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Drug Interactions between clotrimazole and diltiazem

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

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Interactions between your drugs

Moderate

dilTIAZem clotrimazole

Applies to: diltiazem and clotrimazole

MONITOR: Coadministration with azole agents may increase the plasma concentrations of calcium channel blockers (CCBs), especially the dihydropyridines (e.g., amlodipine, felodipine, nicardipine, nifedipine, nisoldipine). The mechanism involves inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme primarily responsible for the metabolic clearance of most CCBs. In a pharmacokinetic study, nisoldipine mean peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 11- and 24-fold, respectively, during concomitant treatment with ketoconazole. Significant increases of severalfold in felodipine and nifedipine plasma concentrations have also been observed during coadministration with itraconazole. Theoretically, the interaction may potentiate the risk of ventricular dysfunction, congestive heart failure, and peripheral and pulmonary edema, particularly in patients with preexisting risk factors (e.g., a history of congestive heart failure; cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disorder; edematous disorders such as renal failure). There have been case reports of leg and ankle edema in patients treated with various itraconazole-dihydropyridine combinations.

MANAGEMENT: Close monitoring of clinical response and tolerance is recommended if calcium channel blockers are used in combination with azole agents. Dosage reduction may be required for the calcium channel blocker, particularly if it is a dihydropyridine. Patients should be advised to seek medical attention if they experience edema or swelling of the lower extremities; sudden, unexplained weight gain; difficulty breathing; chest pain or tightness; or hypotension as indicated by dizziness, fainting, or orthostasis.

References

  1. Rosen T (1994) "Debilitating edema associated with itraconazole therapy." Arch Dermatol, 130, p. 260-1
  2. Neuvonen PJ, Suhonen R (1995) "Itraconazole interacts with felodipine." J Am Acad Dermatol, 33, p. 134-5
  3. Tailor SAN, Gupta AK, Walker SE, Shear NH (1996) "Peripheral edema due to nifedipine-itraconazole interaction: a case report." Arch Dermatol, 132, p. 350-2
  4. Tailor SAN (1996) "Peripheral edema due to nifedipine-itraconazole interaction: a case report." Arch Dermatol, 132, p. 1374
  5. Jalava KM, Olkkola KT, Neuvonen PJ (1997) "Itraconazole greatly increases plasma concentrations and effects of felodipine." Clin Pharmacol Ther, 61, p. 410-5
  6. Heinig R, Adelmann HG, Ahr G (1999) "The effect of ketoconazole on the pharmacokinetics, pharmacodynamics and safety of nisoldipine." Eur J Clin Pharmacol, 55, p. 57-60
  7. Sandstrom R, Knutson TW, Knutson L, Jansson B, Lennernas H (1999) "The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)-verapamil in humans." Br J Clin Pharmacol, 48, p. 180-9
  8. (2006) "Product Information. Noxafil (posaconazole)." Schering-Plough Corporation
View all 8 references

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Drug and food interactions

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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