Eur J Clin PharmacolDOI 10.1007/s00228-007-0394-1 Identification of severe potential drug-drug interactionsusing an Italian general-practitioner database L. Magro & A. Conforti & F. Del Zotti & R. Leone &M. L. Iorio & I. Meneghelli & D. Massignani & E. Visonà &U. Moretti Received: 9 July 2007 / Accepted: 27 September 2007 number of different types of severe potential DDIs was 119, Objective To analyze prescriptions in a general-practitioner which occurred 1,037 times in 758 patients (4.7% of the total database over 1 year to determine the frequency, the number of patients). More than 80% of drugs involved in characteristics, and the monitoring of the severe potential severe potential DDIs were cardiovascular drugs. Digoxin was the most frequently involved drug. Electrolyte disturbances, Methods We retrospectively analyzed the clinical records from increase in serum digoxin levels, risk of hemorrhage, severe 16 general practitioners in the Veneto region, an area in northern myopathy or rhabdomyolysis, and cardiac arrhythmias were Italy. The study covered the period from January 1 to December the most commonly implicated potential risks. When consid- 31, 2004. We selected all severe and well-documented ering patients using digoxin with loop or thiazide diuretics for interactions according to the book Drug Interaction Facts by more than 5 months, 72% had at least one test to monitor David S. Tatro (Facts and Comparisons, St. Louis, MO, potential digoxin toxicity, whereas 28% had no tests. Sixty- 2006). We grouped severe potential DDIs according to their four percent of patients using digoxin with amiodarone, specific potential risk, and for the most frequently interacting verapamil, or propafenone had an ECG and/or digoxin drug pairs, we investigated whether some specific tests had monitoring, and 36% of them did not have any tests.
been prescribed by physicians for safety monitoring.
Conclusions The present study revealed that, in a group of Results During the study period, 16,037 patients (55% female) Italian general practitioners, the risks of severe potential with at least one drug prescription were recorded, and a total of drug interactions are relatively low and the drugs concerned 185,704 prescriptions relating to 1,020 different drugs were are few. Analyses of specific tests showed that physicians analyzed. Ramipril was the most frequently prescribed drug are generally aware of the potential risks caused by digoxin followed by acetylsalicylic acid and atorvastatin. The final drug associations. However not all patients were closelymonitored and this should be improved.
L. Magro A. Conforti R. Leone M. L. Iorio I. Meneghelli U. MorettiClinical Pharmacology Unit, University of Verona, Severe potential drug-drug interactions . Monitoring European General Practice Research Network (EGRPN),Verona, Italy In the broadest sense, a drug-drug interaction (DDI) may be defined as the pharmacological or clinical response to the Società Italiana Medicina Generale (SIMG), administration of a drug combination that is different from that anticipated from the known effects of the two agents when given alone and that can result in reduced effective- Clinical Pharmacology Unit, Policlinico G.B. Rossi, ness or increased toxicity []. A DDI can be the consequence of various situations that reflect the growing 37134 Verona, Italye-mail: number of drugs available on the market. The increasing complexity of polytherapy is a major source of DDIs. The three levels of severity—major, moderate, and minor—and very widespread practice of self-medication makes the five categories of degree of documentation—established, situation more severe and difficult.
probable, suspected, possible, and unlikely. Based on a In the literature, most studies on drug interactions have combination of these two elements, he assigns a signifi- analyzed patients in hospitals, and it has been estimated that cance rating (from 1 to 5) to each DDI.
drug interactions may affect up to 63% of all hospitalized By excluding drugs not used in primary care and not patients Data about outpatients exposed to drug available in the Italian market, a list of 895 DDIs with interactions are limited, and a few studies set in the context significance rating of 1 (major severity and established or of general practice have generated a wide range of probable or suspected documentation) were selected. In the estimates. In primary health care, from 9 to 70% of patients database, we looked for patients who were concomitantly are reported to use concomitant drugs with the risk of a potential DDI ], even if these are serious only in a We assumed that consumption of a drug started the same fraction of these patients (from 0.5 to 2%) [, day the drug was prescribed, and for each patient we According to the literature, many factors contribute to calculated the period of exposure to each interacting drug these wide ranges, either in a hospital or an outpatient by multiplying the number of defined daily doses (DDD) setting, including the target population, the number of by the number of prescribed packs. Severe potential DDIs prescribed drugs, or the differences in methods used.
