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SOTALOL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Sotalol is a non-cardioselective beta blocker which lacks significant intrinsic sympathomimetic activity and membrane stabilizing properties. It has Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties.

Specific Substances

    1) Sotalol hydrochloride
    2) CAS 3930-20-9
    3) C12-H20-N2-O3-S.HCl
    1.2.1) MOLECULAR FORMULA
    1) C12H20N2O3S.HCl

Available Forms Sources

    A) FORMS
    1) ORAL: Sotalol is available in tablets of 80, 160 and 240 mg (Prod Info BETAPACE AF(R) oral tablets, 2011).
    2) INTRAVENOUS: It is available in 10 mL vials containing 150 mg sotalol hydrochloride (15 mg/mL) (Prod Info sotalol hydrochloride IV injection, 2009).
    B) USES
    1) Sotalol is used primarily in the maintenance of sinus rhythm in patients who are highly symptomatic with atrial fibrillation and atrial flutter and it is also indicated for the treatment of life-threatening ventricular dysrhythmias. Because it can cause QT prolongation and torsades de pointes it is less often used to treat less serious supraventricular dysrhythmias. QT interval prolongation is directly related to the dose of sotalol (Prod Info BETAPACE AF(R) oral tablets, 2011; Prod Info sotalol hydrochloride IV injection, 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Sotalol is a beta-adrenergic blocking agent that has both Vaughan Williams Class II and III antiarrhythmic effects. It is used to treat atrial and ventricular dysrhythmias.
    B) PHARMACOLOGY: Sotalol is a beta-blocker which has both beta adrenoreceptor blocking and cardiac action potential duration prolongation effects. Sotalol is a racemic mixture of d- and l-sotalol. Both isomers have similar class III antiarrhythmic effects while the l-isomer is responsible for the nearly all of the beta-blocking activity. The beta-blocking effect of sotalol is noncardioselective with both beta-1 and beta-2-receptor blocking activity. Vaughan Williams Class III effects are seen only at larger doses (greater than or equal to 160 mg/day or more in adults).
    C) TOXICOLOGY: Overdose causes beta-adrenergic blockade and lengthening of action potential duration, which predisposes patients to torsades de pointes and ventricular dysrhythmias.
    D) EPIDEMIOLOGY: Sotalol overdoses are fairly rare, but can result in severe dysrhythmias and death.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: The most common adverse effects seen at therapeutic doses include: bradycardia, chest pain, palpitations, fatigue, dizziness, lightheadedness, weakness, and dyspnea. Other less common adverse effects include edema, hypotension, syncope, congestive heart failure, torsades de pointes, peripheral vascular disorders, headaches, sleeping problems, mental confusion, anxiety, depression, pruritus, rash, decreased sexual ability, nausea and/or vomiting, diarrhea, abdominal discomfort, flatulence, impotence, bleeding, extremity pain, paresthesia, back pain, visual problems, upper respiratory problems, and asthma. RARE: There have been rare reports of adverse effects including alopecia, paralysis, and pulmonary edema.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild to moderate overdose can cause bradycardia, mild hypotension, and a prolonged QTc interval.
    2) SEVERE TOXICITY: Clinical events can include: syncope, CNS depression, seizures, hypotension, torsades de pointes, ventricular tachycardia, ventricular fibrillation and death.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Bradycardia, QTc prolongation and ventricular dysrhythmias, particularly torsades de pointes or ventricular tachycardia, are the most common cardiovascular effects. In severe cases hypotension and ventricular fibrillation may develop.
    B) WITH POISONING/EXPOSURE
    1) Bradycardia, QTc prolongation and ventricular dysrhythmias, particularly torsades de pointes or ventricular tachycardia, are the most common cardiovascular effects. In severe cases hypotension and ventricular fibrillation may develop.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Syncope, CNS depression and seizures may develop in patients with ventricular dysrhythmias.
    B) WITH POISONING/EXPOSURE
    1) Syncope, CNS depression and seizures may develop in patients with ventricular dysrhythmias.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH THERAPEUTIC USE
    1) Hypokalemia predisposes patients to the development of dysrhythmias.
    0.2.20) REPRODUCTIVE
    A) Sotalol is pregnancy category B. It crosses the placenta and is concentrated in breast milk.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for QTc prolongation.
    C) Monitor serum electrolytes including magnesium and calcium, renal function and blood glucose.
    D) Specific sotalol plasma levels are not clinically useful or readily available.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Mild to moderate sotalol exposures require only symptomatic and supportive care. Patients can be monitored via a cardiac monitor and fluids can be given for hypotension and atropine for symptomatic bradycardia.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Intubate patients with severe toxicity early. Primary focus is treatment of ventricular dysrhythmias and hypotension. Cardiovert unstable ventricular dysrhythmias. Correct electrolyte abnormalities. Treat torsades de pointes with IV magnesium, overdrive pacing is second-line therapy. Treat hypotension initially with IV fluids, add vasopressors, if unresponsive. Consider glucagon, calcium and insulin euglycemia if hypotension persists, although experience is limited.
    C) DECONTAMINATION
    1) PREHOSPITAL: Not recommended because of the potential for hemodynamic instability, somnolence and seizures.
    2) HOSPITAL: Activated charcoal if recent, substantial ingestion, and patient is cooperative and able to protect their airway.
    D) AIRWAY MANAGEMENT
    1) Perform early in patients with severe intoxication (depressed mental status, seizures, dysrhythmias).
    E) ANTIDOTE
    1) No specific antidote exists.
    F) HYPOTENSION
    1) Initial management can be with fluids (500 mL boluses up to 3L) and atropine if patient is bradycardic. Catecholamines should be given those who do not respond to IV fluids. No one agent has been shown to be consistently effective, though there is some data suggesting that norepinephrine or epinephrine might be more effective than dopamine. Glucagon can also be given. Initial dosing is 5 to 15 mg by slow IV administration with doses repeated as needed. An infusion of the initial dose that elicited a response per hour may then be administered. HIE (high dose insulin euglycemia) is another potential therapy, though there is little experience with sotalol overdose. Insulin dose: A bolus of insulin at 1 unit/kg concomitantly with 25 g glucose and then an insulin infusion of 0.5 to 1 unit/kg/hr with a dextrose infusion (D10 in an adult) with frequent monitoring of blood glucose to maintain euglycemia. Monitor for hypokalemia and supplement potassium as needed.
    G) TORSADES DE POINTES
    1) Cardiovert unstable rhythms. Correct electrolyte abnormalities. Treat with magnesium sulfate IV. Dose: Adult: 1 to 2 g IV over 5 minutes, may repeat once, then an infusion of 0.5 to 1 g/hr; Pediatric: 25 to 50 mg/kg over 5 to 15 min up to 2 g maximum. Overdrive pacing if not responding to magnesium.
    H) VENTRICULAR DYSRHYTHMIAS
    1) Cardiovert unstable rhythms. Correct electrolyte abnormalities. Lidocaine may be used if dysrhythmias persist. Use amiodarone with caution as it can cause torsades de pointes.
    I) EXTRACORPOREAL SUPPORT
    1) For patients with intractable dysrhythmias or hypotension, consider cardiopulmonary bypass, intra-aortic balloon pump, or extracorporeal membrane oxygenation early to preserve perfusion until severe toxicity abates.
    J) SEIZURE
    1) Seizures are most often secondary to dysrhythmias and hypotension. Once these are treated, use benzodiazepine, add barbiturates or propofol, if seizures persist.
    K) ENHANCED ELIMINATION
    1) Sotalol is not protein bound and has a moderate volume of distribution (1 to 2 L/kg). It is removed by hemodialysis, and dialysis has been shown to shorten half-life in patients with renal failure. Hemodialysis has been used in a case of overdose. Consider emergent hemodialysis in patients with large ingestions or severe toxicity, although unstable dysrhythmias or hypotension may make dialysis difficult.
    L) PATIENT DISPOSITION
    1) HOME CRITERIA: Healthy asymptomatic patients (including children) who inadvertently ingest less than or equal to a maximum single therapeutic dose for age (up to 160 mg in adults, or 4 mg/kg in children) may be observed at home and referred to a health care facility if symptoms develop. Torsades de pointes has been reported in adults after therapeutic doses, although many of these patients had concomitant conditions (electrolyte abnormalities, cardiac disease, use of drugs that cause QT prolongation) that may have predisposed them to dysrhythmias. Patients with a sotalol overdose who have an underlying cardiovascular disease or predisposing risk factors (ie, other antidysrhythmic drugs, diuretics) should be referred to a healthcare facility.
    2) OBSERVATION CRITERIA: Symptomatic patients, those with serious underlying cardiac disease, those taking a calcium channel blocker, and any patient with a deliberate ingestion should be referred to a healthcare facility. Inadvertent ingestions in adults who ingest greater than 160 mg and children who ingest greater than 4 mg/kg should be referred to a healthcare facility. All patients should be monitored for 12 hours. If asymptomatic with a normal ECG during this time, they may be discharged.
    3) ADMISSION CRITERIA: Patients with cardiovascular symptoms (hypotension, bradycardia), central nervous system toxicity (somnolence, seizures, coma) or persistent QTc prolongation should be admitted to an intensive care setting. Symptomatic patients should be admitted for further observation/treatment until they are asymptomatic for a prolonged period (several hours) of time without therapy.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (hypotension, seizures, dysrhythmias), or in whom the diagnosis in not clear.
    M) PITFALLS
    1) These patients may require early aggressive treatment to avoid potentially severe sequelae from an overdose.
    N) PHARMACOKINETICS
    1) Well absorbed, bioavailability 90% or more, peak serum concentrations 2.5 to 4 hours after ingestion onset of action of 1 to 2 hours. Duration of action 8 to 16 hours. The volume of distribution of sotalol is from 1.2 to 2.4 L/kg with no protein binding. Sotalol is not significantly metabolized, it is excreted unchanged in urine. It is not metabolized. Half-life of elimination is roughly 12 hours in adults and 9.5 hours in children. Elimination half-life is increased with renal dysfunction.
    O) TOXICOKINETICS
    1) Half-life of sotalol in overdose has been reported from 11 to 15 hours. In one case report, the half-life was reported to be biphasic after a 47-year-old man ingested 11.2 g of sotalol. The initial half-life was 30.1 hours followed by a second half-life of 11.6 hours. The initial slower half-life was thought to be secondary to hypotension causing reduced glomerular filtration.
    P) PREDISPOSING CONDITIONS
    1) Patients with electrolyte abnormalities such as hypokalemia, hypocalcemia, and hypomagnesemia, renal insufficiency, or taking other medications that can prolong ventricular repolarization may be at high risk to develop dysrhythmias. Patients with renal dysfunction will have an increased half-life of elimination for sotalol.
    2) In general, any patient taking beta blockers with asthma, severe allergies, conduction abnormalities, diabetes, heart failure, myasthenia gravis, peripheral vascular disease, pheochromocytoma (untreated), and psychiatric disease may be at high risk for adverse effects from these medications.
    Q) DIFFERENTIAL DIAGNOSIS
    1) Other antihypertensive medications (other beta-blockers, calcium channel blockers, digoxin, clonidine), infections, sepsis and other toxic ingestions may present with some similar clinical features (eg, some antipsychotics may cause some hypotension and depressed mental status).

