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Drug Interactions between bortezomib and Di-Phen

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

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Interactions between your drugs

Major

phenytoin bortezomib

Applies to: Di-Phen (phenytoin) and bortezomib

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may decrease the plasma concentrations and pharmacologic effects of bortezomib, which is primarily metabolized by the isoenzyme with secondary contribution from CYP450 2C19. In a study of patients with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma treated with intravenous bortezomib (1.3 mg/m2 on days 1, 4, 8 and 11 of each 21-day cycle) for 3 cycles, six patients who were coadministered the potent CYP450 3A4 inducer rifampin (600 mg once daily on days 4 to 10 of cycle 3) had an approximately 23% decrease in bortezomib peak plasma concentration (Cmax) and 45% decrease in systemic exposure (AUC) compared to 12 patients treated with bortezomib alone. Because the study was not designed to exert the maximum effect of rifampin on bortezomib pharmacokinetics, greater decreases may be possible. In the same study, seven patients who were coadministered the weaker CYP450 3A4 inducer dexamethasone (40 mg once daily on days 1 to 4 and 9 to 12 of cycle 3) did not demonstrate significant changes in the pharmacokinetics of bortezomib compared to patients administered bortezomib alone. In a phase I trial to determine the dose-limiting toxicities and maximum tolerated dose (MTD) of bortezomib in patients with recurrent high-grade gliomas, patients who received concomitant enzyme-inducing antiepileptic drugs (primarily phenytoin, but also carbamazepine, oxcarbazepine, phenobarbital, and primidone) were found to tolerate a higher dosage of bortezomib compared to those who either did not receive antiepileptic medications or received ones that did not significantly induce hepatic microsomal enzymes. Bortezomib doses were escalated to 2.5 mg/m2 without reaching the MTD in the former group, whereas MTD was found to be 1.7 mg/m2 in the latter group. Moreover, maximum proteasome inhibition was reached at a higher dosage of bortezomib in the former group relative to the latter group. Although pharmacokinetics of bortezomib were not examined in the trial, these results suggest enhanced clearance of bortezomib in the presence of enzyme-inducing antiepileptic drugs.

MANAGEMENT: Given the potential for diminished pharmacologic effects of bortezomib in the presence of potent CYP450 3A4 inducers, concomitant use is not recommended.

References

  1. (2003) "Product Information. Velcade (bortezomib)." Millennium Pharmaceuticals Inc
  2. Uttamsingh V, Lu C, Miwa GT, Gan LS (2005) "Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4 to the hepatic metabolism of teh protosome inhibitor bortezomib." Drug Metab Dispos, 33, p. 1723-8
  3. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  4. Pekol T, Daniels JS, Labutti J, et al. (2005) "Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites." Drug Metab Dispos, 33, p. 771-7
  5. Hellmann A, Rule S, Walewski J, et al. (2011) "Effect of cytochrome P450 3A4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with multiple myeloma or Non-Hodgkin's lymphoma." Clin Pharmacokinet, 50, p. 781-91
  6. Phuphanich S, Supko JG, Carson KA, et al. (2010) "Phase 1 clinical trial of bortezomib in adults with recurrent malignant glioma." J Neurooncol, 100, p. 95-103
View all 6 references

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Drug and food interactions

Moderate

phenytoin food

Applies to: Di-Phen (phenytoin)

ADJUST DOSING INTERVAL: Phenytoin bioavailability may decrease to subtherapeutic levels when the suspension is given concomitantly with enteral feedings. The mechanism may be related to phenytoin binding to substances in the enteral formula (e.g., calcium, protein) and/or binding to the tube lumen. Data have been conflicting and some studies have reported no changes in phenytoin levels, while others have reported significant reductions.

MONITOR: Acute consumption of alcohol may increase plasma phenytoin levels. Chronic consumption of alcohol may decrease plasma phenytoin levels. The mechanism of this interaction is related to induction of phenytoin metabolism by ethanol during chronic administration. Other hydantoin derivatives may be similarly affected by ethanol.

MANAGEMENT: Some experts have recommended interrupting the feeding for 2 hours before and after the phenytoin dose, giving the phenytoin suspension diluted in water, and flushing the tube with water after administration; however, this method may not entirely avoid the interaction and is not always clinically feasible. Patients should be closely monitored for clinical and laboratory evidence of altered phenytoin efficacy and levels upon initiation and discontinuation of enteral feedings. Dosage adjustments or intravenous administration may be required until therapeutic serum levels are obtained. In addition, patients receiving phenytoin therapy should be warned about the interaction between phenytoin and ethanol and they should be advised to notify their physician if they experience worsening of seizure control or symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, nausea, or ataxia.

