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Torsades de Pointes Ventricular Tachycardia Associated With Overdose of Astemizole

1994; Elsevier BV; Volume: 69; Issue: 6 Linguagem: Inglês

10.1016/s0025-6196(12)62252-6

1942-5546

K.A. Radha Krishna Rao, Arun Adlakha, Bikram Verma-Ansil, Thomas D. Meloy, Marshall S. Stanton,

Cardiac pacing and defibrillation studies

An overdose of astemizole predisposes the myocardium to ventricular dysrhythmias, including torsades de pointes. Herein we describe a case of astemizole-induced torsades de pointes ventricular tachycardia and also review previous case reports in the literature. All the patients were young, and dysrhythmias developed only in those with corrected QT intervals greater than 500 ms. Although several mechanisms have been postulated, no clear explanation has been provided for why astemizole promotes myocardial dysrhythmias. Treatment of astemizole-induced torsades de pointes includes discontinuing use of astemizole, intravenous administration of magnesium sulfate and isoproterenol, temporary cardiac pacing, and, when necessary, direct current cardioversion. A cardiac cause of syncope or convulsions must not be overlooked, especially in patients taking H1 antagonists because they often have these symptoms before hospitalization or detection of torsades de pointes (or both). An overdose of astemizole predisposes the myocardium to ventricular dysrhythmias, including torsades de pointes. Herein we describe a case of astemizole-induced torsades de pointes ventricular tachycardia and also review previous case reports in the literature. All the patients were young, and dysrhythmias developed only in those with corrected QT intervals greater than 500 ms. Although several mechanisms have been postulated, no clear explanation has been provided for why astemizole promotes myocardial dysrhythmias. Treatment of astemizole-induced torsades de pointes includes discontinuing use of astemizole, intravenous administration of magnesium sulfate and isoproterenol, temporary cardiac pacing, and, when necessary, direct current cardioversion. A cardiac cause of syncope or convulsions must not be overlooked, especially in patients taking H1 antagonists because they often have these symptoms before hospitalization or detection of torsades de pointes (or both). Astemizole (Hismanal), a long-acting and highly selective H1 antagonist, was recently introduced in the United States for symptomatic relief of allergic rhinitis. Its widespread use is primarily due to its highly selective actions as an H1 receptor antagonist with minimal central and anticholinergic side effects.1Niemegeers CJE Awouters F Janssen PAJ The pharmacological profile of a specific, safe, effective and non-sedative anti-allergic, astemizole.Agents Actions. 1986; 18: 141-144Crossref PubMed Scopus (22) Google Scholar Although the manufacturer advertised the safety of the drug, several cases of life-threatening cardiac dysrhythmias due to overdose have been reported in the literature.2Craft TM Torsade de pointes after astemizole overdose.BMJ. 1986; 292: 660Crossref PubMed Scopus (154) Google Scholar, 3Snook J Boothman-Burrell D Watkins J Colin-Jones D Torsade de pointes ventricular tachycardia associated with astemizole overdose.Br J Clin Pract. 1988; 42: 257-259PubMed Google Scholar, 4Simons FER Kesselman MS Giddins NG Pelech AN Simons KJ Astemizole-induced torsade de pointes [letter].Lancet. 1988; 2: 624Abstract PubMed Scopus (116) Google Scholar, 5Bishop RO Gaudry PL Prolonged Q-T interval following astemizole overdose.Arch Emerg Med. 1989; 6: 63-65Crossref PubMed Scopus (40) Google Scholar, 6Clark A Love H Astemizole-induced ventricular arrhythmias: an unexpected cause of convulsions.Int J Cardiol. 1991; 33: 165-167Abstract Full Text PDF PubMed Scopus (36) Google Scholar, 7Leor J Harman M Rabinowitz B Mozes B Giant U waves and associated ventricular tachycardia complicating astemizole overdose: successful therapy with intravenous magnesium.Am J Med. 1991; 91: 94-97Abstract Full Text PDF PubMed Scopus (31) Google Scholar, 8Hoppu K Tikanoja T Tapanainen P Remes M Saarenpää O Kouvalainen K Accidental astemizole overdose in young children.Lancet. 