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Drug Interactions between diltiazem and terfenadine

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

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Interactions between your drugs

Moderate

dilTIAZem terfenadine

Applies to: diltiazem and terfenadine

MONITOR: Coadministration with diltiazem may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by diltiazem.

MANAGEMENT: Caution is advised if diltiazem must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever diltiazem is added to or withdrawn from therapy.

References

  1. Sakai H, Kobayashi S, Hamada K, et al. (1991) "The effects of diltiazem on hepatic drug metabolizing enzymes in man using antipyrine, trimethadione and debrisoquine as model substrates." Br J Clin Pharmacol, 31, p. 353-5
  2. Abernethy DR, Egan JM, Dickinson TH, Carrum G (1988) "Substrate-selective inhibition by verapamil and diltiazem: differential disposition of antipyrine and theophylline in humans." J Pharmacol Exp Ther, 244, p. 994-9
  3. Sutton D, Butler AM, Nadin L, Murray M (1997) "Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites." J Pharmacol Exp Ther, 282, p. 294-300
  4. Renton KW (1985) "Inhibition of hepatic microsomal drug metabolism by the calcium channel blockers diltiazem and verapamil." Biochem Pharmacol, 34, p. 2549-53
  5. Varis T, Backman JT, Kivisto KT, Neuvonen PJ (2000) "Diltiazem and mibefradil increase the plasma concentrations and greatly enhance the adrenal-suppressant effect of oral methylprednisolone." Clin Pharmacol Ther, 67, p. 215-21
View all 5 references

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Drug and food interactions

Major

terfenadine food

Applies to: terfenadine

CONTRAINDICATED: The consumption of grapefruit juice has been associated with significantly increased plasma concentrations of terfenadine. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. Terfenadine in high serum levels has been associated with prolongation of the QT interval and development of torsade de pointes, a potentially fatal ventricular arrhythmia.

MANAGEMENT: Due to the risk of cardiotoxicity, patients receiving the drug should be advised to avoid consumption of grapefruit products. Loratadine, cetirizine, and fexofenadine may be safer alternatives in patients who may have trouble adhering to the dietary restriction.

References

  1. Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR Jr (1992) "Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin." Clin Pharmacol Ther, 52, p. 231-8
  2. Zimmermann M, Duruz H, Guinand O, et al. (1992) "Torsades de Pointes after treatment with terfenadine and ketoconazole." Eur Heart J, 13, p. 1002-3
  3. Mathews DR, McNutt B, Okerholm R, et al. (1991) "Torsades de pointes occurring in association with terfenadine use." JAMA, 266, p. 2375-6
  4. Monahan BP, Ferguson CL, Killeavy ES, et al. (1990) "Torsades de pointes occurring in association with terfenadine use." JAMA, 264, p. 2788-90
  5. Honig PK, Wortham DC, Zamani K, et al. (1993) "Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences." JAMA, 269, p. 1513-8
  6. Pohjola-Sintonen S, Viitasalo M, Toivonene L, Neuvonen P (1993) "Torsades de pointes after terfenadine-itraconazole interaction." BMJ, 306, p. 186
  7. Cortese LM, Bjornson DC (1992) "Potential interaction between terfenadine and macrolide antibiotics." Clin Pharm, 11, p. 675
  8. Paris DG, Parente TF, Bruschetta HR, Guzman E, Niarchos AP (1994) "Torsades-de-pointes induced by erythromycin and terfenadine." Am J Emerg Med, 12, p. 636-8
  9. Zechnich AD, Haxby DG (1996) "Drug interactions associated with terfenadine and related nonsedating antihistamines." West J Med, 164, p. 68-9
  10. Honig PK, Wortham DC, Lazarev A, Cantilena LR (1996) "Grapefruit juice alters the systemic bioavailability and cardiac repolarization of terfenadine in poor metabolizers of terfenadine." J Clin Pharmacol, 36, p. 345-51
  11. Woosley RL (1996) "Cardiac actions of antihistamines." Annu Rev Pharmacol Toxicol, 36, p. 233-52
  12. Benton RE, Honig PK, Zamani K, Cantilena LR, Woosley RL (1996) "Grapefruit juice alters terfenadine pharmacokinetics resulting in prolongation of repolarization on the electrocardiogram." Clin Pharmacol Ther, 59, p. 383-8
  13. Hsieh MH, Chen SA, Chiang CE, et al. (1996) "Drug-induced torsades de pointes in one patient with congenital long QT syndrome." Int J Cardiol, 54, p. 85-8
  14. Clifford CP, Adams DA, Murray S, Taylor GW, Wilkins MR, Boobis AR, Davies DS (1996) "Pharmacokinetic and cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice." Br J Clin Pharmacol, 42, p662
  15. Rau SE, Bend JR, Arnold JMO, Tran LT, Spence JD, Bailey DG (1997) "Grapefruit juice terfenadine single-dose interaction: Magnitude, mechanism, and relevance." Clin Pharmacol Ther, 61, p. 401-9
  16. Bailey DG, Malcolm J, Arnold O, Spence JD (1998) "Grapefruit juice-drug interactions." Br J Clin Pharmacol, 46, p. 101-10
  17. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR (2000) "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther, 68, p. 468-77
View all 17 references

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Moderate

dilTIAZem food

Applies to: diltiazem

MONITOR: Like many CNS-active agents, alcohol can exhibit hypotensive effects. Coadministration with antihypertensive agents including diltiazem may result in additive effects on blood pressure and orthostasis.

