Sotalol is indicated for the maintenance of normal sinus rhythm [delay in time to recurrence of atrial fibrillation/atrial flutter (AFIB/AFL)] in patients with symptomatic AFIB/AFL who are currently in sinus rhythm.

Sotalol is indicated for the treatment of life-threatening ventricular tachycardia. Antiarrhythmic drugs may not enhance survival in patients with ventricular arrhythmias.

For either indication, intravenous sotalol can substitute for oral sotalol in patients unable to take oral drugs or be used to achieve steady state concentration faster compared to the conventional oral dosing.

Intravenous sotalol must be diluted for infusion.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Dilute intravenous sotalol in saline, 5% dextrose in water (D5W), or Ringer's lactate. Choose a volume convenient for administration and consistent with fluid restriction. Use a volumetric infusion pump.

To match the exposure to oral sotalol, use the same dosing frequency with intravenous administration and infuse the adjusted dose (see Table 1) over 5 hours.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Intravenous doses for sotalol infusion when used as a substitute for oral sotalol </span> </caption> <tbody class="Headless"> <tr class="First"> <td align="center"><span class="Bold"> Oral dose</span></td><td align="center"><span class="Bold"> Intravenous dose</span></td><td align="center"><span class="Bold"> Undiluted volume</span></td> </tr> <tr> <td align="center"><span class="Bold"> 80 mg</span></td><td align="center"><span class="Bold"> 75 mg</span></td><td align="center"><span class="Bold"> 5 mL</span></td> </tr> <tr> <td align="center"><span class="Bold"> 120 mg</span></td><td align="center"><span class="Bold"> 112.5 mg</span></td><td align="center"><span class="Bold"> 7.5 mL</span></td> </tr> <tr class="Last"> <td align="center"><span class="Bold"> 160 mg</span></td><td align="center"><span class="Bold"> 150 mg</span></td><td align="center"><span class="Bold"> 10 mL</span></td> </tr> </tbody> </table></div>

Initiate or uptitrate intravenous sotalol in a facility that can provide continuous ECG monitoring and cardiac resuscitation. Personnel should be trained in the management of serious ventricular arrhythmias. Withdraw other antiarrhythmic therapy before starting sotalol hydrochloride.

Measure and normalize serum potassium and magnesium levels before initiation. If the baseline QTc is >450 ms (JT >330 ms if QRS over 100 ms), sotalol is not recommended.

Infuse the loading dose over one hour. Monitor QTc interval every 15 minutes during infusion. Continue to monitor QTc around Tmax (2 to 4 hours post-dose) following the first oral dose (in all patients) and second oral dose (in patients with CrCL≥60 mL/min). If the QTc interval prolongs to >500 ms or increases 20% from baseline when initiating for an oral dose of 80 mg, discontinue drug; if initiating for an oral dose of 120 mg discontinue drug and consider a lower dose. If re-initiation at a lower dose of 80 mg is desired, wait at least 1 day (in patients with CrCL≥60 mL/min), or at least 3 days (in patients with CrCL ≥30 to <60 mL/min), or 7 days (in patients with CrCL ≥10 to <30 mL/min).

The intravenous loading dose depends on the target oral dose and creatinine clearance; the dosing interval for oral administration of sotalol and the minimum delay between the end of the infusion and the first oral dose also depend on renal function; see Table 2 [see Clinical Studies (14.4)].