1991; 338: 538-540Abstract PubMed Scopus (80) Google Scholar, 9Tobin JR Doyle TP Ackerman AD Brenner JI Astemizole-induced cardiac conduction disturbances in a child.JAMA. 1991; 266: 2737-2740Crossref PubMed Scopus (38) Google Scholar, 10Wiley II, JF Gelber ML Henretig FM Wiley CC Sandhu S Loiselle J Cardiotoxic effects of astemizole overdose in children.J Pediatr. 1992; 120: 799-802Abstract Full Text PDF PubMed Scopus (75) Google Scholar Herein we describe such a case and review the literature. A 20-year-old woman with a history of vasomotor rhinitis was brought to the emergency department for assessment of seizurelike activity. Eight hours before admission, she had ingested 25 to 30 astemizole tablets (10 mg each) for severe influenza symptoms; subsequently, she experienced 3 episodes of tonic seizurelike activity. Each episode lasted only 1 to 2 minutes. Her medical history included no psychiatric ailment, cardiac disease, deafness, seizures, or concurrent use of other medications. The family medical history showed no sudden death, cardiac disease, or deafness. Findings on physical examination in the emergency department were unremarkable. Results of a neurologic examination were normal; she was conscious, alert, and oriented to time, place, and person. On admission, laboratory tests yielded the following normal results: serum potassium, 4.2 mEq/L; calcium, 9.6 mg/dL; and magnesium, 2.0 mg/dL. In the emergency department, she had two more similar brief tonic seizurelike episodes; no aura, postictal drowsiness, or confusion was noted. (Cardiac rhythm was not monitored during these episodes.) An electrocardiogram showed a prolonged corrected QT (QTc) interval of 600 ms, measured in lead II,11 with no other pronounced abnormalities (Fig. 1). During computed tomographic scanning of the head, the patient was noted to have brief generalized tonic seizurelike activity. After the patient had been taken to a hospital room, she had another seizurelike episode. She recovered completely with no postictal activity. Shortly thereafter the patient felt faint; a few seconds later her eyes rolled backward, and she began having clonic movements of her hands. Subsequently, she experienced apnea, and her pulses were undetectable. She recovered spontaneously. Within a few minutes, another episode occurred, and cardiac monitoring showed polymorphic ventricular tachycardia (VT) consistent with torsades de pointes (Fig. 2). The patient was given 100 mg of lidocaine and 2 g of magnesium intravenously; cardioversion to normal sinus rhythm was achieved with 200 J. She was then transferred to the coronary-care unit, where two more episodes of torsades de pointes occurred; on both occasions, cardioversion was successful with 200 J. An infusion of isoproterenol was instituted, and the episodes of VT diminished substantially. Overall, she had six episodes of documented VT, which was suppressed after the rate of infusion of isoproterenol was increased to 8 μg/min. After the dose of isoproterenol was gradually tapered, the patient was observed for 48 hours; no additional episodes of VT were noted. She was then transferred to a hospital room. The QTc interval gradually shortened and stabilized at 440 ms. After a total hospital stay of 5 days, her condition was stable, and she was dismissed. A review of the English literature and a summary of the other reported cases of cardiac arrhythmias and electrocardiographic abnormalities associated with an overdose of astemizole are presented in Table 1. All the patients were young; the mean age was 7.7 years (range, 1.5 to 22). Of the 18 patients, 26% had a history of seizure or syncope (or both).3Snook J Boothman-Burrell D Watkins J Colin-Jones D Torsade de pointes ventricular tachycardia associated with astemizole overdose.Br J Clin Pract. 1988; 42: 257-259PubMed Google Scholar, 4Simons FER Kesselman MS Giddins NG Pelech AN Simons KJ Astemizole-induced torsade de pointes [letter].Lancet. 1988; 2: 624Abstract PubMed Scopus (116) Google Scholar, 6Clark A Love H Astemizole-induced ventricular arrhythmias: an unexpected cause of convulsions.Int J Cardiol. 1991; 33: 165-167Abstract Full Text PDF PubMed Scopus (36) Google Scholar, 8Hoppu K Tikanoja T Tapanainen P Remes M Saarenpää O Kouvalainen K Accidental astemizole overdose in young children.Lancet. 