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Drug Interactions between fluorouracil and thalidomide

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

fluorouracil thalidomide

Applies to: fluorouracil and thalidomide

MONITOR CLOSELY: Coadministration of thalidomide with glucocorticoids and/or antineoplastic agents in the treatment of malignancy may potentiate the risk of thromboembolism. The exact mechanism is unknown but likely multifactorial. Thalidomide alone has been associated with the development of deep-vein thrombosis (DVT), and malignancy itself is also a common cause. In a study of 100 patients receiving induction chemotherapy (combinations of dexamethasone, vincristine, doxorubicin, cyclophosphamide, etoposide, and cisplatin) for multiple myeloma, the addition of thalidomide was associated with an increased incidence of DVT compared to chemotherapy without thalidomide (28% vs. 4%). Administration of thalidomide was safely resumed in 75% of patients after initiation of appropriate anticoagulation therapy. In another study, 9 of 21 (43%) patients with metastatic renal cell carcinoma (RCC) receiving gemcitabine, 5-FU, and thalidomide developed venous thromboembolism, including one case of fatal cardiac arrest. This rate is substantially higher than the 3% rate observed in a group of 125 patients previously treated at the same institution with similar regimens of gemcitabine and 5-FU but without thalidomide. It is also higher than the 9% rate (12 of 140 patients) the investigators found in a review of published data from five RCC trials that used thalidomide therapy without concomitant cytotoxic therapy. Another study found a significant association of DVT with exposure to doxorubicin in patients receiving thalidomide. Specifically, 31 of 192 (16%) multiple myeloma patients treated with DT-PACE (a regimen of dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) developed DVT, while only 1 of 40 (2.5%) did so on DCEP-T (similar to DT-PACE but without doxorubicin). The time to DVT was also significantly decreased with doxorubicin exposure. In a pooled analysis of 39 prospectively monitored clinical trials involving 1784 thalidomide-treated patients, the incidence of thromboembolism was 5% when thalidomide was used as a single agent, 13% when combined with corticosteroids (8% to 26% has been reported in individual studies with dexamethasone), and 17% when combined with chemotherapy. Among thalidomide-treated patients with multiple myeloma, thromboembolism rates ranged from a low of 1/30 among those treated with concomitant cyclophosphamide, etoposide, and cisplatin to a high of about 1/3 in those treated with doxorubicin-containing regimens.

MANAGEMENT: Close monitoring for DVT or pulmonary embolism is recommended in patients who require thalidomide therapy in combination with glucocorticoids and/or cytotoxic agents. Patients should be advised to seek medical attention if they develop potential signs and symptoms of thromboembolism such as chest pain, shortness of breath, and pain or swelling in the arms or legs. Prophylaxis with anticoagulants such as low-molecular weight heparins or warfarin may be appropriate, but the decision to take thromboprophylactic measures should be made after careful assessment of underlying risk factors. If a thromboembolic event occurs during therapy with thalidomide, treatment must be discontinued and standard anticoagulation therapy started. Once anticoagulation is stabilized and complications of the thromboembolic event under control, thalidomide may be restarted at the original dose if benefit is deemed to outweigh the risks. Anticoagulation therapy should be continued during the remaining course of thalidomide treatment.

References (16)
  1. (2001) "Product Information. Thalomid (thalidomide)." Celgene Corporation
  2. Zangari M, Anaissie E, Barlogie B, et al. (2001) "Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy." Blood, 98, p. 1614-5
  3. Figg WD, Arlen P, Gulley J, et al. (2001) "A randomized phase II trial of docetaxel (taxotere) plus thalidomide in androgen-independent prostate cancer." Semin Oncol, 28(4 Suppl 15), p. 62-6
  4. Escudier B, Lassau N, Leborgne S, Angevin E, Laplanche A (2002) "Thalidomide and venous thrombosis." Ann Intern Med, 136, p. 711
  5. Urbauer E, Kaufmann H, Nosslinger T, Raderer M, Drach J (2002) "Thromboembolic events during treatment with thalidomide." Blood, 99, p. 4247-8
  6. Zangari M, Siegel E, Barlogie B, et al. (2002) "Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy." Blood, 100, p. 1168-71
  7. Cavo M, Zamagni E, Cellini C, et al. (2002) "Deep-vein thrombosis in patients with multiple myeloma receiving first-line thalidomide-dexamethasone therapy." Blood, 100, p. 2272-3
  8. Desai AA, Vogelzang NJ, Rini BI, Ansari R, Krauss S, Stadler WM (2002) "A high rate of venous thromboembolism in a multi-institutional Phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil and daily thalidomide in patients with metastatic renal cell carcinoma." Cancer, 95, p. 1629-36
  9. Rajkumar SV, Hayman S, Gertz MA, et al. (2002) "Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma." J Clin Oncol, 20, p. 4319-23
  10. Bennett CL, Schumock GT, Desai AA, et al. (2002) "Thalidomide-associated deep vein thrombosis and pulmonary embolism." Am J Med, 113, p. 603-6
  11. Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R (2003) "Thalidomide alone or with dexamethasone for previously untreated multiple myeloma." J Clin Oncol, 21, p. 16-9
  12. Fine HA, Wen PY, Maher EA, et al. (2003) "Phase II Trial of Thalidomide and Carmustine for Patients With Recurrent High-Grade Gliomas." J Clin Oncol, 21, p. 2299-304
  13. Lee CK, Barlogie B, Munshi N, et al. (2003) "DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma." J Clin Oncol, 21, p. 2732-9
  14. Zangari M, Barlogie B, Anaissie E, et al. (2004) "Deep vein thrombosis in patients with mutiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation." Br J Haematol, 126, p. 715-21
  15. Osman K, Comenzo R, Rajkumar SV (2001) "Deep venous thrombosis and thalidomide therapy for multiple myeloma." N Engl J Med, 344, p. 1951-2
  16. Bennett CL, Nebeker JR, Samore MH, et al. (2005) "The Research on Adverse Drug Events and Reports (RADAR) project." JAMA, 293, p. 2131-40