were identified when the exposure periods to two interact- Some studies have quantified the outcome of specific ing drugs overlapped. Severe potential DDIs were grouped interactions , however little or nothing is known according to their specific potential risk, as described in about the actual number of patients with serious conse- We considered the most frequently interacting drug pairs quences resulting from potential DDIs in primary health and investigated whether some specific tests had been care [The few published studies are related to hospital prescribed by physicians for safety monitoring of poten- settings. Some authors suggest that even if many patients use potentially interacting drugs, the real risk related tothese associations seems to be low or modest , Onthe other hand, other authors suggest that DDIs are a major The purpose of this study was to analyze prescriptions in During the study period, 16,037 patients with at least one drug a general-practitioner database over 1 year to determine the prescription were recorded by 16 GPs. Every physician had frequency, the characteristics, and the monitoring of the approximately the same number of patients. Table shows the general characteristics of the patients in the database. Themean age was 53.1 years; the majority of individuals (66%)fell in the age range between 15 and 64 years, and there was an evident prevalence of women in older age groups (61%were female in the patients >75 years). A total of 185,704 We retrospectively analyzed the clinical records from 16 prescriptions relating to 1,020 different drugs (available as general practitioners (GPs) in the Veneto region, an area in single or combined formulations) were analyzed.
northern Italy. The study covered the period from January 1 As shown in Fig. , most patients (48%) received two to to December 31, 2004. During this year every physician five different drugs, whereas 35% of them had prescriptions used the same software to record all drug prescriptions, for more than five drugs. Seventeen percent of patients medical tests and the most important clinical events foreach patient in a personal clinical record. Data from all Table 1 Characteristics of general-practice patient database (16 GPs) computerized clinical records were pooled in a singledatabase. Patients with at least one drug prescription during All drugs prescribed to each patient in the study period were registered, since in Italy a prescription by the GP is necessary to have the drug or the medical test reimbursed by the National Health System, which covers the majority To define severe DDIs, we used the book Drug Interaction Facts by David S. Tatro, one of the primary sources for drug information [, The author defines 895 different types of severe DDIsa researched in 16,037 patients 119 different types of severe potential DDIs found in 758 patients (4.7% of the total number of patients) % of patients
- 559 patients with one DDI- 144 patients with 2 different DDIs - 36 patients with 3 different DDIs- 13 patients with 4 different DDIs Number of different drugs
Fig. 1 Number of different drugs per patient could not have DDIs because they received prescriptions Fig. 2 Flow chart showing identification of severe potential DDIs for only one drug. The median number of different drugsper patient was three (range 1–35).
interactions). Diuretics, amiodarone, warfarin, verapamil, and Table shows the 10 most frequently prescribed drugs, ACE inhibitors were also frequently involved.
expressed as total DDDs during the study year, and their Among the antibacterial drugs, the macrolide azithro- ranking in the national consumption database in the same mycin was associated with atorvastatin (18 patients) and period. Ramipril was the most frequently prescribed drug simvastatin (13), and the fluoroquinolone levofloxacin was followed by acetylsalicylic acid and atorvastatin. All drugs associated with amiodarone (17 patients). In 15 patients were present in the national top 10 list except for atenolol treated with acetylsalicylic acid, the nonsteroidal anti- and the association ramipril-hydrochlorothiazide ].
inflammatory ketorolac was also used.