<div class="scrollingtable"><table> <caption> <span>Table 2: Recommended Loading Dosage</span> </caption> <colgroup> <col width="120"/> <col width="120"/> <col width="120"/> <col width="120"/> <col width="120"/> </colgroup> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Calculated using Cockcroft Gault formula</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Recommended starting dose</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" rowspan="3"><span class="Bold">Creatinine Clearance <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> [mL/min] </span></td><td align="center" class="Lrule Rrule Toprule" colspan="4"><span class="Bold">Intravenous loading dose [mg] to be administered over 1 hour when the oral dose is going from</span></td><td align="center" class="Lrule Rrule Toprule" rowspan="3"><span class="Bold">Minimum delay to first oral dose [hours]</span></td><td align="center" class="Lrule Rrule Toprule" rowspan="3"><span class="Bold">Oral dosing interval [hours]</span></td> </tr> <tr> <td align="center" class="Lrule Rrule Toprule" colspan="2"><span class="Bold">Sotalol Initiation</span></td><td align="center" class="Lrule Rrule Toprule" colspan="2"><span class="Bold">Sotalol Escalation</span></td> </tr> <tr> <td align="center" class="Lrule Rrule Toprule"><span class="Bold">0 to 80 mg <a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">0 to 120 mg</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">80 to 120 mg</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">120 to 160 mg</span></td> </tr> <tr> <td class="Lrule Rrule Toprule">&gt;90</td><td align="center" class="Lrule Rrule Toprule">60</td><td align="center" class="Lrule Rrule Toprule">90</td><td align="center" class="Lrule Rrule Toprule">75</td><td align="center" class="Lrule Rrule Toprule">90</td><td align="center" class="Lrule Rrule Toprule">4</td><td align="center" class="Lrule Rrule Toprule">12</td> </tr> <tr> <td class="Lrule Rrule Toprule">60-90</td><td align="center" class="Lrule Rrule Toprule">82.5</td><td align="center" class="Lrule Rrule Toprule">125</td><td align="center" class="Lrule Rrule Toprule">82.5</td><td align="center" class="Lrule Rrule Toprule">105</td><td align="center" class="Lrule Rrule Toprule">4</td><td align="center" class="Lrule Rrule Toprule">12</td> </tr> <tr> <td class="Lrule Rrule Toprule">30-60</td><td align="center" class="Lrule Rrule Toprule">75</td><td align="center" class="Lrule Rrule Toprule">112.5</td><td align="center" class="Lrule Rrule Toprule">82.5</td><td align="center" class="Lrule Rrule Toprule">105</td><td align="center" class="Lrule Rrule Toprule">6</td><td align="center" class="Lrule Rrule Toprule">24</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule">10-30</td><td align="center" class="Lrule Rrule Toprule">75</td><td align="center" class="Lrule Rrule Toprule">112.5</td><td align="center" class="Lrule Rrule Toprule">82.5</td><td align="center" class="Lrule Rrule Toprule">105</td><td align="center" class="Lrule Rrule Toprule">12</td><td align="center" class="Lrule Rrule Toprule">48</td> </tr> </tbody> </table></div>

Intravenous sotalol has not been studied in children. Potency is thought to be similar in children, so a dose of 30 mg/m 2 every 8 hours should give exposure similar to that with 160 mg daily in adults. Table 3 shows suggested starting doses in children with normal renal function. With impaired renal function, start lower and titrate less frequently.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3. Suggesting starting doses [mg/kg] in children with normal renal function. </span> </caption> <tbody class="Headless"> <tr class="First"> <td align="center"><span class="Bold">Age</span></td><td align="center"><span class="Bold"> Dose [mg/kg]</span></td> </tr> <tr> <td> 3 days</td><td align="center"> 0.32</td> </tr> <tr> <td> 6 days</td><td align="center"> 0.51</td> </tr> <tr> <td> 9 days</td><td align="center"> 0.69</td> </tr> <tr> <td> 12 days</td><td align="center"> 0.81</td> </tr> <tr> <td> 2 weeks</td><td align="center"> 0.90</td> </tr> <tr> <td> 3 weeks</td><td align="center"> 1.0</td> </tr> <tr> <td> 1 month to 6 years</td><td align="center">�1.2</td> </tr> <tr> <td> 6-12 years</td><td align="center"> 1.1</td> </tr> <tr class="Last"> <td> &gt;12 years</td><td align="center"> 0.95</td> </tr> </tbody> </table></div>

Injection: 150 mg sotalol hydrochloride as a clear solution (15 mg/mL) in 10 mL clear, colorless single-dose vials.