Range Of Toxicity

    A) TOXICITY: Adults who ingest greater than 160 mg and children who ingest greater than 4 mg/kg have the potential to develop toxicity. Toxicity can occur even at therapeutic dosing, especially in those with renal impairment, baseline prolonged QTc interval or other predisposing conditions. Fatalities have occurred in adults after ingestions of 3.2 and 14.4 g of sotalol. Adults have survived severe toxicity with intensive supportive care after overdoses in the range of 2 to 13 g.
    B) THERAPEUTIC DOSE: ADULT: ORAL: 80 mg twice daily; maximum: 160 mg twice daily (total: 320 mg/day) if the patient has a calculated clearance of greater than 60 mL/min. Higher doses have resulted in torsades de pointes and are not recommended. IV: 75 mg infused over 5 hours twice daily. PEDIATRIC: Not approved for use in children. However, children have been treated with weight-based dosing of 2 mg/kg/day orally in 2 or 3 divided doses initially, may be titrated up to 8 mg/kg/day. Dosing can also be initiated via body surface area with an initial dose in children over 2 years of age of 90 to 100 mg/m(2)/day in 2 to 3 divided doses; maintenance dose ranges from 100 to 250 mg/m(2)/day in 2 to 3 divided doses.

Clinical Effects

Summary Of Exposure

    A) USES: Sotalol is a beta-adrenergic blocking agent that has both Vaughan Williams Class II and III antiarrhythmic effects. It is used to treat atrial and ventricular dysrhythmias.
    B) PHARMACOLOGY: Sotalol is a beta-blocker which has both beta adrenoreceptor blocking and cardiac action potential duration prolongation effects. Sotalol is a racemic mixture of d- and l-sotalol. Both isomers have similar class III antiarrhythmic effects while the l-isomer is responsible for the nearly all of the beta-blocking activity. The beta-blocking effect of sotalol is noncardioselective with both beta-1 and beta-2-receptor blocking activity. Vaughan Williams Class III effects are seen only at larger doses (greater than or equal to 160 mg/day or more in adults).
    C) TOXICOLOGY: Overdose causes beta-adrenergic blockade and lengthening of action potential duration, which predisposes patients to torsades de pointes and ventricular dysrhythmias.
    D) EPIDEMIOLOGY: Sotalol overdoses are fairly rare, but can result in severe dysrhythmias and death.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: The most common adverse effects seen at therapeutic doses include: bradycardia, chest pain, palpitations, fatigue, dizziness, lightheadedness, weakness, and dyspnea. Other less common adverse effects include edema, hypotension, syncope, congestive heart failure, torsades de pointes, peripheral vascular disorders, headaches, sleeping problems, mental confusion, anxiety, depression, pruritus, rash, decreased sexual ability, nausea and/or vomiting, diarrhea, abdominal discomfort, flatulence, impotence, bleeding, extremity pain, paresthesia, back pain, visual problems, upper respiratory problems, and asthma. RARE: There have been rare reports of adverse effects including alopecia, paralysis, and pulmonary edema.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild to moderate overdose can cause bradycardia, mild hypotension, and a prolonged QTc interval.
    2) SEVERE TOXICITY: Clinical events can include: syncope, CNS depression, seizures, hypotension, torsades de pointes, ventricular tachycardia, ventricular fibrillation and death.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) HYPOTENSION
    1) WITH POISONING/EXPOSURE
    a) Hypotension may occur following overdoses.
    b) Mild to moderate hypotension (80 to 100 mm Hg systolic) is common with sotalol overdose; profound hypotension generally develops only with severe ventricular dysrhythmias (Neuvonen et al, 1981; Montagna & Groppi, 1980; Totterman et al, 1982; Perrot et al, 1988; Alderfliegel et al, 1993).
    2) WITH THERAPEUTIC USE
    a) Therapeutic doses of sotalol can cause mild reductions in blood pressure (Edvardsson et al, 1980).
    B) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Severe bradycardia may develop in overdose (Gupta, 1985; Perrot et al, 1988).
    b) Mild bradycardia (50 to 60 beats/minute) complicated by ventricular dysrhythmias is more common (Totterman et al, 1982; Elonen et al, 1979; Neuvonen et al, 1981; Beattie, 1984; Edvardsson et al, 1980; Montagna & Groppi, 1980; Alderfliegel et al, 1993).
    2) WITH THERAPEUTIC USE
    a) Sotalol decreases heart rate at therapeutic doses (Edvardsson et al, 1980).