As shown in Fig. , we found 119 different severe potential Table lists the 1,037 severe potential DDIs grouped DDIs (out of 895), which occurred 1,037 times in 758 according to the potential risk as described in [].
patients (4.7% of the total number of patients). The majority Electrolyte disturbances, increase in serum digoxin levels, of patients (74%) had only one potential DDI, but in six risk of hemorrhage, severe myopathy or rhabdomyolysis, patients (0.04%), five different potential DDIs were detected.
and cardiac arrhythmias were the most commonly impli- Table shows the severe potential DDIs occurring in more than 10 patients. The drug pairs listed in the table represent We focused on digoxin toxicity since it was the most 69% of total potential interactions and the digoxin/furosemide frequently involved drug and looked for medical tests pair was the most frequent one (23%). Forty-three severe Table 3 Drug pairs causing severe potential DDIs concomitantly used potential DDIs occurred only once. More than 80% of in more than 10 patients and cumulative percentages involved drugs were cardiovascular drugs, and digoxin wasthe most frequently implicated drug (47% of total potential Table 2 The top 10 prescribed drugs among study patients expressed Table 4 Severe potential DDIs (1,037) grouped according to their potential risk Furosemide (243) or thiazide diuretics (142) disturbances may predisposeto digitalis-induced arrhythmias ACE-inhibitors (178), angiotensin II-receptor antagonists (53), or potassium preparations (19) Amiodarone (57), verapamil (28), propafenone (7), clarithromycin (5), doxycycline (1), or quinidine (1) increase in the pharmacologicand toxic effects of digoxin Amiodarone (59), cotrimoxazole (5), sulfinpyrazone (1), macrolide antibiotics (8), fibric acids (5), azole antifungal agents (3), or metronidazole (1) Macrolide antibiotics (48), cyclosporine (7), Antiarrhythmic agents (21), tricyclic antidepressants NSAIDS (14), sulfasalazine (4), or amoxicillin (3) Risperidone (7) or selective 5-HT1-receptor indicating physician awareness of potential risks. We followed by a careful evaluation of the patient in order to investigated whether electrocardiograms were carried out consider possible risk factors, concomitant pathologies, and or serum potassium or digoxin concentration levels were measured by physicians in patients treated for at least In the present study, the analysis of prescriptions by 16 5 months with digoxin in association with diuretics (165 GPs over 1 year showed that, in general practice, 4.7% of patients) and anti-arrhythmics (53 patients). Tables and the patients concomitantly used drugs that could cause a show the patients who underwent specific tests after the severe potential DDI. Previous studies showed that 0.5–2% beginning of these drug associations. Thirty-five percent of of patients are exposed to serious potential drug interactions patients had one test, 26% had two tests and 11% had threetests. However 28% of them were treated with the Table 5 Number of tests [ECG, digoxin level, potassium (K) serum combination for more than 5 months without any testing.
level] in 165 patients with at least 5 months of co-administration ofdigoxin and diuretics Sixty-four percent of patients using digoxin with amiodar-one, verapamil, or propafenone had an ECG, digoxin monitoring or both, but 36% of them did not have any tests.
The correct use of a drug is determined by several or ECG + K serum level, or digoxin +K serum level) important factors, including the awareness of product All (ECG + digoxin level + K serum level) characteristics, such as contraindications and warnings, Table 6 Number of tests (ECG, digoxin level) in 53 patients with at effects of digoxin, particularly in patients with cardiac least 5 months of co-administration of digoxin and amiodarone, The administration of amiodarone, verapamil, or propafe- none to patients on stable doses of digoxin results in increaseddigoxin serum levels. The increase in serum digoxin level after the addition of amiodarone has been reported in the literature as between 69 and 800% , ]. Verapamil and digoxin have additional effects to slow atrio-ventricularconduction; investigations in healthy volunteers and cardiac in primary health care However differences in the patients indicated that verapamil raises plasma digoxin selection of interactions or in the target population could concentrations 60–75% In addition, verapamil explain these discrepancies. In our study, the most decreased digoxin elimination and total body digoxin commonly interacting drugs were cardiovascular drugs clearance was reduced by approximately 35% []. There (more than 80%). Bjerrum and colleagues showed that in was an increase in premature ventricular contraction fre- primary health care most of the potential interactions quency in 1 out of 10 patients on the combination [] and emerged in patients treated with cardiovascular drugs another study reported digoxin toxicity in 7 out of 49 (diuretics, ACE inhibitors, digoxin, beta-blockers and patients treated with verapamil [], but it is still unclear if calcium channel blockers), NSAIDs, oral antidiabetics, an increased risk of digoxin-induced arrhythmias exists.