1991; 338: 538-540Abstract PubMed Scopus (80) Google Scholar Vomiting, epigastric pain, slight drowsiness, lethargy, and fatigue were noted in some patients; some had no symptoms. Time of onset of symptoms after ingestion of astemizole varied from 0.5 to 72 hours, and time of onset of arrhythmias after ingestion or admission varied from 1 to 36 hours. Most patients older than 3 years were female. The amount of overdose ranged from 30 mg (in a 4-year-old child)10Wiley II, JF Gelber ML Henretig FM Wiley CC Sandhu S Loiselle J Cardiotoxic effects of astemizole overdose in children.J Pediatr. 1992; 120: 799-802Abstract Full Text PDF PubMed Scopus (75) Google Scholar to 740 mg (in a 22-year-old patient).7Leor J Harman M Rabinowitz B Mozes B Giant U waves and associated ventricular tachycardia complicating astemizole overdose: successful therapy with intravenous magnesium.Am J Med. 1991; 91: 94-97Abstract Full Text PDF PubMed Scopus (31) Google Scholar Of the patients younger than 3 years of age, most were male and had taken smaller doses of the drug (range, 30 to 200 mg)8Hoppu K Tikanoja T Tapanainen P Remes M Saarenpää O Kouvalainen K Accidental astemizole overdose in young children.Lancet. 1991; 338: 538-540Abstract PubMed Scopus (80) Google Scholar than did their older counterparts. For children 6 to 12 years of age, the daily oral dose of astemizole is 5 mg (half the adult dose); for children younger than 6 years, the daily dose is 0.2 mg/kg.Table 1Summary of Reported Cases of Cardiac Arrhythmias and Electrocardiographic Abnormalities Due to Overdose of Astemizole*A = accidental; AVB = atrioventricular block; ECG = electrocardiogram; IV = intravenous; PVC = premature ventricular contraction; QTc = corrected QT; RBBB = right bundle-branch block: S = suicidal; VT = ventricular tachycardia.IngestionReferenceAge (yr) and sexModeAmount (mg)Initial symptoms†Onset of symptoms varied from 0.5 to 72 hours.Conduction abnormality (time of onset)Maximal QTc interval (ms)TreatmentHospital stay (days)Craft,2Craft TM Torsade de pointes after astemizole overdose.BMJ. 1986; 292: 660Crossref PubMed Scopus (154) Google Scholar 198616 F?200VomitingTorsades de pointes (8 h‡After ingestion.)650Lidocaine, amiodarone, isoproterenol, cardioversion5Snook et al,3Snook J Boothman-Burrell D Watkins J Colin-Jones D Torsade de pointes ventricular tachycardia associated with astemizole overdose.Br J Clin Pract. 1988; 42: 257-259PubMed Google Scholar 198817 M?? (30§Plasma level (mg/mL).)Palpitations, light-headedness, syncopeMultiform PVCs, brief salvoes of VT, torsades de pointes (1 hAfter admission.)610Lidocaine, flecainide, cardioversion5Simons et al,4Simons FER Kesselman MS Giddins NG Pelech AN Simons KJ Astemizole-induced torsade de pointes [letter].Lancet. 1988; 2: 624Abstract PubMed Scopus (116) Google Scholar 198815 F?? (44.6§Plasma level (mg/mL).)SyncopeMultiform PVCs, 1° AVB, torsades de pointes (5 hAfter admission.)620Lidocaine, propranolol6Bishop & Gaudry,5Bishop RO Gaudry PL Prolonged Q-T interval following astemizole overdose.Arch Emerg Med. 1989; 6: 63-65Crossref PubMed Scopus (40) Google Scholar 198916 FS250Slight drowsinessSinus tachycardia, prolonged QT interval590Ipecac, charcoal2Clark & Love,6Clark A Love H Astemizole-induced ventricular arrhythmias: an unexpected cause of convulsions.Int J Cardiol. 1991; 33: 165-167Abstract Full Text PDF PubMed Scopus (36) Google Scholar 199115 FS200–250SeizureSinus bradycardia with type II Mobitz block and prolonged QT interval, frequent torsades de pointes (30 h‡After ingestion.)650Ipecac, isoproterenol, transvenous pacemaker (temporary)12Leor et al,7Leor J Harman M Rabinowitz B Mozes B Giant U waves and associated ventricular tachycardia complicating astemizole overdose: successful therapy with intravenous magnesium.Am J Med. 1991; 91: 94-97Abstract Full Text PDF PubMed Scopus (31) Google Scholar 199122 MS740NoneU waves, frequent PVCs, monomorphic ventricular episodes (7 h‡After ingestion.)580Ipecac, charcoal, lidocaine, IV magnesium sulfate5Hoppu et al,8Hoppu K Tikanoja T Tapanainen P Remes M Saarenpää O Kouvalainen K Accidental astemizole overdose in young children.Lancet. 