Heent

    3.4.3) EYES
    A) MYDRIASIS
    1) WITH POISONING/EXPOSURE
    a) Dilated pupils with no reaction to light developed in a 58-year-old man with severe sotalol overdose (Perrot et al, 1988).
    B) MIOSIS
    1) WITH POISONING/EXPOSURE
    a) Miotic pupils were described in a 47-year-old man with a fatal sotalol ingestion (Montagna & Groppi, 1980).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Bradycardia, QTc prolongation and ventricular dysrhythmias, particularly torsades de pointes or ventricular tachycardia, are the most common cardiovascular effects. In severe cases hypotension and ventricular fibrillation may develop.
    B) WITH POISONING/EXPOSURE
    1) Bradycardia, QTc prolongation and ventricular dysrhythmias, particularly torsades de pointes or ventricular tachycardia, are the most common cardiovascular effects. In severe cases hypotension and ventricular fibrillation may develop.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Therapeutic doses of sotalol cause mild reductions in blood pressure (Prod Info BETAPACE AF(R) oral tablets, 2011; Edvardsson et al, 1980).
    2) WITH POISONING/EXPOSURE
    a) Mild to moderate hypotension (80 to 100 mm/Hg systolic) is common with sotalol overdose (Neuvonen et al, 1975; (Neuvonen et al, 1981; Belton et al, 1982; Elonen et al, 1979; Baliga, 1985; Edvardsson & Varnauskas, 1987).
    b) Profound hypotension generally develops only with severe ventricular dysrhythmias (Montagna & Groppi, 1980; Totterman et al, 1982; Perrot et al, 1988; Adlerfliegel et al, 1993; Gustavsson et al, 1997).
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Sotalol decreases heart rate at therapeutic doses (Prod Info BETAPACE AF(R) oral tablets, 2011; Edvardsson et al, 1980).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Severe bradycardia (10 to 15 beats/minute) developed in a fatal case (Perrot et al, 1988). Severe bradycardia (20 to 34 beats/minute) developed in an 80-year-old woman after taking 560 mg over 2 days (Gupta, 1985).
    b) Mild bradycardia (50 to 60 beats/minute) complicated by ventricular dysrhythmias is more often described (Totterman et al, 1982; Elonen et al, 1979; Neuvonen et al, 1981; Beattie, 1984)(Edvarsson & Varnauskas, 1987) (Montagna & Groppi, 1980; Adlerfliegel et al, 1993; Gustavsson et al, 1997).
    c) Severe bradycardia was reported in a 12-year-old girl following ingestion of 1.92 g of sotalol in a suicide attempt (Hermanns-Clausen & Desel, 2002).
    d) According to a retrospective study analyzing sotalol overdoses reported to two poison centers in Germany from 1996 to 2001, minor bradycardia or QT prolongation were reported in adults following sotalol doses of 640 mg (Hermanns-Clausen & Desel, 2002).
    C) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) Sotalol prolongs the duration of the action potential and can cause QTc prolongation at therapeutic doses (Prod Info BETAPACE AF(R) oral tablets, 2011; Neuvonen et al, 1981; Neuvonen et al, 1982; Baliga, 1985; Link et al, 1997; Gottlieb et al, 1997) .
    1) Fusion of the T and U waves has also been described (Pellinen et al, 1981).
    2) In as series of 2897 sotalol treated patients with an ECG available before and at least one ECG after initiation of therapy, female gender, baseline JTc, dose, serum creatinine and history of sustained ventricular tachydysrhythmias were found to be independent predictors of JTc prolongation (Lehmann et al, 1999). The sex difference was independent of dose and not solely attributable to the gender difference in baseline JTc.
    2) WITH POISONING/EXPOSURE
    a) Sotalol prolongs the duration of the action potential and can cause QTc prolongation in overdose (Neuvonen et al, 1981; Neuvonen et al, 1982; Baliga, 1985; Gottlieb et al, 1997; Link et al, 1997).
    1) Fusion of the T and U waves has also been described (Pellinen et al, 1981).
    b) CASE SERIES: In a series of 6 patients with sotalol overdose, the mean time to normalization of the QTc interval was 82 hours (Neuvonen et al, 1981).
    c) According to a retrospective study analyzing sotalol overdoses reported to 2 poison centers in Germany from 1996 to 2001, minor bradycardia or QT prolongation were reported in adults following sotalol doses of 640 mg (Hermanns-Clausen & Desel, 2002).
    D) ASYSTOLE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 70-year-old woman intentionally ingested 6.72 g of sotalol approximately 12 hours before presentation. She had an initial heart rate of 50 beats/min and blood pressure 110/70 mmHg with no evidence of cardiac failure. An ECG showed a normal QRS complex and a QT interval of 820 ms (corresponded to a QT interval corrected for the actual heart rate (QTc) of 750 ms). The patient received activated charcoal and glucagon. Two hours after admission, a sudden decrease in heart rate (25 beats/min) occurred that was unresponsive to atropine; isoprenaline (10 mcg/min) was started. External chest compressions and adrenaline were needed for 2 episodes of asystole. External ventricular pacing was added. By day 2, the QT was 470 ms and the patient was discharged from intensive care with no cardiac or neurologic sequelae (Adlerfliegel et al, 1993).
    E) SHOCK
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 29-year-old woman intentionally ingested 2.6 g verapamil and 4.8 g sotalol and was found unconscious. She was admitted with dilated pupils and bradycardia which deteriorated into circulatory collapse. Prolonged normothermic CPR (4 hours) was required and extracorporeal heart lung assist (ECHLA) was started 4 hours later. The patient remained on extracorporeal support for 20 hours with no myocardial contractions; she responded to painful stimuli. ECHLA was required for a total of 69 hours; the patient was gradually weaned and extubated on day 5. Complications included compartment syndrome of the arm, renal failure secondary to rhabdomyolysis, intestinal bleeding and transient nerve paralysis. She recovered almost completely with no CNS or cardiac deficits, but had some residual dysfunction of her arm (Rygnestad et al, 2005).
    F) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) TORSADE DE POINTES
    1) Torsades de pointes has been reported in patients taking therapeutic doses of sotalol (Prod Info BETAPACE AF(R) oral tablets, 2011; Dancey et al, 1997; Huynh-Do et al, 1996; Laakso et al, 1981; Kontopoulos et al, 1981; McKibbin et al, 1984; Laakso et al, 1984) (Rackovec et al, 1984) (Kuck et al, 1984; Krapf & Gertsch, 1985; Bennett et al, 1985; Gossinger et al, 1987) (Sinhg et al, 1991)(Patrick et al, 1994; Gottlieb et al, 1997).
    2) RISK FACTORS: Hypokalemia, renal insufficiency, preexisting QTc prolongation, underlying repolarization abnormalities, and concomitant use of other drugs which prolong ventricular repolarization may have been contributing factors in many of these patients. Alterations in QT dispersion and prolonged QT intervals are indicators of proarrhythmia (Cammu et al, 1999; van Uum et al, 1997; Haverkamp et al, 1998).
    a) In patients with a history of renal failure it has been suggested that sotalol should be discontinued if the QTc interval is prolonged (ie, a maximal QTc interval of 500 ms). There have been several case reports of sotalol induced-torsades de pointes in patients with renal failure that were currently on hemodialysis and receiving low dose sotalol therapy (Dancey et al, 1997; Huynh-Do et al, 1996).
    3) INCIDENCE: The following list describes the relationship between QTc interval prolongation and torsades de pointes. Note: The highest on-therapy QTc was in most cases the one reported at the time that the patient developed torsades de pointes; this may than overstate the predictive value of a high QTc (Prod Info BETAPACE AF(R) oral tablets, 2007):
    1) QTc interval while on sotalol therapy and incidence of torsades:
    a) less than 500 msec: 1.3% (n=1787)
    b) 500 to 525 msec: 3.4% (n=236)
    c) 525 to 550 msec: 5.6% (n=125)
    d) greater than 550 msec: 10.8% (n=157)
    2) Change in QTc interval from baseline and incidence of torsades:
    a) less than 65 msec: 1.6% (n=1516)
    b) 65 to 80 msec: 3.2% (n=158)
    c) 80 to 100 msec: 4.1% (n=146)
    d) 100 to 130 msec: 5.2% (n=115)
    e) greater than 130 msec: 7.1% (n=99)
    4) Chronic oral administration of sotalol is associated with a 2% to 4% risk of developing Torsade de pointes. In a meta-analysis of 37 reports of patients receiving at least 1.5 mg/kg or 100 mg IV sotalol over 30 minutes or less, only one of 962 patients (0.1%) developed Torsade de pointes (Marill & Runge, 2001).
    5) CASE REPORT: A 55-year-old woman with hypertension had been maintained on acebutolol, and a combination product containing cyclopenthiazide and potassium (McKibbin et al, 1984). She was switched to a combination of sotalol 160 mg and hydrochlorothiazide 25 mg. Two hours after the first dose she developed dizziness and recurrent syncope and presented to the hospital in torsades de pointes with a potassium of 3.6 mEq/L.
    b) ONSET: In a series of 6 patients with sotalol the risk of severe dysrhythmias was highest 4 to 20 hours after ingestion (Neuvonen et al, 1981).
    2) WITH POISONING/EXPOSURE
    a) TORSADE DE POINTES
    1) Ventricular dysrhythmias including polymorphic ventricular tachycardia (torsades de pointes) are common after sotalol overdose (Neuvonen et al, 1979; Totterman et al, 1982; Elonen et al, 1979) (Salzburg & Gallagher, 1980) (Allberry, 1983; Link et al, 1997; Montagna & Groppi, 1980; Neuvonen et al, 1981; Beattie, 1984; Edvardsson & Varnauskas, 1987).
    2) CASE REPORT: A 70-year-old man developed torsade de pointes after intentionally ingesting 3 to 4 g sotalol and 300 to 350 mg enalapril in a suicide attempt. Five hours after presentation, the patient developed polymorphic ventricular tachycardia consistent with torsade de pointes and lost consciousness. He initially received a 100 mg bolus of lidocaine and was started on an infusion of lidocaine. Over the next 36 hours, all infusions were stopped and the QT interval normalized (Assimes & Malcolm, 1998).
    3) According to a retrospective study analyzing sotalol overdoses reported to 2 poison centers in Germany between 1996 and 2001, torsade de pointes in combination with bradycardia and hypotension occurred in adults following sotalol doses of 1.6 grams or more (Hermanns-Clausen & Desel, 2002).
    b) VENTRICULAR DYSRHYTHMIA: Multifocal premature ventricular contractions are common in sotalol overdose (Neuvonen et al, 1979; Elonen et al, 1979; Neuvonen et al, 1981; Totterman et al, 1982; Beattie, 1984).
    c) VENTRICULAR FIBRILLATION: Ventricular fibrillation may develop (Elonen et al, 1979; Neuvonen et al, 1979; Montagna & Groppi, 1980; Neuvonen et al, 1981; Beattie, 1984; Singh et al, 1991; van Uum et al, 1997).
    d) JUNCTIONAL RHYTHM: Junctional bradycardia has been reported after overdose (Adlerfliegel et al, 1993; Gupta, 1985).
    1) ONSET: In a series of 6 patients with sotalol the risk of severe dysrhythmias was highest 4 to 20 hours after ingestion (Neuvonen et al, 1981).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Respiratory depression or arrest develops in patients with severe dysrhythmias (Perrot et al, 1988).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RESPIRATORY DEPRESSION
    a) In a rat model of severe sotalol toxicity achieved by continuous infusion, artificial ventilation resulted in an increase in survival time and lethal dose, suggesting that centrally mediated respiratory depression is the usual cause of death in this model (Langmeijer et al, 1986).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Syncope, CNS depression and seizures may develop in patients with ventricular dysrhythmias.
    B) WITH POISONING/EXPOSURE
    1) Syncope, CNS depression and seizures may develop in patients with ventricular dysrhythmias.
    3.7.2) CLINICAL EFFECTS
    A) SYNCOPE
    1) WITH THERAPEUTIC USE
    a) Syncope is a common complaint in patients with self limited ventricular dysrhythmias, particularly torsades de pointes (Kontopoulos et al, 1981; McKibbin et al, 1984; Beattie, 1984) (Rackovec et al, 1984)(Kuck et al, 1984; Totterman et al, 1982).
    2) WITH POISONING/EXPOSURE
    a) Syncope is a common complaint in patients with self limited ventricular dysrhythmias, particularly torsades de pointes (Kontopoulos et al, 1981; McKibbin et al, 1984; Beattie, 1984) (Rackovec et al, 1984)(Kuck et al, 1984; Totterman et al, 1982).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures are not as common as with some other beta blockers. They may develop in patients with severe ventricular dysrhythmias (Montagna & Groppi, 1980; Belton et al, 1982).
    C) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) CNS depression ranging from drowsiness to coma may develop in patients with hypotension or severe dysrhythmias (Gupta, 1985; Perrot et al, 1988).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) RETROPERITONEAL FIBROSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 55-year-old woman developed retroperitoneal fibrosis after taking sotalol 160 mg daily for 5 years and retinoic acid 50 mg daily for 6 months (Laakso et al, 1982).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Acute anuric renal failure developed in a patient with severe prolonged hypotension after overdose (Perrot et al, 1988).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Metabolic acidosis developed in a patient with severe prolonged hypotension after overdose (Perrot et al, 1988).

