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Drug Interactions between Lanoxin and MY-E

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

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Interactions between your drugs

Moderate

erythromycin digoxin

Applies to: MY-E (erythromycin) and Lanoxin (digoxin)

MONITOR: Macrolide antibiotics that inhibit P-glycoprotein may increase the plasma concentrations of digoxin. The proposed mechanism is inhibition of the P-glycoprotein-mediated intestinal efflux and/or renal tubular secretion of digoxin. The interaction has been described in numerous case reports in the medical literature, the majority of which involved clarithromycin, a potent P-glycoprotein inhibitor. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Exposure to macrolides, specifically clarithromycin, azithromycin and erythromycin, has been identified as a risk factor for digoxin toxicity. A population-based, case-control study using records from Ontario, Canada's administrative health databases from 1994 to 2000 identified 1051 case patients who had been hospitalized with digoxin toxicity. These patients were about 12 times more likely to have received a prescription for clarithromycin in the previous week compared to controls without digoxin toxicity (n=51,896). Overall, 27 of the case patients (2.6%) had been exposed to clarithromycin within the previous week, compared to 101 controls (0.2%), which represented an adjusted odds ratio of 11.7. Fifty-five patients (5.2%) had been exposed to clarithromycin within the preceding 3 weeks, compared to 274 controls (0.5%), representing an adjusted OR of 8.5. A subsequent study using data from 1993 to 2008 from the same databases and focusing specifically on macrolide-induced digoxin toxicity found that the risk was significantly higher in patients who had received clarithromycin within the previous 2 weeks than in controls who did not receive antibiotics (adjusted OR=14.8). The risk of digoxin toxicity was 4 times higher following treatment with clarithromycin than with azithromycin or erythromycin (adjusted OR=3.71 and 3.69, respectively). Although little data exist, the interaction may also occur with digitoxin. Two cases of suspected azithromycin-induced digitoxin toxicity have been reported in the literature.

MANAGEMENT: Caution is advised when digoxin or digitoxin is used in combination with macrolide antibiotics that are inhibitors of P-glycoprotein. Serum digitalis levels and pharmacologic effects should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of the macrolide in patients who are stabilized on their digitalis regimen. Patients should be advised to notify their physician if they experience signs of digitalis toxicity such as nausea, anorexia, visual disturbances, slow pulse, or irregular heartbeats.

