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Drug Interactions between diltiazem / enalapril and Yosprala

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

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Moderate

enalapril aspirin

Applies to: diltiazem / enalapril and Yosprala (aspirin / omeprazole)

MONITOR: Some investigators suggest that coadministration with aspirin may attenuate the vasodilator and hypotensive effects of ACE inhibitors. In addition, some have found that the benefits of ACE inhibitors on morbidity and mortality in post-acute myocardial infarction, coronary heart disease, and particularly congestive heart failure may be compromised or even nullified by aspirin. The proposed mechanism is aspirin inhibition of cyclooxygenase, resulting in suppression of prostaglandin synthesis and prostaglandin-mediated hemodynamic effects of ACE inhibitors. However, evidence of a negative interaction is largely contradictory, and interpretation of relevant data has often been complicated by multiple confounding elements as well as the retrospective or post hoc nature of most studies. Available data seem to indicate that low-dose aspirin (less than 236 mg/day, and especially less than 100 mg/day) is unlikely, or at least significantly less likely, to interfere with ACE inhibitor effects, although susceptibility to the interaction may be subject to some degree of interpatient variability.

MANAGEMENT: Based on current data, it is difficult to determine the likelihood of a negative interaction between aspirin and ACE inhibitors and its clinical relevance during long-term therapy, particularly in congestive heart failure. Current recommendations generally do not preclude combination use in patients with cardiovascular diseases or risk factors that might otherwise benefit from the drugs independently. However, patients receiving long-term therapy with the combination should undergo regular blood pressure and other appropriate clinical monitoring such as renal function assessments. The lowest therapeutic dosage of aspirin should be used.

References

  1. Moore TJ, Crantz FR, Hollenberg NK "Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension." Hypertension 3 (1981): 168-73
  2. Silberbauer K, Stanek B, Templ H "Acute hypotensive effect of captopril in man modified by prostaglandin synthesis inhibition." Br J Clin Pharmacol 14 (1982): s87-93
  3. Pfeffer MA, Braunwald E, Moye LA, et al. "Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial." N Engl J Med 327 (1992): 669-77
  4. Hall D, Zeitler H, Rudolph W "Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure." J Am Coll Cardiol 20 (1992): 1549-55
  5. Acute Infarction Ramipril Efficacy (AIRE) Study Investigators "Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure." Lancet 342 (1993): 821-8
  6. Polonia J, Boaventura I, Gama G, Camoes I, Bernardo F, Andrade P, Nunes JP, Brandao F, Cerqueiragomes M "Influence of non-steroidal anti-inflammatory drugs on renal function and 24h ambulatory blood pressure-reducing effects of enalapril and nifedipine gastrointestinal therapeutic system in hypertensive patients." J Hypertens 13 (1995): 925-31
  7. Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, Videbaek J, Cole DS, Auclert L, Pauly NC, et al. "A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group." N Engl J Med 333 (1995): 1670-6
  8. Nguyen KN, Aursnes I, Kjekshus J "Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the cooperative new scandinavian enalapril survival study II (CONSENSUS II)." Am J Cardiol 79 (1997): 115-9
  9. Oosterga M, Anthonio RL, deKam PJ, Kingma JH, Crijns HJGM, vanGilst WH "Effects of aspirin on angiotensin-converting enzyme inhibition and left ventricular dilation one year after acute myocardial infarction." Am J Cardiol 81 (1998): 1178-81
  10. Spaulding C, Charbonnier B, CohenSolal A, Juilliere Y, Kromer EP, Benhamda K, Cador R, Weber S "Acute hemodynamic interaction of aspirin and ticlopidine with enalapril: Results of a double-blind, randomized comparative trial." Circulation 98 (1998): 757-65
  11. Song KH, Fedyk R, Hoover R "Interaction of ACE inhibitors and aspirin in patients with congestive heart failure." Ann Pharmacother 33 (1999): 375-7
  12. Leor J, ReicherReiss H, Goldbourt U, Boyko V, Gottlieb S, Battler A, Behar S "Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors - A cohort study of 11,575 patients with coronary artery disease." J Am Coll Cardiol 33 (1999): 1920-5
  13. The Heart Outcomes Prevention Evaluation Study Investigators "Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients." N Engl J Med 342 (2000): 145-53
  14. Massie BM, Teerlink JR "Interaction between aspirin and angiotensin-converting enzyme inhibitors: Real or imagined." Am J Med 109 (2000): 431-3
  15. Meune C, Mahe I, Mourad JJ, Simoneau G, Knellwolf AL, Bergmann JF, Caulin C "Interaction between angiotensin-converting enzyme inhibitors and aspirin: a review." Eur J Clin Pharmacol 56 (2000): 609-20
  16. Mahe I, Meune C, Diemer M, Caulin C, Bergmann JF "Interaction between aspirin and ACE inhibitors in patients with heart failure." Drug Saf 24 (2001): 167-82
  17. Zanchetti A, Hansson L, Leonetti G, et al. "Low-dose aspirin does not interfere with the blood pressure-lowering effects of antihypertensive therapy." J Hypertens 20 (2002): 1015-1022
  18. Ahmed A "Interaction between aspirin and angiotensin-converting enzyme inhibitors: should they be used together in older adults with heart failure?" J Am Geriatr Soc 50 (2002): 1293-6
  19. Lapane KL, Hume AL, Barbour MM, Lipsitz LA "Does aspirin attenuate the effect of angiotensin-converting enzyme inhibitors on health outcomes of very old patients with heart failure?" J Am Geriatr Soc 50 (2002): 1198-204
  20. Nawarskas JJ, Spinler SA "Update on the interaction between aspirin and angiotensin-converting enzyme inhibitors." Pharmacotherapy 20 (2000): 698-710
  21. Nawarskas JJ, Spinler SA "Does aspirin interfere with the therapeutic efficacy of angiotensin-converting enzymen inhibitors in hypertension or congestive heart failure?" Pharmacotherapy 18 (1998): 1041-52
  22. Teo K, Yusuf S, Pfeffer M, et al. "Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review." Lancet 360 (2002): 1037
  23. Guazzi M, Brambilla R, Reina G, Tumminello G, Guazzi MD "Aspirin-angiotensin-converting enzyme inhibitor coadministration and mortality in patients with heart failure: a dose-related adverse effect of aspirin." Arch Intern Med 163 (2003): 1574-9
View all 23 references