Reproductive

    3.20.1) SUMMARY
    A) Sotalol is pregnancy category B. It crosses the placenta and is concentrated in breast milk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Rats and rabbits administered sotalol doses of 9 and 7 times, respectively the maximum recommended human dose (MRHD) did not produce an increase in congenital abnormalities. A slight increase in fetal deaths was observed in rabbits at sotalol doses 16 times the MRHD. It was also associated with maternal toxicity. Toxicity did not occur at sotalol doses 3 times the MRHD. In rats, a sotalol dose 18 times the MRHD increased the number or early resorptions (Prod Info SOTYLIZE(TM) oral solution, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Sotalol is pregnancy category B (Prod Info SOTYLIZE(TM) oral solution, 2014)
    B) PLACENTAL BARRIER
    1) Sotalol crosses the placenta (Prod Info SOTYLIZE(TM) oral solution, 2014). Concentrations in cord serum are similar to maternal concentrations, with maternal:fetal ratios of 1.2 to 1.4 (Hackett et al, 1990; Wagner et al, 1990). No adverse effects were reported in 2 infants born to mothers taking sotalol throughout pregnancy.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Sotalol is concentrated in breast milk at high levels. In 5 mothers whose mean sotalol dose was 433 mg/day, sotalol concentration in milk ranged from 4.8 to 2.02 mg/L (mean: 10.5 mg/L). A milk-plasma ratio of 5.5:1 (range: 2.2 to 8.8) was observed. The calculated infant dose was 0.8 to 3.4 mg/kg (similar to recommended therapeutic doses in neonates) (Prod Info sotalol hydrochloride IV injection, 2009).
    2) In another study, the ratio of breast milk concentration to maternal serum concentration was 2.4 to 5.6 (Hackett et al, 1990; Wagner et al, 1990).
    3) No adverse effects were reported in an infant being breast fed by a mother taking sotalol. It was estimated that an infant ingesting 0.15 L/kg of breast milk would ingest 20% to 23% of the maternal dose (Hackett et al, 1990).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) RATS: Fertility was not reduced in rats exposed to sotalol doses approximately 100 times the maximum recommended human dose as mg/kg prior to mating, other than a slight decrease in litter size (Prod Info SOTYLIZE(TM) oral solution, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for QTc prolongation.
    C) Monitor serum electrolytes including magnesium and calcium, renal function and blood glucose.
    D) Specific sotalol plasma levels are not clinically useful or readily available.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Obtain serum electrolytes including potassium, calcium, and magnesium in patients taking diuretics or other potassium wasting drugs and those manifesting dysrhythmias or QTc prolongation.
    2) Obtain renal function tests in patients at risk for renal insufficiency (hypertension, diabetes, other nephrotoxic drugs) as renal insufficiency prolongs sotalol clearance and may predispose to toxicity at lower doses.
    4.1.3) URINE
    A) URINARY LEVELS
    1) Sotalol may falsely elevate levels of urinary metanephrines determined spectraphotometrically (Sheps, 1994).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Obtain serial ECGs and institute continuous cardiac monitoring.

