoposide pharmacokinetics were seen when oral etoposide 100mg was given immediately after oral cyclophosphamide 100 mg/m(See reference number 2) and methotrexate 12.5 mg/m(See reference number 2)in 8 patients with SCLC. In addition, no changes were seen when same dose of oral etoposide was given 15 minutes after intravenous doxorubicin 35 mg/m(See reference number 2) and oral procarbazine 60 mg/m(See reference number 2).(See reference number 3) Oral etoposide pharmacokinetics appear not to be affected by these antineoplastics.

For lack of effect of platinum derivatives, see Etoposide + Cisplatin or Carboplatin interaction.

Van Hoogenhuijze J,Lankelma J, Stam J, Pinedo HM. Unchanged pharmacokinetics of VP16-213 (etoposide, NSC 141540) during concomitant administration of doxorubicin and cyclophosphamide. Eur J Cancer Clin Oncol (1987) 23, 807–11.

Busse D,Würthwein G, Hinske C, Hempel G, Fromm MF, Eichelbaum M, Kroemer HK,Busch FW. Pharmacokinetics of intravenous etoposide in patients with breast cancer: influenceof dose escalation and cyclophosphamide and doxorubicin coadministration. Naunyn Schmiedebergs Arch Pharmacol (2002) 366, 218–25.

Harvey VJ,Slevin ML, Joel SP, Johnston A, Wrigley PFM. The effect of food and concurrentchemotherapy on the bioavailability of oral etoposide. Br J Cancer (1985) 52, 363–7.

Ketoconazole appears not to interact with exemestane,whereasrifampicin reduces exemestane levels.

Clinical evidence,mechanism, importance and management

The manufacturers say that in vitro evidence shows that while exemestane is metabolised by both cytochrome P450 isoenzyme CYP3A4 and aldoketoreductases, a clinical study found that ketoconazole (a specific inhibitor of CYP3A4) had no significant effects on pharmacokinetics of exemestane. The manufacturers therefore suggest that interactions with CYP3A4 enzyme inhibitors are unlikely (See reference number 1,2).

However, in an interaction study potent enzyme inducer rifampicin reduced AUC and maximum plasma levels of exemestane by 54 % and 41%, respectively.

The manufacturers therefore caution use of exemestane with CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin and St John’s wort (See reference number 1,2). The clinical relevance of these potential interactions is unknown, but it would seem prudent to monitor outcome of concurrent use to ensure exemestane efficacy.

Aromasin (Exemestane). Pharmacia Ltd. UK Summary of product characteristics,August2005.

Aromasin (Exemestane). Pharmacia & Upjohn Company. US Prescribing information,February 2007.

The absorption of estramustine is reduced by milk,foods, anddrugs containing calcium.

A randomised three-way crossover study in 6 patients with prostate cancer showed that absorption of single-doses of estramustine disodium (equivalent to 140mg of estramustine) was reduced by 59 % when taken with 200 mL of milk, and by 33 % when taken with a standardised breakfast (2 pieces of white bread with margarine, ham, tomato, marmalade and water). Peak serum estramustine levels were reduced by 68 % and 43%,respectively (See reference number 1).

In vitro studies suggest that estramustine combines with calcium ions in milk and food to form a poorly-soluble complex that is not as well absorbed as parent compound (See reference number 1)

An established interaction although information is limited. The manufacturers recommend that estramustine should be taken not less than 1 hour before or 2 hrs after meals,and that it should not be taken with milk, milk products, calcium-rich foods,(See reference number 2,3) or drugs (such as calcium-containing antacids) (See reference number 3).

Gunnarsson P O,Davidsson T, Andersson S-B, Backman C, Johansson S-Å. Impairment of estramustine phosphate absorption by concurrent intake of milk and food. Eur J Clin Pharmacol (1990) 38, 189–93.

Estracyt (Estramustine sodium phosphate). Pharmacia Ltd. UK Summary of product characteristics,July 2007.

Emcyt (Estramustine phosphate sodium). Pharmacia & Upjohn Co. US Prescribing information,February 2006.