1991; 338: 538-540Abstract PubMed Scopus (80) Google Scholar 19911.6 MA180FatigueProlonged QT interval450Ipecac, charcoal…2.5 FA35NoneProlonged QT interval440Ipecac, charcoal…2 FA200 (250§Plasma level (mg/mL).)Vomiting, collapse1° and 2° AVB, multifocal PVCs, VT, fibrillation (36 h‡After ingestion.)660Ipecac, charcoal, lidocaine, amiodarone. cardioversion52 MA30–40 (15.9§Plasma level (mg/mL).)FatigueProlonged QT interval460Ipecac, charcoal23 MA 600Charcoal2Wiley et al,10Wiley II, JF Gelber ML Henretig FM Wiley CC Sandhu S Loiselle J Cardiotoxic effects of astemizole overdose in children.J Pediatr. 1992; 120: 799-802Abstract Full Text PDF PubMed Scopus (75) Google Scholar 19924 MA30Lethargy2° AVB, RBBB, ventricular bigeminy (4 h‡After ingestion.)550Charcoal31.5A?NoneVT, RBBB520Charcoal, other drugs?311A?None…470Charcoal12.5A?None…520Charcoal33A?None…470Charcoal2Rao et al (current case)20 FA?300SeizuresTorsades de pointes (18 h‡After ingestion.)600Lidocaine, calcium, magnesium, isoproterenol, cardioversion5* A = accidental; AVB = atrioventricular block; ECG = electrocardiogram; IV = intravenous; PVC = premature ventricular contraction; QTc = corrected QT; RBBB = right bundle-branch block: S = suicidal; VT = ventricular tachycardia.† Onset of symptoms varied from 0.5 to 72 hours.‡ After ingestion.§ Plasma level (mg/mL).// After admission. Open table in a new tab The QTc. interval was prolonged in most patients; it ranged from 440 to 660 ms. For those patients in whom specific QTc values were provided, the mean QTc interval was 560 ms. Electrocardiographic abnormalities included torsades de pointes, first-degree atrioventricular (AV) block, sinus bradycardia with type II second-degree AV block, monomorphic VT with giant U waves, right and left bundle-branch blocks, and isolated prolonged QTc interval. Virtually all the patients with pronounced ventricular arrhythmias received lidocaine and another agent such as isoproterenol, propranolol, calcium, or magnesium. The cardiac dysrhythmias responded quickly to treatment, but the QTc interval remained prolonged for several days. Astemizole has a half-life of 18 to 20 days, and why cardiac dysrhythmias occur only during the first 4 to 5 days after overdose (although plasma values remain increased for extended periods) is unclear. A similar phenomenon occurs with proarrhythmia due to amiodarone, which has a half-life of about 60 days.12Stanton MS Prystowsky EN Fineberg NS Miles WM Zipes DP Heger JJ Arrhythmogenic effects of antiarrhythmic drugs: a study of 506 patients treated for ventricular tachycardia or fibrillation.J Am Coll Cardiol. 1989; 14: 209-215Abstract Full Text PDF PubMed Scopus (118) Google Scholar Astemizole, pharmacologically an H1 antagonist, is a member of the newest antihistamine group—the piperidines. After oral administration of single doses of 10,20, and 30 mg of astemizole, plasma concentrations peak within 1 to 4 hours. Once bound to H1 receptors, astemizole dissociates slowly with a serum elimination half-life steady state of 19 days; it is nondialyzable.13Richards DM Brogden RN Heel RC Speight TM Avery GS Astemizole: a review of its pharmacodynamic properties and therapeutic efficacy.Drugs. 1984; 28: 38-61Crossref PubMed Scopus (158) Google Scholar Astemizole was considered a safe antihistamine because of its highly specific pharmacologic action at the level of the H1 receptor and its inability to cross the blood-brain barrier.1Niemegeers CJE Awouters F Janssen PAJ The pharmacological profile of a specific, safe, effective and non-sedative anti-allergic, astemizole.Agents Actions. 1986; 18: 141-144Crossref PubMed Scopus (22) Google Scholar Its absence of anticholinergic side effects also contributed to the theory that it was safer than the other antihistamines because cardiotoxicity of those agents has been attributed to their anticholinergic actions. Since the mid-1970s, histamine receptors from the myocardium have been isolated, characterized, and studied, although their physiologic significance has not been determined.14Levi R Capurro N Lee C-H Pharmacological characterization of cardiac histamine receptors: sensitivity to H1- and H2-receptor agonists and antagonists.Eur J Pharmacol. 