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Drug Interactions between Isoptin and propranolol

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

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Major

propranolol verapamil

Applies to: propranolol and Isoptin (verapamil)

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

propranolol food

Applies to: propranolol

ADJUST DOSING INTERVAL: The bioavailability of propranolol may be enhanced by food.

MANAGEMENT: Patients may be instructed to take propranolol at the same time each day, preferably with or immediately following meals.

References

  1. Olanoff LS, Walle T, Cowart TD, et al. "Food effects on propranolol systemic and oral clearance: support for a blood flow hypothesis." Clin Pharmacol Ther 40 (1986): 408-14
  2. Byrne AJ, McNeil JJ, Harrison PM, Louis W, Tonkin AM, McLean AJ "Stable oral availability of sustained release propranolol when co-administered with hydralazine or food: evidence implicating substrate delivery rate as a determinant of presystemic drug interactions." Br J Clin Pharmacol 17 (1984): s45-50

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Moderate

verapamil food

Applies to: Isoptin (verapamil)

GENERALLY AVOID: Consumption of large quantities of grapefruit juice may be associated with significantly increased plasma concentrations of oral verapamil. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. One study reported no significant effect of a single administration of grapefruit juice on the pharmacokinetics of verapamil in ten hypertensive patients receiving chronic therapy. In another study conducted in nine healthy male volunteers, administration of 120 mg oral verapamil twice daily for 3 days following pretreatment with 200 mL grapefruit juice twice daily for 5 days resulted in a 57% increase in S-verapamil peak plasma concentration (Cmax), a 36% increase in S-verapamil systemic exposure (AUC), a 40% increase in R-verapamil Cmax, and a 28% increase in R-verapamil AUC compared to administration following orange juice. Elimination half-life and renal clearance of both S- and R-verapamil were not affected by grapefruit juice, and there were no significant effects on blood pressure, heart rate, or PR interval. A third study reported a 1.63-fold increase in Cmax and a 1.45-fold increase in AUC of (R,S)-verapamil in 24 young, healthy volunteers given verapamil sustained-release 120 mg twice daily for 7 days with 250 mL grapefruit juice four times daily on days 5 through 7. Two subjects developed PR interval prolongation of more than 350 ms during grapefruit juice coadministration. A high degree of interindividual variability has been observed in these studies. The interaction was also suspected in a case report of a 42-year-old woman who developed complete heart block, hypotension, hypoxic respiratory failure, severe anion gap metabolic acidosis, and hyperglycemia following accidental ingestion of three verapamil sustained-release 120 mg tablets over a span of six hours. The patient's past medical history was remarkable only for migraine headaches, for which she was receiving several medications including verapamil. Prior to admission, the patient had a 2-week history of poorly controlled migraine, and the six hours preceding hospitalization she suffered from worsening headache and palpitations progressing to altered sensorium. An extensive workup revealed elevated verapamil and norverapamil levels more than 4.5 times above the upper therapeutic limits. These levels also far exceeded those reported in the medical literature for patients taking verapamil 120 mg every 6 hours, or 480 mg in a 24-hour period. The patient recovered after receiving ventilator and vasopressor support. Upon questioning, it was discovered that the patient had been drinking large amounts of grapefruit juice (3 to 4 liters total) the week preceding her admission due to nausea. No other sources or contributing factors could be found for the verapamil toxicity.

MANAGEMENT: Patients treated with oral verapamil should avoid the consumption of large amounts of grapefruit or grapefruit juice to prevent any undue fluctuations in serum drug levels. 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. McAllister RG, Jr "Clinical pharmacology of slow channel blocking agents." Prog Cardiovasc Dis 25 (1982): 83-102
  2. "Product Information. Covera-HS (verapamil)." Searle PROD (2001):
  3. Zaidenstein R, Dishi V, Gips M, Soback S, Cohen N, Weissgarten J, Blatt A, Golik A "The effect of grapefruit juice on the pharmacokinetics of orally administered verapamil." Eur J Clin Pharmacol 54 (1998): 337-40
  4. Ho PC, Ghose K, Saville D, Wanwimolruk S "Effect of grapefruit juice on pharmacokinetics and pharmacodynamics of verapamil enantiomers in healthy volunteers." Eur J Clin Pharmacol 56 (2000): 693-8
  5. Fuhr U, Muller-Peltzer H, Kern R, et al. "Effects of grapefruit juice and smoking on verapamil concentrations in steady state." Eur J Clin Pharmacol 58 (2002): 45-53
  6. Bailey DG, Dresser GK "Natural products and adverse drug interactions." Can Med Assoc J 170 (2004): 1531-2
  7. Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions. 1998." Br J Clin Pharmacol 58 (2004): S831-40; discussion S841-3
  8. Arayne MS, Sultana N, Bibi Z "Review: grape fruit juice - drug interactions." Pak J Pharm Sci 18 (2005): 45-57
  9. Pillai U, Muzaffar J, Sandeep S, Yancey A "Grapefruit juice and verapamil: a toxic cocktail." South Med J 102 (2009): 308-9
View all 9 references

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Moderate

verapamil food

Applies to: Isoptin (verapamil)

GENERALLY AVOID: Verapamil may increase the blood concentrations and intoxicating effects of ethanol. The exact mechanism of interaction is unknown but may involve verapamil inhibition of ethanol metabolism. In 10 healthy, young volunteers, verapamil (80 mg orally every 8 hours for 6 days) increased the mean peak blood concentration (Cmax) and the 12-hour area under the concentration-time curve (AUC) of ethanol (0.8 g/kg single oral dose) by 17% and 30%, respectively, compared to placebo. Verapamil AUCs were positively correlated to increased ethanol blood AUC values. Subjectively (i.e. each subject's perception of intoxication as measured on a visual analog scale), verapamil also significantly increased the area under the ethanol effect versus time curve but did not change the peak effect or time to peak effect.

MANAGEMENT: Patients treated with verapamil should be counseled to avoid alcohol consumption.

References

  1. Bauer LA, Schumock G, Horn J, Opheim K "Verapamil inhibits ethanol elimination and prolongs the perception of intoxication." Clin Pharmacol Ther 52 (1992): 6-10
  2. "Product Information. Isoptin (verapamil)." Knoll Pharmaceutical Company PROD (2001):

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Moderate

propranolol food

Applies to: propranolol

ADJUST DOSING INTERVAL: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers. The exact mechanism of interaction is unknown. In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively. The elimination half-life increased by 44%. Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone. However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments. The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

MANAGEMENT: It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours. Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.

References

  1. Kirch W, Schafer-Korting M, Axthelm T, Kohler H, Mutschler E "Interaction of atenolol with furosemide and calcium and aluminum salts." Clin Pharmacol Ther 30 (1981): 429-35

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Moderate

verapamil food

Applies to: Isoptin (verapamil)

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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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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