and anticoagulants. Considering only major potential Due to the considerable risk of the above-mentioned interactions, the most frequently involved drugs were interactions, many authors agree that some relevant potassium-sparing diuretics and anticoagulants []. A study parameters should be closely monitored and that the dosage relating to multiple-drug prescribing by GPs in Germany of digoxin should be individualized and reduced when concluded that the most frequently found drug pairs patients receive these medications concurrently , implicated in potential DDIs were digitalis/diuretics, digi- In our study, 72% of patients using digoxin with loop or talis/calcium channel blockers, and theophylline/quinolones thiazide diuretics for at least 5 months had some tests ]. Other authors, looking at elderly outpatients, found relating to the monitoring of digoxin. On the other hand, in that the most common potential interactions were between 28% no tests of any kind related to the risk of interaction beta-adrenergic blockers and anti-diabetics, followed by were done, showing inadequate monitoring. General practi- potassium-sparing diuretics and potassium preparations [].
tioners are probably aware of the risk of digoxin combina- In our results the most frequently interacting drug was tions and made the prescriptions because they thought the digoxin, involved in almost half of total severe potential DDIs.
benefits of the drugs outweighed the risks. However our Although this drug has been used for more than two centuries, findings strengthen the need to improve their knowledge of its role in the management of chronic heart failure has been the proviso that all patients should be monitored. It should more precisely defined by recent clinical trials showing that be underlined that 322 out of 385 patients treated with digoxin therapy was associated with no beneficial effects on digoxin and diuretics received concomitant administration mortality, but only with a reduction in clinical symptoms and of ACE inhibitors, sartans, potassium, or potassium-sparing in the frequency of heart failure-related hospitalization diuretics, known to induce hyperkalemia. In this group, 162 ]. Therefore digoxin, even at low doses, is currently patients (50%) had at least one potassium serum level test, considered most beneficial in symptomatic patients who are showing hyperkalemia (K>5.3 mEq/l) in 17 patients, and in already undergoing adequate diuretic therapy and taking only one case hypokalemia (K<3.5 mEq/l).
ACE inhibitors with or without beta blockers [, ].
Physicians seem to be less aware of the risk from the The relationship between diuretic-induced electrolyte combination of digoxin with amiodarone, verapamil, or depletion and digitalis-induced arrhythmia, as well as the propafenone; 36% of patients using these drug associations connection between the toxic effects of digoxin and the use for at least 5 months had no related tests in the period of anti-arrhythmic drugs, is known and widely accepted , In an intensive-care study, patients treated with Potassium-sparing diuretics were commonly prescribed digitalis and diuretics had an approximately 1.5-fold higher along with either ACE inhibitors, sartans, or potassium risk of digoxin toxicity compared to those treated with preparations by the physicians participating in this study. The digitalis alone ]. In a review on digoxin, the association risk of hyperkalemia due to this association is well documented between digoxin and loop and thiazide diuretics proved in the literature. Many authors reported life-threatening hyper- among the most important drug interactions, causing a kalemia in patients treated with spironolactone associated with dose-dependent reduction in serum potassium and magne- ACE inhibitors or sartans [, –even if in other sium [This reduction increases the arrhythmogenic published studies this risk has been reported as infrequent ].