Methods

    A) CHROMATOGRAPHY
    1) Methods to quantitate sotalol in biological material using high performance liquid chromatography with fluorescence detection, and thin-layer chromatography have been described (Fiset et al, 1993; Boutagy & Shenfield, 1991) (Montagne & Groppi, 1980) (Perrot et al, 1988).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) SUMMARY: Patients with cardiovascular symptoms (hypotension, bradycardia), central nervous system toxicity (somnolence, seizures, coma) or persistent QTc prolongation should be admitted to an intensive care setting. Symptomatic patients should be admitted for further observation/treatment until they are asymptomatic for a prolonged period (several hours) of time without therapy.
    B) Obtain a baseline electrocardiogram and monitor patient for a minimum of 12 hours.
    C) Patients who at presentation or during Emergency Department observation show evidence of significant cardiovascular (bradycardia, heart block, hypotension, QTc prolongation, ventricular dysrhythmias) respiratory (respiratory depression) or neurologic toxicity (syncope, CNS depression or seizures), independent of the dose ingested, should be admitted to a monitored setting for at least 24 hours of observation and treatment.
    D) Patients should not be discharged until dysrhythmias have resolved and the QTc interval has returned to normal.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Healthy asymptomatic patients (including children) who inadvertently ingest less than or equal to a maximum single therapeutic dose for age (up to 160 mg in adults, or 4 mg/kg in children) may be observed at home and referred to a health care facility if symptoms develop (Wax et al, 2005).
    B) Torsades de pointes has been reported in adults after therapeutic doses, although many of these patients had concomitant conditions (electrolyte abnormalities, cardiac disease, use of drugs that cause QT prolongation) that may have predisposed them to dysrhythmias. Patients with a sotalol overdose who have an underlying cardiovascular disease or predisposing risk factors (ie, other antidysrhythmic drugs, diuretics) should be referred to a healthcare facility.
    C) PREDISPOSING FACTORS: Because dysrhythmias have been reported after a single therapeutic dose in patients with predisposing factors (McKibbin et al, 1984), all such patients should be referred to a health care facility for decontamination, a baseline electrocardiogram and monitoring for a minimum of 12 hours regardless of the amount ingested. This includes:
    1) Any patient taking diuretics or other drugs that cause hypokalemia, hypomagnesemia, or hypocalcemia;
    2) Those with medical conditions which may cause hypokalemia, hypomagnesemia, or hypocalcemia (diarrhea, vomiting, excessive sweating, etc);
    3) Patients with a history of cardiovascular disease, dysrhythmias, prolonged QT syndrome, or renal insufficiency;
    4) Patients taking other antidysrhythmic drugs; and those taking other drugs which cause conduction abnormalities (eg, tricyclic antidepressants, terfenadine, astemizole, phenothiazines, propoxyphene, pentamidine, beta blockers, calcium antagonists, cardiac glycosides, other antiarrhythmics).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (ie, hypotension, seizures, dysrhythmias), or in whom the diagnosis in not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic patients, those with serious underlying cardiac disease, those taking a calcium channel blocker, and any patient with a deliberate ingestion should be referred to a healthcare facility.
    B) Inadvertent ingestions in adults who ingest greater than 160 mg and children who ingest greater than 4 mg/kg should be referred to a healthcare facility (Wax et al, 2005).
    C) Patients who present and remain asymptomatic and without signs of toxicity or QTc prolongation during 12 hours of Emergency Department observation may be discharged (Wax et al, 2005). Obtain a psychiatric consultation if indicated.
    D) Patients who develop signs of toxicity during observation should be admitted.