1975; 30: 328-335Crossref PubMed Scopus (82) Google Scholar Histamine itself enhances normal cardiac automaticity, depresses AV conduction, and renders the ventricle susceptible to ventricular tachyarrhythmias.15Levi R Chenouda AA Trzeciakowski JP Guo Z-G Aaronson LM Luskind RD et al.Dysrhythmias caused by histamine release in guinea pig and human hearts.Klin Wochenschr. 1982; 60: 965-971Crossref PubMed Scopus (51) Google Scholar Stimulation of the H1 receptor causes a negative dromotropic effect; thus, the AV conduction time is prolonged. Therefore, H1 receptor agonists mediate slowing of AV conduction. H2 agonists promote ventricular automaticity and have positive inotropic and chronotropic effects. Preferential activation of these receptors by histamine displaced from H1 receptors because of the binding of astemizole could also explain the clinical findings. Recently, an H3 receptor has also been characterized that seems to be an autoreceptor on cells that release histamine and inhibit further release of histamine.16Arrang J-M Garbarg M Schwartz J-C Autoinhibition of histamine synthesis mediated by presynaptic H3-receptors.Neuroscience. 1987; 23: 149-157Crossref PubMed Scopus (277) Google Scholar Astemizole may act as an H3 antagonist and allow histamine to be released; thus, histamine-like action and conduction disturbances occur.9Tobin JR Doyle TP Ackerman AD Brenner JI Astemizole-induced cardiac conduction disturbances in a child.JAMA. 1991; 266: 2737-2740Crossref PubMed Scopus (38) Google Scholar Release of histamine from mast cells in the myocardium by astemizole7Leor J Harman M Rabinowitz B Mozes B Giant U waves and associated ventricular tachycardia complicating astemizole overdose: successful therapy with intravenous magnesium.Am J Med. 1991; 91: 94-97Abstract Full Text PDF PubMed Scopus (31) Google Scholar and nonhistamine receptor-mediated effects of astemizole may also lead to cardiac arrhythmias.9Tobin JR Doyle TP Ackerman AD Brenner JI Astemizole-induced cardiac conduction disturbances in a child.JAMA. 1991; 266: 2737-2740Crossref PubMed Scopus (38) Google Scholar The current treatment of an overdose of astemizole is supportive. Gastric lavage and administration of charcoal are useful therapeutic measures if the patient seeks medical intervention at an early stage inasmuch as astemizole is rapidly absorbed. The drug is nondialyzable because of its extensive protein-binding activity. Cardiac monitoring in an intensive-care setting is indicated for all patients who have a prolonged QTc interval after an overdose. In 6 of the 13 patients (46%) in the literature who had a QTc interval greater than 500 ms, cardiac arrhythmias developed that necessitated pharmacologic therapy, whereas none of the 5 patients with a QTc interval less than 500 ms required therapeutic intervention other than charcoal or ipecac. Therefore, patients who have a QTc interval greater than 500 ms should be carefully monitored. In some patients, intravenous administration of magnesium sulfate has been successful in the management of torsades de pointes.7Leor J Harman M Rabinowitz B Mozes B Giant U waves and associated ventricular tachycardia complicating astemizole overdose: successful therapy with intravenous magnesium.Am J Med. 1991; 91: 94-97Abstract Full Text PDF PubMed Scopus (31) Google Scholar Isoproterenol, cardioversion, and temporary cardiac pacing may also be necessary. For example, administration of isoproterenol or use of temporary ventricular pacing at 100 beats/min (or both) can be effective. Investigators postulate that increasing the cardiac rate decreases dispersion of refractoriness or suppresses triggered activity caused by early afterdepolarizations; both have been theorized as underlying mechanisms for torsades de pointes.17Zipes DP The long QT interval syndrome: a Rosetta stone for sympathetic related ventricular tachyarrhythmias.Circulation. 