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Moderate

dilTIAZem aspirin

Applies to: diltiazem / enalapril and Yosprala (aspirin / omeprazole)

MONITOR: Several case reports have suggested that verapamil and aspirin may have synergistic antiplatelet effects. The mechanism of this interaction has not been fully elucidated. Also, one study of five patients has suggested that aspirin may reverse the antihypertensive effect of verapamil. The mechanism may be related to antagonism of the effect of verapamil on prostacyclin. Diltiazem has been shown to interact with aspirin in a similar manner.

MANAGEMENT: Close observation for prolonged bleeding time and reduced antihypertensive effect is recommended if these drugs must be used together. Patients should be advised to notify their physician if they experience unusual bleeding, bruising, or petechiae. Aspirin should be discontinued if an interaction is suspected.

References

  1. Das UN "Modification of anti-hypertensive action of verapamil by inhibition of endogenous prostaglandin synthesis." Prostaglandins Leukot Med 9 (1982): 167-9
  2. Ring ME, Corrigan JJ, Fenster PE "Effects of oral diltiazem on platelet function: alone and in combination with "low dose" aspirin." Thromb Res 44 (1986): 391-400
  3. Altman R, Scazziota A, Dujovne C "Diltiazem potentiates the inhibitory effect of aspirin on platelet aggregation." Clin Pharmacol Ther 44 (1988): 320-5
  4. Verzino E, Kaplan B, Ashley JV, Burdette M "Verapamil-aspirin interaction." Ann Pharmacother 28 (1994): 536-7
  5. "Product Information. Covera-HS (verapamil)." Searle PROD (2001):
View all 5 references

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Minor

enalapril dilTIAZem

Applies to: diltiazem / enalapril and diltiazem / enalapril

Calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors may have additive hypotensive effects. While these drugs are often safely used together, careful monitoring of the systemic blood pressure is recommended during coadministration, especially during the first one to three weeks of therapy.

References

  1. Kaplan NM "Amlodipine in the treatment of hypertension." Postgrad Med J 67 Suppl 5 (1991): s15-9
  2. DeQuattro V "Comparison of benazepril and other antihypertensive agents alone and in combination with the diuretic hydrochlorothiazide." Clin Cardiol 14 (1991): iv28-32;
  3. Sun JX, Cipriano A, Chan K, John VA "Pharmacokinetic interaction study between benazepril and amlodipine in healthy subjects." Eur J Clin Pharmacol 47 (1994): 285-9
  4. Di Somma S, et al. "Antihypertensive effects of verapamil, captopril and their combination at rest and during dynamic exercise." Arzneimittelforschung 42 (1992): 103
View all 4 references

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Minor

aspirin omeprazole

Applies to: Yosprala (aspirin / omeprazole) and Yosprala (aspirin / omeprazole)

Coadministration with proton pump inhibitors may decrease the oral bioavailability of aspirin and other salicylates. The interaction has been studied with omeprazole and aspirin, although data are conflicting. In one study, pretreatment with omeprazole (20 mg/day for 2 days) in 11 healthy volunteers led to a significant and progressively greater reduction in the mean serum salicylate level at 30, 60, and 90 minutes after administration of aspirin (650 mg single dose). The investigators suggest that acid suppression may reduce the lipophilic nature of aspirin, thereby adversely affecting its absorption from the gastrointestinal tract. Another study found no effect of omeprazole pretreatment (20 mg/day for 4 days) on plasma salicylate and aspirin levels, skin bleeding times, or antiplatelet effect of low-dose aspirin (125 mg single dose) in 14 healthy volunteers. However, these results do not exclude the possibility that omeprazole might interfere with the analgesic, antipyretic, or anti-inflammatory effects of aspirin, which has been demonstrated in rats.