In our study, 250 potential DDIs occurred between potassium-sparing diuretics and ACE inhibitors, sartans, orpotassium supplements, although in all but four patients, The present study revealed that, in a group of Italian loop or thiazide diuretics were concomitantly prescribed.
general practitioners, the numbers of severe potential drug This co-prescription could have reduced the risk of hyper- interactions are relatively low and the drugs concerned are few. The monitoring of patients treated with digoxin and Many patients with cardiac arrhythmias in our database other cardiovascular drugs should be improved. The use of received concomitant therapy with warfarin and amiodar- concomitant drugs to compensate for hyperkalemia or one. This association requires a significant warfarin dose hypokalemia induced by some cardiovascular drugs seems reduction, due to the risk of hemorrhage. Moreover thyroid to indicate physicians′ awareness of potential electrolyte disorders may affect warfarin sensitivity, with hypothyroid- disturbances. Moreover precise and updated information on ism and thyrotoxicosis resulting in increased or decreased interacting drugs could prevent the occurrence of known warfarin requirements, respectively ].
interactions, particularly when therapeutic alternatives exist.
In the present study, about 50 patients were treated concomitantly with statins and macrolides, mainly repre- We thank all general practitioners involved in sented by atorvastatin and azithromycin. The risk of this study for collecting the clinical records. The authors have no myopathy and rhabdomyolysis, well documented in statin conflicts of interest directly relevant to the content of this study.
users, increases in cases of concomitant prescription withcytochrome P450 (CYP) inhibitors such as macrolides ].
Simvastatin and atorvastatin are mostly metabolized by the Azithromycin shows a lower affinity to this isoenzyme 1. Tatro DS (ed) (2006) Drug interaction facts—the authority on drug interactions. Facts and Comparisons, St. Louis, MO compared to other macrolides –Consequently, the 2. Grönroos PE, Irjala KM, Huupponen RK, Scheinin H, Forsström associations with azithomycin are less risky, even if clinical J, Forsström JJ (1997) A medication database-a tool for detecting case reports suggest there is some potential for drug drug interactions in hospital. Eur J Clin Pharmacol 53(1):13–17 3. Glintborg B, Andersen SE, Dalhoff K (2005) Drug-drug inter- actions among recently hospitalized patients-frequent but mostly A recent study analyzed whether statin-macrolide concom- clinically insignificant. Eur J Clin Pharmacol 61(9):675–681 itant prescriptions were commonly written by a group of 4. Cruciol-Souza JM, Thomson JC (2006) Prevalence of potential Italian GPs. They concluded that 63.5% of GPs co-adminis- drug-drug interactions and its associated factors in a Brazilian tered statins and macrolides at high risk of interaction at least teaching hospital. J Pharm Pharm Sci 9(3):427–433 5. Bjerrum L, Andersen M, Petersen G, Kragstrup J (2003) Exposure once ]. Other authors agree that co-prescription of to potential drug interactions in primary health care. Scand J Prim medications not compatible with statins occurs frequently It is possible that physicians underestimate the risks of 6. Jankel CA, Speedie SM (1990) Detecting drug interactions: a this interaction, given that other antimicrobial drugs could be review of the literature. DICP 24(10):982–989 7. Björkman IK, Fastbom J, Schmidt IK, Bernsten CB, Pharmaceu- tical Care of the Elderly in Europe Research (PEER) Group The present study has some limitations. The reference (2002) Drug-drug interactions in the elderly. Ann Pharmacother book used to select severe DDIs is one of the primary sources for drug information, but many other sources could 8. Bergendal L, Friberg A, Schaffrath A (1995) Potential drug-drug interactions in 5,125 mostly elderly out-patients in Gothenburg, Another limit is that over-the-counter drugs as well as 9. Costa AJ (1991) Potential drug interactions in an ambulatory drugs or tests done during hospitalization have not been geriatric population. Fam Pract 8(3):234–236 10. Rosholm JU, Bjerrum L, Hallas J, Worm J, Gram LF (1998) Polypharmacy and the risk of drug-drug interactions among Moreover the period of exposure was calculated on the Danish elderly. A prescription database study. Dan Med Bull 45 basis of the DDD prescribed, which does not necessary reflect the exact consumption by each patient (dosage, compliance).