References

  1. Sandor P, Sellers EM, Dumbrell M, Khouw V (1981) "Effect of short- and long-term alcohol use on phenytoin kinetics in chronic alcoholics." Clin Pharmacol Ther, 30, p. 390-7
  2. Holtz L, Milton J, Sturek JK (1987) "Compatibility of medications with enteral feedings." JPEN J Parenter Enteral Nutr, 11, p. 183-6
  3. Sellers EM, Holloway MR (1978) "Drug kinetics and alcohol ingestion." Clin Pharmacokinet, 3, p. 440-52
  4. (2001) "Product Information. Dilantin (phenytoin)." Parke-Davis
  5. Doak KK, Haas CE, Dunnigan KJ, et al. (1998) "Bioavailability of phenytoin acid and phenytoin sodium with enteral feedings." Pharmacotherapy, 18, p. 637-45
  6. Rodman DP, Stevenson TL, Ray TR (1995) "Phenytoin malabsorption after jejunostomy tube delivery." Pharmacotherapy, 15, p. 801-5
  7. Au Yeung SC, Ensom MH (2000) "Phenytoin and enteral feedings: does evidence support an interaction?" Ann Pharmacother, 34, p. 896-905
  8. Ozuna J, Friel P (1984) "Effect of enteral tube feeding on serum phenytoin levels." J Neurosurg Nurs, 16, p. 289-91
  9. Faraji B, Yu PP (1998) "Serum phenytoin levels of patients on gastrostomy tube feeding." J Neurosci Nurs, 30, p. 55-9
  10. Marvel ME, Bertino JS (1991) "Comparative effects of an elemental and a complex enteral feeding formulation on the absorption of phenytoin suspension." JPEN J Parenter Enteral Nutr, 15, p. 316-8
  11. Fleisher D, Sheth N, Kou JH (1990) "Phenytoin interaction with enteral feedings administered through nasogastric tubes." JPEN J Parenter Enteral Nutr, 14, p. 513-6
  12. Haley CJ, Nelson J (1989) "Phenytoin-enteral feeding interaction." DICP, 23, p. 796-8
  13. Guidry JR, Eastwood TF, Curry SC (1989) "Phenytoin absorption in volunteers receiving selected enteral feedings." West J Med, 150, p. 659-61
  14. Krueger KA, Garnett WR, Comstock TJ, Fitzsimmons WE, Karnes HT, Pellock JM (1987) "Effect of two administration schedules of an enteral nutrient formula on phenytoin bioavailability." Epilepsia, 28, p. 706-12
  15. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  16. Cerner Multum, Inc. "Australian Product Information."
View all 16 references

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Moderate

bortezomib food

Applies to: bortezomib

GENERALLY AVOID: Data from in vitro and animal (mice) studies suggest that green tea may antagonize the cytotoxic effects of bortezomib. Polyphenols in green tea such as (-)-epigallocatechin gallate (EGCG) have been shown to block the proteasome inhibitory action of bortezomib in multiple myeloma and glioblastoma cancer cell lines. The mechanism appears to involve a direct chemical reaction between the boronic acid moiety of bortezomib and the 1,2-benzenediol groups present in certain polyphenols leading to inactivation of bortezomib. However, one group of investigators reported that no antagonism of bortezomib was observed in preclinical in vivo experiments where EGCG plasma concentrations are commensurate with dietary or supplemental intake.

MANAGEMENT: Until more data are available, it may be advisable to avoid or limit consumption of green tea and green tea products during treatment with bortezomib. The interaction has not been demonstrated for other, non-boronic acid proteasome inhibitors.

References

  1. Bannerman B, Xu L, Jones M, et al. (2011) "Preclinical evaluation of the antitumor activity of bortezomib in combination with vitamin C or with epigallocatechin gallate, a component of green tea." Cancer Chemother Pharmacol, 68, p. 1145-54
  2. Golden EB, Lam PY, Kardosh A, et al. (2009) "Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid–based proteasome inhibitors." Blood, 113, p. 5927-37
  3. Jia L, Liu FT (2013) "Why bortezomib cannot go with 'green'?" Cancer Biol Med, 10, p. 206-13

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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.

Further information

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