Proton pump inhibitors may enhance the release rate of salicylates from enteric-coated formulations due to premature disruption of the coating and intragastric release of the drug secondary to an increase in gastric pH. In eight healthy volunteers, omeprazole pretreatment (20 mg/day for 4 days) did not affect the bioavailability of salicylate from uncoated aspirin tablets but significantly increased the absorption rate of salicylate from enteric-coated sodium salicylate tablets. The clinical significance of this interaction is unknown. Theoretically, it may increase the risk of gastric adverse effects associated with salicylates.

References

  1. Nefesoglu FZ, Ayanoglu-Dulger G, Ulusoy NB, Imeryuz N "Interaction of omeprazole with enteric-coated salicylate tablets." Int J Clin Pharmacol Ther 36 (1998): 549-53
  2. Anand BS, Sanduja SK, Lichetenberger LM "Effect of omeprazole on the bioavailability of aspirin: a randomized controlled study on healthy volunteers." Gastroenterology 116 (1999): A371
  3. Inarrea P, Esteva F, Cornudella R, Lanas A "Omeprazole does not interfere with the antiplatelet effect of low-dose aspirin in man." Scand J Gastroenterol 35 (2000): 242-6

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Drug and food interactions

Moderate

enalapril food

Applies to: diltiazem / enalapril

GENERALLY AVOID: Moderate-to-high dietary intake of potassium can cause hyperkalemia in some patients who are using angiotensin converting enzyme (ACE) inhibitors. In some cases, affected patients were using a potassium-rich salt substitute. ACE inhibitors can promote hyperkalemia through inhibition of the renin-aldosterone-angiotensin (RAA) system.

MANAGEMENT: It is recommended that patients who are taking ACE inhibitors be advised to avoid moderately high or high potassium dietary intake. Particular attention should be paid to the potassium content of salt substitutes.

References

  1. "Product Information. Vasotec (enalapril)." Merck & Co., Inc PROD (2002):
  2. Good CB, McDermott L "Diet and serum potassium in patients on ACE inhibitors." JAMA 274 (1995): 538
  3. Ray K, Dorman S, Watson R "Severe hyperkalaemia due to the concomitant use of salt substitutes and ACE inhibitors in hypertension: a potentially life threatening interaction." J Hum Hypertens 13 (1999): 717-20

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Moderate

dilTIAZem food

Applies to: diltiazem / enalapril

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

enalapril food

Applies to: diltiazem / enalapril

MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

References

  1. Sternbach H "Fluoxetine-associated potentiation of calcium-channel blockers." J Clin Psychopharmacol 11 (1991): 390-1
  2. Shook TL, Kirshenbaum JM, Hundley RF, Shorey JM, Lamas GA "Ethanol intoxication complicating intravenous nitroglycerin therapy." Ann Intern Med 101 (1984): 498-9
  3. Feder R "Bradycardia and syncope induced by fluoxetine." J Clin Psychiatry 52 (1991): 139
  4. Ellison JM, Milofsky JE, Ely E "Fluoxetine-induced bradycardia and syncope in two patients." J Clin Psychiatry 51 (1990): 385-6
  5. Rodriguez de la Torre B, Dreher J, Malevany I, et al. "Serum levels and cardiovascular effects of tricyclic antidepressants and selective serotonin reuptake inhibitors in depressed patients." Ther Drug Monit 23 (2001): 435-40
  6. Cerner Multum, Inc. "Australian Product Information." O 0
  7. Pacher P, Kecskemeti V "Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns?" Curr Pharm Des 10 (2004): 2463-75
  8. Andrews C, Pinner G "Postural hypotension induced by paroxetine." BMJ 316 (1998): 595
View all 8 references

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Moderate

aspirin food

Applies to: Yosprala (aspirin / omeprazole)

GENERALLY AVOID: The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

References

  1. "Product Information. Motrin (ibuprofen)." Pharmacia and Upjohn PROD (2002):

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Moderate

dilTIAZem food

Applies to: diltiazem / enalapril

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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Minor

aspirin food

Applies to: Yosprala (aspirin / omeprazole)

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.

References

  1. Yoovathaworn KC, Sriwatanakul K, Thithapandha A "Influence of caffeine on aspirin pharmacokinetics." Eur J Drug Metab Pharmacokinet 11 (1986): 71-6

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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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