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Drug Interactions between carvedilol and Dilt-XR

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

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Interactions between your drugs

Major

dilTIAZem carvedilol

Applies to: Dilt-XR (diltiazem) and carvedilol

MONITOR CLOSELY: Additive reductions in heart rate, cardiac conduction, and cardiac contractility may occur when calcium channel blockers, especially verapamil and diltiazem, are used concomitantly with beta blockers. While this combination may be useful and effective in some situations, potentially serious cardiovascular adverse effects such as congestive heart failure, severe hypotension, and/or exacerbation of angina may occur. Ventricular asystole, sinus arrest, and heart block have also been reported. The risk is increased with high dosages, IV administration, left ventricular dysfunction, or AV conduction abnormalities. Beta blocker ophthalmic solutions may also interact, as they are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels. Bradycardia (36 bpm) with wandering atrial pacemaker occurred in a patient taking oral verapamil and timolol ophthalmic drops. The proposed mechanisms include additive slowing in AV conduction, reduced cardiac contractility secondary to beta-blockade, and decreased peripheral vascular resistance secondary to calcium channel blockade. In addition, verapamil and diltiazem may decrease the clearance of some beta blockers and use of diltiazem with beta blockers has been associated with an increased risk of depression.

MANAGEMENT: Close clinical monitoring of patient hemodynamic response and tolerance is recommended if these agents are used together, and the dosage of one or both agents adjusted as necessary. Patients should be advised to promptly report any symptoms including fatigue, headache, fainting, swelling of the extremities, weight gain, shortness of breath, chest pain, increased or decreased heartbeat, or irregular heartbeat.