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered diltiazem in some patients. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In a study of ten healthy male volunteers, administration of a single 120 mg oral dose of immediate-release diltiazem in combination with 250 mL of grapefruit juice increased the diltiazem peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 22% and 20%, respectively, compared to administration with water. The time to reach Cmax (Tmax) and the terminal half-life were not affected, and no statistically significant differences in blood pressure and heart rate were observed during administration with grapefruit juice relative to water. In a different study, repeated administration of 200 mL of grapefruit juice at 0, 2, 4, 8 and 12 hours had no significant effect on the Cmax or AUC of a single 120 mg oral dose of diltiazem, but increased its half-life from 4.1 to 5.1 hours. The ratios for the N-demethyl and deacetyl metabolites to diltiazem were also not affected by grapefruit juice. However, because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients should be advised that alcohol may potentiate the hypotensive effects of diltiazem, especially during the initiation of therapy and following a dosage increase. Caution should be exercised when rising from a sitting or recumbent position, and patients should notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients who regularly consume grapefruit or grapefruit juice should be monitored for increased adverse effects of diltiazem such as such as headache, irregular heartbeat, edema, unexplained weight gain, and chest pain. Grapefruit and grapefruit juice should be avoided if an interaction is suspected.

References

  1. Bailey DG, Arnold JMO, Spence JD (1994) "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet, 26, p. 91-8
  2. Sigusch H, Henschel L, Kraul H, Merkel U, Hoffmann A (1994) "Lack of effect of grapefruit juice on diltiazem bioavailability in normal subjects." Pharmazie, 49, p. 675-9
  3. Bailey DG, Malcolm J, Arnold O, Spence JD (1998) "Grapefruit juice-drug interactions." Br J Clin Pharmacol, 46, p. 101-10
  4. Christensen H, Asberg A, Holmboe AB, Berg KJ (2002) "Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers." Eur J Clin Pharmacol, 58, p. 515-520
  5. Cerner Multum, Inc. "UK Summary of Product Characteristics."
View all 5 references

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Moderate

dilTIAZem food

Applies to: diltiazem

MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity.

MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.

References

  1. Henry M, Kay MM, Viccellio P (1985) "Cardiogenic shock associated with calcium-channel and beta blockers: reversal with intravenous calcium chloride." Am J Emerg Med, 3, p. 334-6
  2. Moller IW (1987) "Cardiac arrest following intravenous verapamil combined with halothane anaesthesia." Br J Anaesth, 59, p. 522-6
  3. Oszko MA, Klutman NE (1987) "Use of calcium salts during cardiopulmonary resuscitation for reversing verapamil-associated hypotension." Clin Pharm, 6, p. 448-9
  4. Schoen MD, Parker RB, Hoon TJ, et al. (1991) "Evaluation of the pharmacokinetics and electrocardiographic effects of intravenous verapamil with intravenous calcium chloride pretreatment in normal subjects." Am J Cardiol, 67, p. 300-4
  5. O'Quinn SV, Wohns DH, Clarke S, Koch G, Patterson JH, Adams KF (1990) "Influence of calcium on the hemodynamic and anti-ischemic effects of nifedipine observed during treadmill exercise testing." Pharmacotherapy, 10, p. 247
  6. Woie L, Storstein L (1981) "Successful treatment of suicidal verapamil poisoning with calcium gluconate." Eur Heart J, 2, p. 239-42
  7. Morris DL, Goldschlager N (1983) "Calcium infusion for reversal of adverse effects of intravenous verapamil." JAMA, 249, p. 3212-3
  8. Guadagnino V, Greengart A, Hollander G, Solar M, Shani J, Lichstein E (1987) "Treatment of severe left ventricular dysfunction with calcium chloride in patients receiving verapamil." J Clin Pharmacol, 27, p. 407-9
  9. Luscher TF, Noll G, Sturmer T, Huser B, Wenk M (1994) "Calcium gluconate in severe verapamil intoxication." N Engl J Med, 330, p. 718-20
  10. Bar-Or D, Gasiel Y (1981) "Calcium and calciferol antagonise effect of verapamil in atrial fibrillation." Br Med J (Clin Res Ed), 282, p. 1585-6
  11. Lipman J, Jardine I, Roos C, Dreosti L (1982) "Intravenous calcium chloride as an antidote to verapamil-induced hypotension." Intensive Care Med, 8, p. 55-7
  12. McMillan R (1988) "Management of acute severe verapamil intoxication." J Emerg Med, 6, p. 193-6
  13. Perkins CM (1978) "Serious verapamil poisoning: treatment with intravenous calcium gluconate." Br Med J, 2, p. 1127
  14. Moroni F, Mannaioni PF, Dolara A, Ciaccheri M (1980) "Calcium gluconate and hypertonic sodium chloride in a case of massive verapamil poisoning." Clin Toxicol, 17, p. 395-400
View all 14 references

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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.

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