Drug and food interactions

Major

fluorouracil food

Applies to: fluorouracil

MONITOR CLOSELY: Coadministration with folate therapy may potentiate the pharmacologic effects of 5-fluorouracil (5-FU). The exact mechanism of interaction is unknown. Although enhancement of 5-FU cytotoxicity may be used to advantage in some cancer patients, increased toxicity should also be considered. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. In a clinical study consisting of 148 patients with advanced untreated colorectal cancer, weekly administration of 5-FU (600 mg/m2) in combination with leucovorin (500 mg/m2) was associated with a higher response rate than 5-FU alone (23% versus 8%). However, the combination was also more toxic than 5-FU alone, as evidenced by a higher incidence of grade 3 to 4 diarrhea (19.5% versus 8.5%) and conjunctivitis (26.5% versus 5.6%), as well as one recorded toxic death versus none. No differences in median survival and time to progression were observed between the two groups. Similar results were observed in another study with capecitabine, a prodrug of 5-FU. The interaction has also been reported with folic acid. A published case report describes two patients who were hospitalized for presumed 5-FU toxicity (anorexia, severe mouth ulceration, bloody diarrhea, vaginal bleeding) during concomitant treatment with a multivitamin containing folic acid (0.5 mg in one and 5 mg in the other). Both patients tolerated subsequent courses of 5-FU at the previous dosage following discontinuation of the multivitamin. Another published report describes a breast cancer patient who died during treatment with capecitabine (2500 mg/m2 daily for 14 days every 3 weeks) while taking folic acid 15 mg/day. The patient developed diarrhea, vomiting, and hand-foot syndrome eight days after starting capecitabine therapy. Her condition improved briefly following discontinuation of capecitabine and then folic acid, but she subsequently developed necrotic colitis and died from septic shock and vascular collapse.

MANAGEMENT: Caution is advised if 5-FU or any of its prodrugs (e.g., capecitabine, tegafur) are prescribed in combination with leucovorin. A lower dosage of 5-FU or the prodrug may be required. Therapy with leucovorin and fluorouracil should not be initiated or continued in patients with symptoms of gastrointestinal toxicity until such symptoms have resolved. Closely monitor patients with diarrhea until it resolves. Monitor for other potential toxicities of 5-FU such as neutropenia, thrombocytopenia, stomatitis, cutaneous reactions, and neuropathy. Patients should be instructed to avoid taking folic acid supplementation or multivitamin preparations containing folic acid without first speaking with their physician.

References (9)
  1. Schalhorn A, Kuhl M (1992) "Clinical pharmacokinetics of fluorouracil and folinic acid." Semin Oncol, 19, p. 82-92
  2. Nobile MT, Rosso R, Sertoli MR, Rubagotti A, Vidili MG, Guglielmi A, Venturini M, Canobbio L, Fassio T, Gallo L, et al. (1992) "Randomised comparison of weekly bolus 5-fluorouracil with or without leucovorin in metastatic colorectal carcinoma." Eur J Cancer, 28a, p. 1823-7
  3. Mainwaring P, Grygiel JJ (1995) "Interaction of 5-fluorouracil with folates." Aust N Z J Med, 25, p. 60
  4. "Product Information. Wellcovorin (leucovorin)." Glaxo Wellcome, Research Triangle Park, NC.
  5. (2001) "Product Information. Xeloda (capecitabine)." Roche Laboratories
  6. Clippe C, Freyer G, Milano G, Trillet-Lenoir V (2003) "Lethal toxicity of capecitabine due to abusive folic acid prescription?" Clin Oncol (R Coll Radiol), 15, p. 299-300
  7. EMEA. European Medicines Agency (2007) EPARs. European Union Public Assessment Reports. http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landingpage.jsp&mid
  8. (2008) "Product Information. Levoleucovorin (levoleucovorin)." Spectrum Chemical
  9. (2022) "Product Information. Khapzory (LEVOleucovorin)." Acrotech Biopharma LLC
Moderate

thalidomide food

Applies to: thalidomide

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References (4)
  1. Warrington SJ, Ankier SI, Turner P (1986) "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology, 15, p. 31-7
  2. Gilman AG, eds., Nies AS, Rall TW, Taylor P (1990) "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc.
  3. (2012) "Product Information. Fycompa (perampanel)." Eisai Inc
  4. (2015) "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc

Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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