References

  1. Henry M, Kay MM, Viccellio P "Cardiogenic shock associated with calcium-channel and beta blockers: reversal with intravenous calcium chloride." Am J Emerg Med 3 (1985): 334-6
  2. Misra M, Thakur R, Bhandari K "Sinus arrest caused by atenolol-verapamil combination." Clin Cardiol 10 (1987): 365-7
  3. Keech AC, Harper RW, Harrison PM, Pitt A, McLean AJ "Extent and pharmacokinetic mechanisms of oral atenolol-verapamil interaction in man." Eur J Clin Pharmacol 35 (1988): 363-6
  4. Sagie A, Strasberg B, Kusnieck J, Sclarovsky S "Symptomatic bradycardia induced by the combination of oral diltiazem and beta blockers." Clin Cardiol 14 (1991): 314-6
  5. Murdoch DL, Thomson GD, Thompson GG, et al. "Evaluation of potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol in normal subjects." Br J Clin Pharmacol 31 (1991): 323-32
  6. Lee TH, Salomon DR, Rayment CM, Antman EM "Hypotension and sinus arrest with exercise-induced hyperkalemia and combined verapamil/propranolol therapy." Am J Med 80 (1986): 1203-4
  7. McCourty JC, Silas JH, Tucker GT, Lennard MS "The effect of combined therapy on the pharmacokinetics and pharmacodynamics of verapamil and propranolol in patients with angina pectoris." Br J Clin Pharmacol 25 (1988): 349-57
  8. McTavish D, Sorkin EM "Verapamil: an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension." Drugs 38 (1989): 19-76
  9. Zatuchni J "Bradycardia and hypotension after propranolol HCI and verapamil." Heart Lung 14 (1985): 94-5
  10. Keech AC, Harper RW, Harrison PM, et al. "Extent and pharmacokinetic mechanisms of oral atenolol-verapamil interaction in man." Eur J Clin Pharmacol 35 (1988): 363-6
  11. Pieper JA, Miller JH "Serum protein binding interactions between propranolol and calcium channel blockers." Drug Intell Clin Pharm 18 (1984): 492
  12. Reddy PS, Uretsky BF, Steinfeld M "The hemodynamic effects of intravenous verapamil in patients on chronic propranolol therapy." Am Heart J 107 (1984): 97-101
  13. Winniford MD, Fulton KL, Hillis LD "Symptomatic sinus bradycardia during concomitant propranolol-verapamil administration." Am Heart J 110 (1985): 498
  14. Lee TH, Salomon DR, Rayment CM, Antman EM "Hypotension and sinus arrest with exercise-induced hyperkalemia and combined verapamil-propranolol therapy." Am J Med 80 (1986): 1203-4
  15. Bailey DG, Carruthers SG "Interaction between oral verapamil and beta-blockers during submaximal exercise: relevance of ancillary properties." Clin Pharmacol Ther 49 (1991): 370-6
  16. Carruthers SG, Freeman DJ, Bailey DG "Synergistic adverse hemodynamic interaction between oral verapamil and propranolol." Clin Pharmacol Ther 46 (1989): 469-77
  17. Eisenberg JN, Oakley GD "Probable adverse interaction between oral metoprolol and verapamil." Postgrad Med J 60 (1984): 705-6
  18. Ronn O, Bengtsson B, Edgar B, Raner S "Acute haemodynamic effects of felodipine and verapamil in man, singly and with metoprolol." Drugs 29 (1985): 16-25
  19. McLean AJ, Knight R, Harrison PM, Harper RW "Clearance-based oral drug interaction between verapamil and metoprolol and comparison with atenolol." Am J Cardiol 55 (1985): 1628-9
  20. Wayne VS, Harper RW, Laufer E, et al. "Adverse interaction between beta-adrenergic blocking drugs and verapamil: report of three cases." Aust N Z J Med 12 (1982): 285-9
  21. Sinclair NI, Benzie JL "Timolol eye drops and verapamil: a dangerous combination." Med J Aust 1 (1983): 548
  22. Pringle SD, MacEwen CJ "Severe bradycardia due to interaction of timolol eye drops and verapamil." Br Med J 294 (1987): 155-6
  23. Rocha P, Guerret M, David D, Marchand X, Kahn JC "Kinetics and hemodynamic effects of intravenous nicardipine modified by previous propranolol oral treatment." Cardiovasc Drugs Ther 4 (1990): 1525-32
  24. Hunt BA, Bottorff MB, Herring VL, Self Th, Lalonde RL "Effects of calcium channel blockers on the pharmacokinetics of propranolol stereoisomers." Clin Pharmacol Ther 47 (1990): 584-91
  25. Pouleur H, Etienne J, Van Mechelen H, et al. "Effects of nicardipine or nifedipine added to propranolol in patients with coronary artery disease." Postgrad Med J 60 (1984): 23-8
  26. Schoors DF, Vercruysse I, Musch G, Massart DL, Dupont AG "Influence of nicardipine on the pharmacokinetics and pharmacodynamics of propranolol in healthy volunteers." Br J Clin Pharmacol 29 (1990): 497-501
  27. Nievel JG, Havard CW, Douglas-Jones AP "Comparison of concomitant nicardipine hydrochloride and propranolol with propranolol alone in patients with essential hypertension." Eur J Clin Pharmacol 33 (1987): 21-5
  28. Leon MB, Rosing DR, Bonow RO, Epstein SE "Combination therapy with calcium-channel blockers and beta blockers for chronic stable angina pectoris." Am J Cardiol 55 (1985): b69-80
  29. Packer M "Combined beta-adrenergic and calcium-entry blockage in angina pectoris." N Engl J Med 320 (1989): 709-18
  30. Strauss WE, Parisi AF "Combines use of calcium-channel and beta-adrenergic blockers for the treatment of chronic stable angina." Ann Intern Med 109 (1988): 570-81
  31. Levine MA, Ogilvie RI, Leenen FH "Pharmacokinetic and pharmacodynamic interactions between nisoldipine and propranolol." Clin Pharmacol Ther 43 (1988): 39-48
  32. Anastassiades CJ "Nifedipine and beta-blocker drugs." Br Med J 281 (1980): 1251-2
  33. Bleske BE, Welage LS, Touchette MA, Edwards DJ, Rodman DP, Shea MJ "Evaluation of dosage-release formulations on inhibition of drug clearance - effect of sustained-release and immediate-release verapamil on propranolol pharmacokinetic parameters." Ther Drug Monit 16 (1994): 216-20
  34. "Product Information. Covera-HS (verapamil)." Searle PROD (2001):
  35. "Product Information. Toprol-XL (metoprolol)." Astra-Zeneca Pharmaceuticals PROD (2001):
  36. Minish T, Herd A "Symptomatic bradycardia secondary to interaction between topical timolol maleate, verapamil, and flecainide: a case report." J Emerg Med 22 (2002): 247-9
View all 36 references

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Drug and food interactions

Moderate

dilTIAZem food

Applies to: Dilt-XR (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 "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet 26 (1994): 91-8
  2. Sigusch H, Henschel L, Kraul H, Merkel U, Hoffmann A "Lack of effect of grapefruit juice on diltiazem bioavailability in normal subjects." Pharmazie 49 (1994): 675-9
  3. Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10
  4. Christensen H, Asberg A, Holmboe AB, Berg KJ "Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers." Eur J Clin Pharmacol 58 (2002): 515-520
  5. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
View all 5 references

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Moderate

dilTIAZem food

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