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Drug Interactions between Biaxin XL and digoxin

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

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Interactions between your drugs

Major

clarithromycin digoxin

Applies to: Biaxin XL (clarithromycin) and digoxin

MONITOR CLOSELY: Coadministration with clarithromycin may significantly increase the plasma concentrations of digoxin. The proposed mechanism is clarithromycin 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. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Between 35% and greater than 2-fold increases in digoxin systemic exposure (AUC) have been reported in pharmacokinetic studies with clarithromycin, and exposure to clarithromycin has been identified as a risk factor for digoxin toxicity in several studies. 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. Another population-based study conducted by a group of investigators in Taiwan also reported a significantly higher risk of hospitalization for digoxin intoxication in heart failure patients who received clarithromycin, and that the risk could reach as high as 55.4-fold.

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

References

  1. 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
  2. Lindenbaum J, Tse-Eng D, Butler VP, Rund DG (1981) "Urinary excretion of reduced metabolites of digoxin." Am J Med, 71, p. 67-74
  3. Rodin SM, Johnson BF (1988) "Pharmacokinetic interactions with digoxin." Clin Pharmacokinet, 15, p. 227-44
  4. (2002) "Product Information. Biaxin (clarithromycin)." Abbott Pharmaceutical
  5. 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
  6. Amsden GW (1995) "Macrolides versus azalides: a drug interaction update." Ann Pharmacother, 29, p. 906-17
  7. 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
  8. Midoneck SR, Etingin O (1995) "Clarithromycin-related toxic effects of digoxin." N Engl J Med, 333, p. 1505
  9. Brown BA, Wallace RJ, Griffith DE, Warden R (1997) "Clarithromycin-associated digoxin toxicity in the elderly." Clin Infect Dis, 24, p. 92-3
  10. Nawarskas JJ, McCarthy DM, Spinler SA (1997) "Digoxin toxicity secondary to clarithromycin therapy." Ann Pharmacother, 31, p. 864-6
  11. Laberge P, Martineau P (1997) "Clarithromycin-induced digoxin intoxication." Ann Pharmacother, 31, p. 999-1002
  12. Bizjak ED, Mauro VF (1997) "Digoxin-macrolide drug interaction." Ann Pharmacother, 31, p. 1077-82
  13. Guerriero SE, Ehrenpreis E, Gallagher KL (1997) "Two cases of clarithromycin-induced digoxin toxicity." Pharmacotherapy, 17, p. 1035-7
  14. Trivedi S, Hyman J, Lichstein E (1998) "Clarithromycin and digoxin toxicity." Ann Intern Med, 128, p. 604
  15. Nordt SP, Williams SR, Manoguerra AS, Clark RF (1998) "Clarithromycin induced digoxin toxicity." J Accid Emerg Med, 15, p. 194-5
  16. 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
  17. Gooderham MJ, Bolli P, Fernandez PG (1999) "Concomitant digoxin toxicity and warfarin interaction in a patient receiving clarithromycin." Ann Pharmacother, 33, p. 796-9
  18. (2001) "Product Information. Lanoxicaps (digoxin)." Glaxo Wellcome
  19. 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
  20. 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
  21. 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
  22. Tanaka H, Matsumoto K, Ueno K, et al. (2003) "Effect of clarithromycin on steady-state digoxin concentrations." Ann Pharmacother, 37, p. 178-81
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
  28. 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
  29. 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
  30. 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
  31. 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
  32. 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
  33. Alkadi H, Mosfer M, Alkatheri M (2007) "Clarithromycin and azithromicin induced-digoxin toxicity in patients under digoxin therapy." Clin Res Cardiol, 96, p. 424
  34. Gomes T, Mamdani MM, Juurlink DN (2009) "Macrolide-induced digoxin toxicity: a population-based study." Clin Pharmacol Ther, 86, p. 383-6
  35. Kiran N, Azam S, Dhakam S (2004) "Clarithromycin induced digoxin toxicity: case report and review." J Pak Med Assoc, 54, p. 440-1
View all 35 references

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Drug and food interactions

Minor

clarithromycin food

Applies to: Biaxin XL (clarithromycin)

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.

References

  1. Cheng KL, Nafziger AN, Peloquin CA, Amsden GW (1998) "Effect of grapefruit juice on clarithromycin pharmacokinetics." Antimicrob Agents Chemother, 42, p. 927-9

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Minor

digoxin food

Applies to: 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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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.

See also

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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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