References

  1. Friedman HS, Bonventre MV (1982) "Erythromycin-induced digoxin toxicity." Chest, 82, p. 202
  2. Lindenbaum J, Rund DG, Butler VP Jr, Tse-Eng D, Saha JR (1981) "Inactivation of digoxin by the gut flora: reversal by antibiotic therapy." N Engl J Med, 305, p. 789-94
  3. Lindenbaum J, Tse-Eng D, Butler VP, Rund DG (1981) "Urinary excretion of reduced metabolites of digoxin." Am J Med, 71, p. 67-74
  4. Rodin SM, Johnson BF (1988) "Pharmacokinetic interactions with digoxin." Clin Pharmacokinet, 15, p. 227-44
  5. Maxwell DL, Gilmour-White SK, Hall MR (1989) "Digoxin toxicity due to interaction of digoxin with erythromycin." BMJ, 298, p. 572
  6. Morton MR, Cooper JW (1989) "Erythromycin-induced digoxin toxicity." DICP, 23, p. 668-70
  7. Hui J, Wang YMC, Chandrasekaran A, Geraets DR, Caldwell JH, Robertson LW, Reuning RH (1994) "Disposition of tablet and capsule formulations of digoxin in the elderly." Pharmacotherapy, 14, p. 607-12
  8. Amsden GW (1995) "Macrolides versus azalides: a drug interaction update." Ann Pharmacother, 29, p. 906-17
  9. Ford A, Smith LC, Baltch AL, Smith RP (1995) "Clarithromycin-induced digoxin toxicity in a patient with AIDS." Clin Infect Dis, 21, p. 1051-2
  10. Midoneck SR, Etingin O (1995) "Clarithromycin-related toxic effects of digoxin." N Engl J Med, 333, p. 1505
  11. Corallo CE, Rogers IR (1996) "Roxithromycin-induced digoxin toxicity." Med J Aust, 165, p. 433-4
  12. Brown BA, Wallace RJ, Griffith DE, Warden R (1997) "Clarithromycin-associated digoxin toxicity in the elderly." Clin Infect Dis, 24, p. 92-3
  13. Nawarskas JJ, McCarthy DM, Spinler SA (1997) "Digoxin toxicity secondary to clarithromycin therapy." Ann Pharmacother, 31, p. 864-6
  14. Laberge P, Martineau P (1997) "Clarithromycin-induced digoxin intoxication." Ann Pharmacother, 31, p. 999-1002
  15. Bizjak ED, Mauro VF (1997) "Digoxin-macrolide drug interaction." Ann Pharmacother, 31, p. 1077-82
  16. Guerriero SE, Ehrenpreis E, Gallagher KL (1997) "Two cases of clarithromycin-induced digoxin toxicity." Pharmacotherapy, 17, p. 1035-7
  17. Trivedi S, Hyman J, Lichstein E (1998) "Clarithromycin and digoxin toxicity." Ann Intern Med, 128, p. 604
  18. Nordt SP, Williams SR, Manoguerra AS, Clark RF (1998) "Clarithromycin induced digoxin toxicity." J Accid Emerg Med, 15, p. 194-5
  19. Wakasugi H, Yano I, Ito T, Hashida T, Futami T, Nohara R, Sasayama S, Inui K (1998) "Effect of clarithromycin on renal excretion of digoxin: Interaction with P-glycoprotein." Clin Pharmacol Ther, 64, p. 123-8
  20. Gooderham MJ, Bolli P, Fernandez PG (1999) "Concomitant digoxin toxicity and warfarin interaction in a patient receiving clarithromycin." Ann Pharmacother, 33, p. 796-9
  21. (2001) "Product Information. Lanoxicaps (digoxin)." Glaxo Wellcome
  22. Kurata Y, Ieiri I, Kimura M, et al. (2002) "Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein." Clin Pharmacol Ther, 72, p. 209-19
  23. Zapater P, Reus S, Tello A, Torrus D, Perez-Mateo M, Horga JF (2002) "A prospective study of the clarithromycin-digoxin interaction in elderly patients." J Antimicrob Chemother, 50, p. 601-6
  24. Tsutsumi K, Kotegawa T, Kuranari M, et al. (2002) "The effect of erythromycin and clarithromycin on the pharmacokinetics of intravenous digoxin in healthy volunteers." J Clin Pharmacol, 42, p. 1159-64
  25. Tanaka H, Matsumoto K, Ueno K, et al. (2003) "Effect of clarithromycin on steady-state digoxin concentrations." Ann Pharmacother, 37, p. 178-81
  26. Drescher S, Glaeser H, Murdter T, Hitzl M, Eichelbaum M, Fromm MF (2003) "P-glycoprotein-mediated intestinal and biliary digoxin transport in humans." Clin Pharmacol Ther, 73, p. 223-31
  27. Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA (2003) "Drug-drug interactions among elderly patients hospitalized for drug toxicity." JAMA, 289, p. 1652-8
  28. Rengelshausen J, Goggelmann C, Burhenne J, et al. (2003) "Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin-clarithromycin interaction." Br J Clin Pharmacol, 56, p. 32-38
  29. Hirata S, Izumi S, Furukubo T, et al. (2005) "Interactions between clarithromycin and digoxin in patients with end-stage renal disease." Int J Clin Pharmacol Ther, 43, p. 30-6
  30. Balayssac D, Authier N, Cayre A, Coudore F (2005) "Does inhibition of P-glycoprotein lead to drug-drug interactions?" Toxicol Lett, 156, p. 319-29
  31. Eberl S, Renner B, Neubert A, et al. (2007) "Role of p-glycoprotein inhibition for drug interactions : evidence from in vitro and pharmacoepidemiological studies." Clin Pharmacokinet, 46, p. 1039-49
  32. Gurley BJ, Swain A, Williams DK, Barone G, Battu SK (2008) "Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics." Mol Nutr Food Res, 52, p. 772-9
  33. Chan AL, Wang MT, Su CY, Tsai FH (2009) "Risk of digoxin intoxication caused by clarithromycin-digoxin interactions in heart failure patients: a population-based study." Eur J Clin Pharmacol, 65, p. 1237-43
  34. Hughes J, Crowe A (2010) "Inhibition of P-glycoprotein-mediated efflux of digoxin and its metabolites by macrolide antibiotics." J Pharmacol Sci, 113, p. 315-24
  35. Lee CY, Marcotte F, Giraldeau G, Koren G, Juneau M, Tardif JC (2011) "Digoxin toxicity precipitated by clarithromycin use: case presentation and concise review of the literature." Can J Cardiol, 27, 870 e15-6
  36. Alkadi H, Mosfer M, Alkatheri M (2007) "Clarithromycin and azithromicin induced-digoxin toxicity in patients under digoxin therapy." Clin Res Cardiol, 96, p. 424
  37. Ten Eick AP, Sallee D, Preminger T, Weiss A, Reed MD (2000) "Possible drug interaction between digoxin and azithromycin in a young child." Clin Drug Investig, 20, p. 61-4
  38. Ten Eick AP, Reed MD (2000) "Hidden dangers of coadministration of antibiotics and digoxin in children: focus on azithromycin." Curr Ther Res, 61, p. 148-60
  39. Gomes T, Mamdani MM, Juurlink DN (2009) "Macrolide-induced digoxin toxicity: a population-based study." Clin Pharmacol Ther, 86, p. 383-6
  40. Kiran N, Azam S, Dhakam S (2004) "Clarithromycin induced digoxin toxicity: case report and review." J Pak Med Assoc, 54, p. 440-1
  41. Thalhammer F, Hollenstein UM, Locker GJ, et al. (1998) "Azithromycin-related toxic effects of digitoxin." Br J Clin Pharmacol, 45, p. 91-2
View all 41 references