1991; 84: 1414-1419Crossref PubMed Scopus (182) Google Scholar Cardiac monitoring in an intensive-care setting should continue for at least 48 hours after normal rhythm has been restored. Lidocaine was the initial drug used for most patients with astemizole-induced torsades de pointes, but it was unsuccessful as a single agent in stopping the arrhythmias. Cardioversion should be used for sustained ventricular arrhythmias. Terfenadine (Seldane), an H1 receptor antagonist like astemizole, has also been noted to cause torsades de pointes after an overdose and when administered in combination with ketoconazole and possibly with erythromycin and cimetidine.18Monahan BP Ferguson CL Killeavy ES Lloyd BK Troy J Cantilena Jr, LR Torsades de pointes occurring in association with terfenadine use.JAMA. 1990; 264: 2788-2790Crossref PubMed Scopus (602) Google Scholar Syncope in conjunction with torsades de pointes has recently been reported in a few patients taking astemizole (10 mg/day) and erythromycin or astemizole, erythromycin, and ketoconazole (Janssen Pharmaceutica. Personal communication). Both erythromycin and ketoconazole may interfere with metabolism of astemizole at the cytochrome P450 enzyme level.19Letter to health care professionals. Janssen Pharmaceutica, Inc., Titusville (NJ)1992 Oct 26Google Scholar In addition, ventricular arrhythmias, including torsades de pointes, have been reported with dosages of astemizole as low as 10 to 30 mg/day, especially in patients with augmenting circumstances (other drugs known to produce prolonged QTc interval, electrolyte abnormalities, and congenital prolonged QTc syndrome) (Janssen Pharmaceutica. Personal communication).20Astemizole package insert (revised). Janssen Pharmaceutica, Inc., Titusville (NJ)1992Google Scholar Caution should be used in prescribing astemizole to patients with an underlying prolongation of their QTc interval, although no data exist to support this statement directly. Other major drugs and toxins that cause torsades de pointes include antiarrhythmic agents (quinidine, procainamide, disopyramide, amiodarone, bepridil, and Sotalol), vasodilators (prenylamine), psychotropic drugs (thioridazine and tricyclic antidepressants), miscellaneous agents (diuretics and corticosteroids), and toxins (organophosphate insecticides and liquid protein diets).21Stratmann HG Kennedy HL Torsades de pointes associated with drugs and toxins: recognition and management.Am Heart J. 1987; 113: 1470-1482Abstract Full Text PDF PubMed Scopus (124) Google Scholar These, in addition to the H1 antagonists, must be considered as potential causes of drug-induced torsades de pointes. After reviewing the literature, we recommend the following guidelines. (1) Astemizole-induced toxicity should be considered in the differential diagnosis of prolonged QTc interval, ventricular tachyarrhythmias, syncope, and seizures. If dizziness, palpitations, syncope, or seizures occur, use of the drug should be discontinued immediately, and the patient should be hospitalized for cardiac monitoring. (2) Patients known to be taking medications or to have conditions associated with a prolonged QTc interval should not take astemizole. (3) Concomitant administration of erythromycin (and other macrolide antibiotics), ketoconazole, and itraconazole, metronidazole, fluconazole, and miconazole nitrate (the last four listed drugs have chemical similarity to ketoconazole) should be avoided. (4) Patients should be advised to adhere to the recommended dosage of 10 mg/day and not increase it. They should seek advice about concurrent use of any other medication with astemizole. (5) Administration of astemizole to patients with hepatic impairment should be done with caution. (6) Accidental ingestion of astemizole in children is dangerous because a few tablets can cause toxic effects. (7) All patients who have taken an overdose of astemizole need early treatment consisting of gastric lavage and oral administration of charcoal; they should be admitted to the hospital for at least 2 to 3 days for cardiac monitoring. Electrocardiographic abnormalities are an absolute indication for admission to the intensive-care unit, and patients should not be dismissed until the arrhythmias have abated or the QTc interval has returned to baseline (or both). (8) Immediate treatment of astemizole-induced ventricular arrhythmias includes intravenous administration of magnesium sulfate or isoproterenol, temporary atrial or ventricular pacing, and, if necessary, direct current cardioversion. (9) Electrolyte abnormalities and drugs that prolong the QTc interval should be avoided.