Monitoring

    A) Monitor vital signs and mental status.
    B) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for QTc prolongation.
    C) Monitor serum electrolytes including magnesium and calcium, renal function and blood glucose.
    D) Specific sotalol plasma levels are not clinically useful or readily available.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended because of the potential for hemodynamic instability, somnolence and seizures.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) EFFICACY
    a) Activated charcoal 50 grams given within 5 minutes of sotalol 160 mg reduced absorption by 99% (Karkkainen & Neuvonen, 1984). Activated charcoal 50 grams given 6 hours after sotalol followed by 12.5 grams of charcoal every 6 hours reduced sotalol half life from 9.4 hours to 7.6 hours.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Mild to moderate sotalol exposures require only symptomatic and supportive care. Monitor cardiac rhythm, administer IV fluids for hypotension, and atropine for symptomatic bradycardia.
    2) Severe exposure may require early intubation. Treat ventricular dysrhythmias and hypotension. Cardiovert unstable ventricular dysrhythmias. Correct electrolyte abnormalities. Treat torsades de pointes with IV magnesium, overdrive pacing is second-line therapy.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status. Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for QTc prolongation. Monitor serum electrolytes including magnesium and calcium, renal function and blood glucose.
    2) Specific sotalol plasma levels are not clinically useful or readily available.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Initial management can be with fluids (500 mL boluses up to 3L) and atropine if patient is bradycardic. Catecholamines should be given those who do not respond to IV fluids. No one agent has been shown to be consistently effective, though there is some data suggesting that norepinephrine or epinephrine might be more effective than dopamine. Glucagon can also be given. Initial dosing is 5 to 15 mg by slow IV administration with doses repeated as needed. An infusion of the initial dose that elicited a response per hour may then be administered. HIE (high dose insulin euglycemia) is another potential therapy, though there is no experience with sotalol overdose. Insulin dose: A bolus of insulin at 1 unit/kg concomitantly with 25 g glucose and then an insulin infusion of 0.5 to 1 unit/kg/hr with a dextrose infusion (D10 in an adult) with frequent monitoring of blood glucose to maintain euglycemia. Monitor for hypokalemia and supplement potassium as needed.
    2) HYPOTENSION
    a) SUMMARY
    1) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    b) NOREPINEPHRINE
    1) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    2) DOSE
    a) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    b) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    c) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    c) DOPAMINE
    1) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    2) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) GLUCAGON
    a) BACKGROUND: Glucagon is considered a first-line antidotal therapy for beta-blocker poisoning (Shepherd, 2006). Glucagon has not been well studied for sotalol overdose.
    b) DOSING: Administer an initial bolus of 50 to 150 mcg/kg (usually about 10 milligrams in adults) over 1 minute; follow this with a continuous intravenous infusion of 50 to 100 mcg/kg/hour (DeWitt & Waksman, 2004). Alternatively, administer a 5 mg glucagon bolus, and repeat every 5 to 10 minutes for up to 3 doses if necessary. If the patient has a response at a particular dose, start an hourly infusion of glucagon at the response dose (eg, if a patient responds to 10 mg, then start an infusion at 10 mg/hour).
    1) In this setting, glucagon should be diluted with preservative-free saline or D5W (Mofenson et al, 1986; Cronk, 1971).
    2) Glucagon may produce a positive chronotropic and inotropic cardiac effect, which occurs despite beta-blockage. The drug has been reported to increase myocardial contractility in patients refractive to isoproterenol. Glucagon is thought to activate the adenylate cyclase system at a different site than isoproterenol (Kosinski & Malindzak, 1973).
    c) ADVERSE EFFECTS: Vomiting is a common adverse effect from glucagon administration. If the patient is unable to protect the airway endotracheal intubation should be strongly considered.
    d) CASE REPORT: Sotalol-induced symptomatic bradycardia was treated with glucagon at a rate of 0.2 mg/min in an elderly woman. After 3.5 mg the rhythm converted to normal sinus rhythm (heart rate 60 beats/min). Over the next 5 hours, 15 mg of glucagon was given for sporadic asymptomatic episodes of sinus arrest. The patient was discharged the following day (Fernandes & Daya, 1995).
    4) INSULIN/DEXTROSE
    a) BACKGROUND: HIE (high dose insulin euglycemia) is another potential therapy, although there is no experience with sotalol overdose. Consider high-dose insulin euglycemia therapy in patients who require catecholamines despite treatment with intravenous fluids, glucagon, and calcium. High-dose insulin euglycemia therapy may allow the practitioner to decrease the dose of catecholamines and avoid the adverse effects of prolonged high-dose catecholamines.
    b) DOSE
    1) Intravenous insulin infusion with supplemental dextrose, and potassium as needed, is recommended in patients with severe or persistent hypotension after calcium channel blocker overdose, and may also be effective for beta blocker overdose. Before, during, and after the therapy, monitor for hypoglycemia and hypokalemia.
    2) Administer a bolus of 1 unit/kg of insulin followed by an infusion of 0.1 to 1 units/kg/hour, titrated to a systolic blood pressure of greater 90 to 100 mmHg (bradycardia may or may not respond). Reassess every 30 minutes to determine the need for a higher rate of insulin.
    a) In some refractory cases, more aggressive high-dose insulin protocols have been suggested, starting with a 1 unit/kg insulin bolus, followed by a 1 unit/kg/hour continuous infusion. If there is no clinical improvement in the patient, the infusion rate may be increased by 2 units/kg/hour every 10 minutes, up to a maximum of 10 units/kg/hour (Engebretsen et al, 2011).
    3) Administer dextrose bolus to patients with an initial blood glucose of less than 250 mg/dL (adults 50 mL dextrose 50%, children 0.25 g/kg dextrose 25%). Begin a dextrose infusion of 0.5 g/kg/hour in all patients. Monitor blood glucose every 15 to 30 minutes until consistently 100 to 200 mg/dL for 4 hours, then monitor every hour. Titrate dextrose infusion to maintain blood glucose in the range of 100 to 200 mg/dL. Supplemental dextrose will be needed for at least several hours after the insulin infusion is discontinued
    4) Administer supplemental potassium initially if patient is hypokalemic (serum potassium less than 2.5 mEq/L). Monitor serum potassium every 4 hours and supplement as needed to maintain potassium level of 2.5 to 2.8 mEq/L.
    D) BRADYCARDIA
    1) ATROPINE
    a) ATROPINE/DOSE
    1) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010a).
    2) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    a) There is no minimum dose (de Caen et al, 2015).
    b) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    2) ISOPROTERENOL
    a) MECHANISM OF ACTION: Isoproterenol is a beta agonist which will competitively antagonize the effect of the beta-blocker.
    b) CAUTION: Hypotension may be aggravated by isoproterenol necessitating careful monitoring of blood pressure and titration of dose (norepinephrine or dopamine may be preferable in severely hypotensive patients).
    c) ISOPROTERENOL INDICATIONS
    1) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010a).
    2) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010a).
    3) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    4) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    E) TORSADES DE POINTES
    1) Hypokalemia, renal insufficiency or failure, preexisting QTc prolongation, underlying repolarization abnormalities, and concomitant use of other drugs which prolong ventricular repolarization may be contributing factors in many patients who develop TDP. Alterations in QT dispersion and prolonged QT intervals are potential indicators of proarrhythmia (Dancey et al, 1997; Huynh-Do et al, 1996).
    2) Low doses of sotalol have produced torsades de pointes in patients with renal failure (Dancey et al, 1997; Huynh-Do et al, 1996).
    3) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010a; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010a). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    4) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010a). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010a). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    5) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010a).
    6) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    7) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010a). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010a). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010a).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010a).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    8) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    9) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    F) VENTRICULAR ARRHYTHMIA
    1) Cardiovert unstable rhythms. Correct electrolyte abnormalities. Lidocaine may be used if dysrhythmias persist. Use amiodarone with caution as it can cause torsades de pointes.
    2) Do NOT use procainamide or disopyramide as their effects may be additive.
    3) LIDOCAINE
    a) CASE REPORT: A 70-year-old man with poor venous access was successfully treated with a 100 mg bolus of lidocaine after developing torsades de pointes and loss of consciousness after intentionally ingesting 3 to 4 g of sotalol and 300 to 350 mg of enalapril approximately 5 hours after presentation. The patient converted to a junctional bradycardia and a return of consciousness. A second 50 mg bolus of lidocaine was given for ectopy followed by a lidocaine infusion at 3 mg/min along with isoproterenol and dopamine. The patient improved and converted to sinus rhythm 12 hours after admission (Assimes & Malcolm, 1998a).
    b) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010a; Vanden Hoek et al, 2010).
    c) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010a). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010a).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    d) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010a).
    e) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    G) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    H) EXTRACORPOREAL PERFUSION
    1) For patients with intractable dysrhythmias or hypotension, consider cardiopulmonary bypass, intra-aortic balloon pump, or extracorporeal membrane oxygenation early to preserve perfusion until severe toxicity abates.
    2) CASE REPORT: A 29-year-old woman intentionally ingested 2.6 g verapamil and 4.8 g sotalol and was found unconscious. She was admitted with dilated pupils and bradycardia which deteriorated into circulatory collapse. Prolonged normothermic CPR (4 hours) was required and extracorporeal heart lung assist (ECHLA) was started 4 hours later. The patient remained on extracorporeal support for 20 hours with no myocardial contractions; she responded to painful stimuli. ECHLA was required for a total of 69 hours; the patient was gradually weaned and extubated on day 5. Complications included compartment syndrome of the arm, renal failure secondary to rhabdomyolysis, intestinal bleeding and transient nerve paralysis. She recovered almost completely with no CNS or cardiac deficits, but had some residual dysfunction of her arm (Rygnestad et al, 2005).

Enhanced Elimination

    A) HEMODIALYSIS
    1) CASE REPORT: A 66-year-old patient administered sotalol 480 mg twice daily developed torsades de pointes that was refractory to conventional therapy. Within 30 minutes after being placed on dialysis, the arrhythmia was eradicated. Prefilter sotalol levels were significantly lower than predialysis levels (2.4 mcg/mL vs 3.4 mcg/mL) (Singh et al, 1991).
    2) In patients with endstage renal failure sotalol half-life during dialysis was 6 to 7 hours compared to a baseline of 41 hours off dialysis (Tjandramaga et al, 1976).
    3) CASE REPORT: A 47-year-old man with hypertension, diabetes and progressive renal insufficiency (medications included sotalol, enalapril, digoxin, insulin, bumetadine and allopurinol) developed QTc prolongation and recurrent torsades de pointes (van Uum et al, 1997). Sotalol half-life during hemodialysis was 4.5 hours and after hemodialysis it was 96 hours.
    B) CONTINUOUS VENO-VENOUS HEMOFILTRATION
    1) CASE REPORT: A 75-year-old man intentionally ingested a massive amount of cardiac drugs which included digoxin (7.125 mg) and sotalol (7.2 g) and was admitted in cardiogenic shock. Initial intensive care measures included pharmacologic management, mechanical ventilation, cardiac pacing, intra-aortic balloon pump support and the administration of digoxin-specific Fab fragments. Due to persistent anuria, continuous veno-venous hemofiltration was initiated shortly after admission and continued for 4 days with return of normal renal function. Although CVVH was not effective in eliminating digoxin, sotalol was efficiently removed by CVVH; the elimination followed first-order kinetics. The patient was extubated 6 days after admission recovered completely (Mulder et al, 2010).