11. Guèdon-Moreau L, Ducrocq D, Duc MF, Quieureux Y, L’Hôte C, Another aspect that should be emphasized is that the drug Deligne J, Caron J (2004) Absolute contraindications in relation topotential drug interactions in outpatient prescriptions: analysis of interactions found in this study were only potential: no actual the first five million prescriptions in 1999. Eur J Clin Pharmacol outcomes or consequences were evaluated. Concerning the management of DDIs by general practitioners, the use of 12. Astrand B, Astrand E, Antonov K, Petersson G (2006) Detections automated alerts could increase the recognition of drug of potential drug interactions-a model for a national pharmacyregister. Eur J Clin Pharmacol 62(9):749–756 interactions by GPs, but their perceived poor specifity may be 13. Steiness E, Olesen KH (1976) Cardiac arrhythmias induced by an important obstacle to efficient utilization of information, and hypokalaemia and potassium loss during maintenance digoxin may prevent such alerts from improving patient safety , ].
14. Schepkens H, Vanholder R, Billiouw JM, Lameire N (2001) Life- 32. Oetgen WJ, Sobol SM, Tri TB, Heydon WH, Rakita L (1984) threatening hyperkalemia during combined therapy with angio- Amiodarone-digoxin interaction. Clinical and experimental obser- tensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases. Am J Med 110(6):438–441 33. Nademanee K, Kannan R, Hendrickson J, Ookhtens M, Kay I, 15. Janchawee B, Owatranporn T, Mahatthanatrakul W, Chongsuvi- Singh BN (1984) Amiodarone-digoxin interaction: clinical signif- vatwong V (2005) Clinical drug interactions in outpatients of a icance, time course of development, potential pharmacokinetic university hospital in Thailand. J Clin Pharm Ther 30(6):583–590 mechanisms and therapeutic implications. J Am Coll Cardiol 4 16. Egger SS, Drewe J, Schlienger RG (2003) Potential drug-drug interactions in the medication of medical patients at hospital 34. Pedersen KE, Christiansen BD, Kjaer K, Klitgaard NA, Nielsen- discharge. Eur J Clin Pharmacol 58(11):773–778 Kudsk F (1983) Verapamil-induced changes in digoxin kinetics 17. Becker ML, Kallewaard M, Caspers PW, Visser LE, Leufkens and intraerythrocytic sodium concentration. Clin Pharmacol Ther HG, Stricker BH (2006) Hospitalisations and emergency depart- ment visits due to drug-drug interactions: a literature review.
35. Schwartz JB, Keefe D, Kates RE, Kirsten E, Harrison DC (1982) Pharmacoepidemiol Drug Saf 16(6):641–651 Acute and chronic pharmacodynamic interaction of verapamil and 18. Doucet J, Chassagne P, Trivalle C, Landrin I, Pauty MD, Kadri N, digoxin in atrial fibrillation. Circulation 65(6):1163–1170 Mènard JF, Bercoff E (1996) Drug-drug interactions related to 36. Klein HO, Lang R, Weiss E, Di Segni E, Libhaber C, Guerriero J, hospital admissions in older adults: a prospective study of 1000 Kaplinsky E (1982) The influence of verapamil on serum digoxin patients. J Am Geriatr Soc 44(8):944–948 concentration. Circulation 65(5):998–1003 19. McDonnell PJ, Jacobs MR (2002) Hospital admissions resulting 37. Magnani B, Malini PL (1995) Cardiac glycosides. Drug inter- from preventable adverse drug reactions. Ann Pharmacother 36 actions of clinical significance. Drug Saf 12(2):97–109 38. Wrenger E, Müller R, Moesenthin M, Welte T, Frölich JC, 20. Vitry AI (2006) Comparative assessment of four drug interaction Neumann KH (2003) Interaction of spironolactone with ACE- compendia. Br J Clin Pharmacol 63(6):709–714 inhibitors or angiotensin receptor blockers: analysis of 44 cases.