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Drug and food interactions

Moderate

erythromycin food

Applies to: MY-E (erythromycin)

ADJUST DOSING INTERVAL: Food may variably affect the bioavailability of different oral formulations and salt forms of erythromycin. The individual product package labeling should be consulted regarding the appropriate time of administration in relation to food ingestion. Grapefruit juice may increase the plasma concentrations of orally administered erythromycin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In an open-label, crossover study consisting of six healthy subjects, the coadministration with double-strength grapefruit juice increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single dose of erythromycin (400 mg) by 52% and 49%, respectively, compared to water. The half-life was not affected. The clinical significance of this potential interaction is unknown.

MANAGEMENT: In general, optimal serum levels are achieved when erythromycin is taken in the fasting state, one-half to two hours before meals. However, some erythromycin products may be taken without regard to meals.

References

  1. Welling PG, Huang H, Hewitt PF, Lyons LL (1978) "Bioavailability of erythromycin stearate: influence of food and fluid volume." J Pharm Sci, 67, p. 764-6
  2. Welling PG, Elliott RL, Pitterle ME, et al. (1979) "Plasma levels following single and repeated doses of erythromycin estolate and erythromycin stearate." J Pharm Sci, 68, p. 150-5
  3. Welling PG (1977) "Influence of food and diet on gastrointestinal drug absorption: a review." J Pharmacokinet Biopharm, 5, p. 291-334
  4. Coyne TC, Shum S, Chun AH, Jeansonne L, Shirkey HC (1978) "Bioavailability of erythromycin ethylsuccinate in pediatric patients." J Clin Pharmacol, 18, p. 194-202
  5. Malmborg AS (1979) "Effect of food on absorption of erythromycin. A study of two derivatives, the stearate and the base." J Antimicrob Chemother, 5, p. 591-9
  6. Randinitis EJ, Sedman AJ, Welling PG, Kinkel AW (1989) "Effect of a high-fat meal on the bioavailability of a polymer-coated erythromycin particle tablet formulation." J Clin Pharmacol, 29, p. 79-84
  7. Kanazawa S, Ohkubo T, Sugawara K (2001) "The effects of grapefruit juice on the pharmacokinetics of erythromycin." Eur J Clin Pharmacol, 56, p. 799-803
View all 7 references

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Minor

digoxin food

Applies to: Lanoxin (digoxin)

Administration of digoxin with a high-fiber meal has been shown to decrease its bioavailability by almost 20%. Fiber can sequester up to 45% of the drug when given orally. Patients should be advised to maintain a regular diet without significant fluctuation in fiber intake while digoxin is being titrated.

Grapefruit juice may modestly increase the plasma concentrations of digoxin. The mechanism is increased absorption of digoxin due to mild inhibition of intestinal P-glycoprotein by certain compounds present in grapefruits. In 12 healthy volunteers, administration of grapefruit juice with and 30 minutes before, as well as 3.5, 7.5, and 11.5 hours after a single digoxin dose (0.5 mg) increased the mean area under the plasma concentration-time curve (AUC) of digoxin by just 9% compared to administration with water. Moreover, P-glycoprotein genetic polymorphism does not appear to influence the magnitude of the effects of grapefruit juice on digoxin. Thus, the interaction is unlikely to be of clinical significance.

References

  1. Darcy PF (1995) "Nutrient-drug interactions." Adverse Drug React Toxicol Rev, 14, p. 233-54
  2. Becquemont L, Verstuyft C, Kerb R, et al. (2001) "Effect of grapefruit juice on digoxin pharmacokinetics in humans." Clin Pharmacol Ther, 70, p. 311-6

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Minor

erythromycin food

Applies to: MY-E (erythromycin)

Ethanol, when combined with erythromycin, may delay absorption and therefore the clinical effects of the antibiotic. The mechanism appears to be due to slowed gastric emptying by ethanol. Data is available only for erythromycin ethylsuccinate. Patients should be advised to avoid ethanol while taking erythromycin salts.

References

  1. Morasso MI, Chavez J, Gai MN, Arancibia A (1990) "Influence of alcohol consumption on erythromycin ethylsuccinate kinetics." Int J Clin Pharmacol, 28, p. 426-9

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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.

Further information

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