Abstracts

Case Reports

    A) ADULT
    1) A 51-year-old man developed QTc prolongation and syncope while taking hydralazine 25 mg 3 times a day, hydrochlorothiazide 50 mg and sotalol 480 mg as single daily doses. His sotalol was divided into 160 mg 3 times a day and his QTc returned to normal. His sotalol was then increased to 640 mg as a single daily dose and his QTc became prolonged again. While on this regimen the patient lost consciousness while on a flight to Leningrad. Resuscitation was started immediately and on arrival to the hospital he was in ventricular fibrillation from which he was successfully defibrillated. Sotalol was stopped and replaced by atenolol with normalization of his QTc (Laakso et al, 1981).
    2) A 55-year-old woman with hypertension had been maintained on acebutolol, and a combination product containing cyclopenthiazide and potassium. She was switched to a combination of sotalol 160 mg and hydrochlorothiazide 25 mg. Two hours after the first dose she developed dizziness and recurrent syncope and presented to the hospital in torsades de pointes with a potassium of 3.6 mEq/L (McKibbin et al, 1984).
    3) A 58-year-old woman ingested 14.4 g of sotalol and 50 mg of triazolam. She presented in deep coma, with severe bradycardia and unmeasurable blood pressure. Isoproterenol was effective in briefly restoring blood pressure, but the pulse remained at 10 to 15 beats/minute. Sodium bicarbonate infusion, cardiac massage, theophylline, glucagon boluses, and intracardiac pacing had a minimal effect in restoring pulse to 65 beats/minute but blood pressure was 65 to 85 mmHg. She died 3.5 hours after admission (Perrot et al, 1988).

Range Of Toxicity

Summary

    A) TOXICITY: Adults who ingest greater than 160 mg and children who ingest greater than 4 mg/kg have the potential to develop toxicity. Toxicity can occur even at therapeutic dosing, especially in those with renal impairment, baseline prolonged QTc interval or other predisposing conditions. Fatalities have occurred in adults after ingestions of 3.2 and 14.4 g of sotalol. Adults have survived severe toxicity with intensive supportive care after overdoses in the range of 2 to 13 g.
    B) THERAPEUTIC DOSE: ADULT: ORAL: 80 mg twice daily; maximum: 160 mg twice daily (total: 320 mg/day) if the patient has a calculated clearance of greater than 60 mL/min. Higher doses have resulted in torsades de pointes and are not recommended. IV: 75 mg infused over 5 hours twice daily. PEDIATRIC: Not approved for use in children. However, children have been treated with weight-based dosing of 2 mg/kg/day orally in 2 or 3 divided doses initially, may be titrated up to 8 mg/kg/day. Dosing can also be initiated via body surface area with an initial dose in children over 2 years of age of 90 to 100 mg/m(2)/day in 2 to 3 divided doses; maintenance dose ranges from 100 to 250 mg/m(2)/day in 2 to 3 divided doses.

Therapeutic Dose

    7.2.1) ADULT
    A) INTRAVENOUS
    1) INITIAL DOSE: 75 mg IV infused over 5 hours once or twice daily in patients based on CrCl, up to 112.5 mg IV infused over 5 hours once or twice daily. Monitor ECG for excessive increase in QTc (Prod Info sotalol HCl intravenous injection, 2014).
    2) VENTRICULAR ARRHYTHMIA: 75 mg IV infused over 5 hours once or twice daily in patients based on CrCl, up to 300 mg IV once or twice daily for refractory life-threatening arrhythmias. Monitor ECG for excessive increase in QTc (Prod Info sotalol HCl intravenous injection, 2014).
    3) VENTRICULAR DYSRHYTHMIA, LIFE THREATENING: The American Heart Association guidelines recommend 1.5 mg/kg or 100 mg IV or 5 minutes for stable, wide-complex ventricular tachycardia in the pericardiac arrest situation (Neumar et al, 2010).
    B) ORAL SOLUTION
    1) The recommended initial dose is 80 mg (16 mL) ORALLY once or twice daily, and titrate as indicated (Prod Info SOTYLIZE(TM) oral solution, 2014).
    2) VENTRICULAR ARRHYTHMIA: The initial recommended dose is 80 mg once or twice daily based on creatinine clearance. The dose can be increased in increments of 80 mg/day every 3 days as needed if the QTc is less than 500 msec. Usual therapeutic effects are usually observed at oral doses of 80 to 160 mg once or twice daily. However, doses as high as 240 to 320 mg once or twice a day have been used in patients with refractory life-threatening arrhythmias (Prod Info SOTYLIZE(TM) oral solution, 2014).
    C) ORAL TABLETS
    1) ATRIAL FIBRILLATION OR ATRIAL FLUTTER: INITIAL DOSE: 80 mg of sotalol orally twice daily for patients with a creatinine clearance greater than 60 mL/min; patients with a creatinine clearance between 40 and 60 mL/min, the dose is administered once daily. The dose may be titrated upward to 120 mg once or twice daily depending on creatinine clearance and patient response (Prod Info BETAPACE AF(R) oral tablets, 2011).
    7.2.2) PEDIATRIC
    A) ROUTE OF ADMINISTRATION
    1) INTRAVENOUS
    a) AGE UNDER 2 YEARS: See dose adjustment factor graph in package insert for detailed information (Prod Info sotalol HCl intravenous injection, 2014).
    b) INITIAL DOSE, AGED 2 YEARS AND OLDER: 30 mg/m(2) IV 3 times daily with close clinical, QTc interval and heart rate monitoring (Prod Info sotalol HCl intravenous injection, 2014).
    c) MAINTENANCE DOSE, AGED 2 YEARS AND OLDER: The dose can than be titrated to a maximum of 60 mg/m(2) IV with close clinical, QTc interval and heart rate monitoring (Prod Info sotalol HCl intravenous injection, 2014).
    2) ORAL SOLUTION
    a) VENTRICULAR ARRHYTHMIA
    1) AGED 2 YEARS AND OLDER: The recommended initial dose is 30 mg/m(2) ORALLY 3 times daily. MAX dose, 60 mg/m(2). Allow at least 36 hours between dose increments (Prod Info SOTYLIZE(TM) oral solution, 2014).
    2) AGED 1 MONTH OR OLDER: The recommended initial dose is 21 mg/m(2) ORALLY 3 times daily (Prod Info SOTYLIZE(TM) oral solution, 2014).
    3) AGED 1 WEEK: The recommended dose is 0.3 times the initial pediatric dose (30 X 0.3 = 9 mg/m(2)) (Prod Info SOTYLIZE(TM) oral solution, 2014)
    3) ORAL TABLET: BODY SURFACE AREA (BSA) DOSING
    a) INITIAL DOSE: 90 to 100 mg/m(2)/day orally in 2 or 3 divided doses (divided every 8 to 12 hours). Gradually increase as needed every 3 to 5 days until stable rhythm is maintained (Ratnasamy et al, 2008; Prod Info BETAPACE AF(R) oral tablets, 2007; Price et al, 2002). Lower (50 mg/m2/day) and higher (200 mg/m(2)/day) initial doses have also been used (Miyazaki et al, 2008; Maragnes et al, 1992).
    b) MAINTENANCE DOSE: Usual maintenance dose ranges from 100 to 250 mg/m(2)/day in 2 or 3 divided doses, although lower or higher doses may be needed (Ratnasamy et al, 2008; Prod Info BETAPACE AF(R) oral tablets, 2007; Price et al, 2002; Tanel et al, 1995; Maragnes et al, 1992). In one study (n=66) in children, a child with ventricular tachycardia required a maintenance dose of 350 mg/m(2)/day (Maragnes et al, 1992). In a retrospective study (n=10) in infants requiring combination therapy with flecainide and sotalol for refractory supraventricular tachycardia, the median effective dose was 175 mg/m(2)/day (range: 100 to 250 mg/m(2)/day) (Price et al, 2002).
    c) Infants with a BSA less than 0.33 m(2) receiving BSA-normalized doses were found to have greater drug exposure and more pronounced beta-blocking and Class III effects than infants and children with a BSA greater than 0.33 m(2) (Saul et al, 2001).
    4) ORAL TABLET: WEIGHT-BASED DOSING
    a) INITIAL DOSE: 2 mg/kg/day orally in 2 or 3 divided doses (divided every 8 to 12 hours). Gradually increase as needed in 1 to 2 mg/kg/day increments every 3 to 5 days until stable rhythm is maintained (Paul et al, 2000; Luedtke et al, 1997; Pfammatter et al, 1995; Colloridi et al, 1992; Maragnes et al, 1992). Higher initial doses (up to 3 to 4 mg/kg/day) have also been used in children (Beaufort-Krol & Bink-Boelkens, 1997; Beaufort-Krol & Bink-Boelkens, 1997a).
    b) MAINTENANCE DOSE: 2 to 8 mg/kg/day orally in 2 or 3 divided doses (Celiker et al, 2001; Paul et al, 2000; Beaufort-Krol & Bink-Boelkens, 1997; Beaufort-Krol & Bink-Boelkens, 1997a; Luedtke et al, 1997; Pfammatter et al, 1995; Colloridi et al, 1992; Maragnes et al, 1992).
    c) In a prospective, multiple-dose pharmacokinetics/pharmacodynamics study (n=76), an age-specific dosing regimen was derived. For infants and children less than 6 years of age, an initial dose of 3 mg/kg/day orally in divided doses every 8 hours with a target dose of 6 mg/kg/day is recommended. For children greater than 6 years of age, an initial dose of 2 mg/kg/day orally in divided doses every 8 hours with a target dose of 4 mg/kg/day is recommended. The dosing regimen was based on a 50% (initial dose) and 95% (target dose) probability to achieve conversion into sinus rhythm (Laer et al, 2005).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) ADULT
    a) Fatalities have occurred in adults after ingestion of 3.2 and 14.4 g (Montagna & Groppi, 1980; Perrot et al, 1988; Hermanns-Clausen & Desel, 2002).