21. Il Pensiero Scientifico (Ed) (2005) L’uso dei Farmaci in Italia- Rapporto Nazionale anno 2004. OsMed (Osservatorio Nazionale 39. Simborg DW (1976) Medication prescribing on a university medical service-the incidence of drug combinations with potential 22. Fux R, Greiner D, Geldmacher M, Mörike K, Gleiter CH (2006) adverse interactions. Johns Hopkins Med J 139(1):23–26 Multiple drug prescribing by general practitioners in a German 40. Johnston RT, de Bono DP, Nyman CR (1992) Preventable sudden region: implications for drug interactions and patient safety. Int J death in patients receiving angiotensin converting enzyme inhibitors and loop/potassium sparing diuretic combinations. Int 23. The Digitalis Investigation Group (1997) The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J 41. Reardon LC, Macpherson DS (1998) Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. Arch Intern Med 24. Ahmed A, Rich MW, Love TE, Lloyd-Jones DM, Aban IB, Colucci WS, Adams KF, Gheorghiade M (2006) Digoxin and reduction in 42. Kurnik D, Loebstein R, Farfel Z, Ezra D, Halkin H, Olchovsky D mortality and hospitalization in heart failure: a comprehensive post (2004) Complex drug-drug-disease interactions between amiodar- hoc analysis of the DIG trial. Eur Heart J 27(2):178–186 one, warfarin, and the thyroid gland. Medicine (Baltimore) 83 25. Hunt SA, American College of Cardiology, American Heart Association Task Force on Practice Guidelines (Writing Committee 43. Farmer JA, Torre-Amione G (2000) Comparative tolerability of to Update the 2001 Guidelines for the Evaluation and Management the HMG-CoA reductase inhibitors. Drug Saf 23(3):197–213 of Heart Failure) (2005) ACC/AHA 2005 guideline update for the 44. Westphal JF (2000) Macrolide-induced clinically relevant drug diagnosis and management of chronic heart failure in the adult: a interactions with cytochrome P-450A (CYP) 3A4: an update report of the American College of Cardiology/American Heart focused on clarithromycin, azithromycin and dirithromycin. Br J Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management 45. Amacher DE, Schomaker SJ, Retsema JA (1991) Comparison of of Heart Failure). J Am Coll Cardiol 46(6):e1–e82 the effects of the new azalide antibiotic, azithromycin, and 26. Adams KF, Gheorghiade M, Uretsky BF, Patterson JH, Schwartz erythromycin estolate on rat liver cytochrome P-450. Antimicrob TA, Young JB (2002) Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardiol 39(6):946–953 46. Nahata M (1996) Drug interactions with azithromycin and the 27. Whang R, Oei TO, Watanabe A (1985) Frequency of hypomag- macrolides; an overview. J Antimicrobic Chemother 37 nesaemia in hospitalized patients receiving digitalis. Arch Inter 47. Piacentini N, Trifirò G, Tari M, Moretti S, Arcoraci V, UVEC 28. Belz GG, Doering W, Munkes R, Matthews J (1983) Interaction Group (2005) Statin-macrolide interaction risk: a population- between digoxin and calcium antagonists and antiarrhythmic based study throughout a general practice database. Eu J Clin drugs. Clin Pharmacol Ther 33(4):410–417 29. Lehmann HU, Witt E, Temmen L, Hochrein H (1978) Life- 48. Stang P, Morris L, Kempf J, Henderson S, Yood MU, Oliveria S threatening digitalis intoxication with and without additional (2007) The coprescription of contraindicated drugs with statins: diuretic treatment. Dtsch Med Wochenschr 103(40):1566–1571 continuing potential for increased risk of adverse events. Am J 30. Eichhorn EJ, Gheorghiade M (2002) Digoxin. Prog Cardiovasc 49. Glassman PA, Simon B, Belperio P, Lanto A (2002) Improving 31. Smith TW, Antman EM, Friedman PL, Blatt CM, Marsh JD recognition of drug interactions: benefits and barriers to using (1984) Digitalis glycosides: mechanism and manifestations of automated drug alerts. Med Care 40(12):1161–1171 toxicity. Parts I and II. Prog Cardiovasc Dis 26(5):413–458; 26 50. Hansten PD (2003) Drug interaction management. Pharm World


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