Maximum Tolerated Exposure

    A) GENERAL
    1) Adults who ingest greater than 160 mg and children who ingest greater than 4 mg/kg have the potential to develop toxicity and should be referred to a healthcare facility (Wax et al, 2005).
    2) QTc prolongation and torsades de pointes have been reported in patients taking therapeutic doses of sotalol (Dancey et al, 1997; Huynh-Do et al, 1996; Laakso et al, 1981; Kontopoulos et al, 1981; McKibbin et al, 1984; Laakso et al, 1984; Kuck et al, 1984; Krapf & Gertsch, 1985; Bennett et al, 1985; Gossinger et al, 1987; Patrick et al, 1994).
    3) Hypokalemia, renal insufficiency, preexisting QTc prolongation and concomitant use of other drugs which prolong ventricular repolarization may have been contributing factors in many of these patients.
    4) The incidence of torsades de pointes and the QTc interval increase with increasing dose (Prod Info BETAPACE AF(R) oral tablets, 2007):
    DAILY DOSE (MG)INCIDENCE OF TORSADESMEAN QTc (MSEC)
    800 (69)463 (17)
    1600.5 (832)467 (181)
    3201.6 (835)473 (344)
    4804.4 (459)483 (234)
    >6403.7 (324)490 (185)
    6405.8 (103)512 (62)
    () number of patients assessed

    5) Acute overdose with 2 to 13 g has been associated with severe ventricular dysrhythmias and survival with aggressive treatment (Neuvonon et al, 1981) (Beattie, 1984; Edvardsson & Varnauskas, 1987; Alderfliegel et al, 1993; Hermanns-Clausen & Desel, 2002).
    6) Maximum tolerated intravenous dose in healthy adults was 160 mg over 5 minutes (Boakes & Boeree, 1973).
    7) According to a retrospective study analyzing sotalol overdoses reported to 2 poison centers in Germany from 1996 to 2001, minor bradycardia or QT prolongation were reported in adults following sotalol doses of 640 mg (Hermanns-Clausen & Desel, 2002).
    8) CASE REPORT (CHILD): A 12-year-old girl developed severe bradycardia after ingesting 1.92 g of sotalol in a suicide attempt. The patient recovered following administration of atropine and glucagon (Hermanns-Clausen & Desel, 2002).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) SUMMARY
    a) Therapeutic levels range from approximately 1.25 to 3 mcg/mL (Edvardsson et al, 1980; Montagna & Groppi, 1980; Perrot et al, 1988).
    b) PEAK PLASMA CONCENTRATION: 2.5 to 4 hours; steady state plasma concentrations are attained within 2 to 3 day (ie, approximately 5 to 6 doses when administered twice daily) (Prod Info BETAPACE AF(R) oral tablets, 2011; Prod Info sotalol hydrochloride IV injection, 2009).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SUMMARY
    a) The threshold for toxic effects is approximately 5.1 mcg/mL (Montagna & Groppi, 1980).
    b) Blood and plasma levels in 2 fatal cases were both 40 mcg/mL (Montagna & Groppi, 1980; Perrot et al, 1988).
    c) Serum sotalol concentration was 20.6 mg/L 3 hours after ingestion in a 37-year-old man who took 11.2 g of sotalol. He developed hypotension, bradycardia, QTc prolongation and premature ventricular contractions, but recovered with supportive care (Gustavsson et al, 1997).
    d) Ingestion of 13 to 14 g produced a plasma sotalol concentration of 36.5 mcg/mL at 11 hours. However, much of the drug was removed by gastric lavage; the patient survived (Edvardsson & Varnauskas, 1987).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Sotalol has both beta-adrenergic blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. Intravenous sotalol is a racemic mixture of d- and l-sotalol; both isomers have Class III antiarrhythmic effects. However, the l-isomer is responsible for virtually all of the beta-blocking activity. Sotalol is a non-cardioselective beta-blocker which lacks significant intrinsic sympathomimetic activity and membrane stabilizing properties. Its beta-blocking effect is half maximal at oral doses of about 80 mg/day and maximal at oral doses between 320 and 640 mg/day. Beta-adrenergic blocking agents compete with endogenous and exogenous beta-adrenergic agonists for receptor sites. It does not have partial agonist or membrane stabilizing activity. Effects include a lowering of blood pressure, negative inotropic and chronotropic effects, and depressed AV conduction (Prod Info BETAPACE AF(R) oral tablets, 2011; Prod Info sotalol hydrochloride IV injection, 2009).

Toxicologic Mechanism

    A) The combined effects of inducing bradycardia and lengthening the duration of the action potential can predispose an individual to torsades de pointes and ventricular dysrhythmias.

Physicochemical

Physical Characteristics

    A) Sotalol hydrochloride is a white, crystalline solid that is soluble in water, propylene glycol, and ethanol, but only slightly soluble in chloroform (Prod Info SOTYLIZE(TM) oral solution, 2014; Prod Info sotalol hydrochloride IV injection, 2009).

Ph

    A) 6 to 7 (Prod Info sotalol hydrochloride IV injection, 2009)

Molecular Weight

    A) 308.8 (Prod Info SOTYLIZE(TM) oral solution, 2014; Prod Info sotalol hydrochloride IV injection, 2009)

References

General Bibliography

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    3) Alderfliegel F , Leeman M , Demaeyer P , et al: Sotalol poisoning associated with asystole. Intensive Care Med 1993; 19(1):57-58.
    4) Allberry RAW: Torsade de pointes. Anaesthesia 1983; 38:910.
    5) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
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    7) Assimes TL & Malcolm I: Torsade de pointes with sotalol overdose treated successfully with lidocaine. Can J Cardiol 1998a; 14(5):753-756.
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    11) Beaufort-Krol GC & Bink-Boelkens MT: Sotalol for atrial tachycardias after surgery for congenital heart disease. Pacing Clin Electrophysiol 1997a; 20(8 Pt 2):2125-2129.
    12) Belton P, Sheridan J, & Mulcahy R: A case of sotalol poisoning. Irish J Med Sci 1982; 151:126-127.
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    16) Boutagy J & Shenfield GM: Simplified procedure for the determination of sotalol in plasma by high-performance liquid chromatography. J Chromatogr 1991; 565:523-528.
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    22) Charlton NP , Lawrence DT , Brady WJ , et al: Termination of drug-induced torsades de pointes with overdrive pacing. Am J Emerg Med 2010; 28(1):95-102.
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    28) Dancey D , Wulffhart Z , & McEwan P : Sotalol-induced torsades de pointes in patients with renal failure. Can J Cardiol 1997; 13(1):55-58.
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