{ "type": "p", "children": [], "text": "Injection: 150 mg sotalol hydrochloride as a clear solution (15 mg/mL) in 10 mL clear, colorless single-dose vials." }

Sotalol hydrochloride is contraindicated in patients with:

{ "type": "p", "children": [], "text": "Sotalol hydrochloride is contraindicated in patients with:" }

{ "type": "ul", "children": [ "Sinus bradycardia (<50 bpm), sick sinus syndrome or second or third degree AV block without a pacemaker", "Congenital or acquired long QT syndromes, QT interval >450 ms", "Cardiogenic shock, decompensated heart failure", "Serum potassium <4 mEq/L", "Bronchial asthma or related bronchospastic conditions", "Known hypersensitivity to sotalol" ], "text": "" }

Sotalol can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QTc prolongation. QTc prolongation is directly related to the concentration of sotalol. Factors such as reduced creatinine clearance, gender (female) and higher dose, bradycardia, history of sustained VT/VF, atrial fibrillation with sinus node dysfunction, heart failure increase the risk of TdP. The risk of TdP can be reduced by adjustment of the sotalol dose according to creatinine clearance and by monitoring the ECG for excessive increases in QTc.

Correct hypokalemia or hypomagnesemia prior to initiating sotalol hydrochloride, as these conditions can exaggerate the degree of QT prolongation and increase the potential for TdP. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or patients receiving concomitant diuretic drugs.

Avoid sotalol with other drugs known to cause QT prolongation [see Drug Interactions ( 7.1)].

Sotalol can cause bradycardia, sinus pauses or sinus arrest. Sotalol-induced bradycardia increases the risk of Torsade de Pointe, particularly following cardioversion. Monitor the ECG in patients receiving concomitant negative chronotropes [see Drug Interactions ( 7.1, 7.2, 7.3)] .

In general, sotalol is not recommended in patients with sick sinus syndrome associated with symptomatic arrhythmias, because it may cause sinus bradycardia, sinus pauses, or sinus arrest. Sotalol augments bradycardia and QTc prolongation following cardioversion. Patients with AFIB/AFL associated with the sick sinus syndrome may be treated with sotalol if they have an implanted pacemaker for control of bradycardia symptoms.

Sotalol produces significant reductions in both systolic and diastolic blood pressures. Monitor hemodynamics during administration.

New onset or worsening heart failure may occur during initiation or up-titration of sotalol because of its beta-blocking effects. Monitor for signs and symptoms of heart failure and discontinue treatment if symptoms occur.

Avoid beta-blockers, like sotalol, in patients with bronchospastic diseases. If sotalol is required, use the smallest effective dose.

Beta-blockade may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or and vomiting). Monitor blood glucose as appropriate.

Avoid abrupt withdrawal of beta-blockade which might be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Beta-blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism.

While taking beta-blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction.

The impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

The following adverse reactions are described elsewhere:

{ "type": "p", "children": [], "text": "\nThe following adverse reactions are described elsewhere:\n \n\n " }

{ "type": "ul", "children": [ "Proarrhythmia (\n \n \n 5.1, \n \n \n 5.2)\n \n \n ", "Negative inotropy (\n \n \n 5.3, \n \n \n 5.4)\n \n \n " ], "text": "" }

Adverse reactions related to sotalol use are those which are typical of its Class II (beta- blocking) and Class III (cardiac action potential duration prolongation) effects. The common documented beta-blocking adverse reactions (bradycardia, dyspnea, and fatigue) and Class III effects (QT interval prolongation) are dose related.

{ "type": "p", "children": [], "text": "Adverse reactions related to sotalol use are those which are typical of its Class II (beta- blocking) and Class III (cardiac action potential duration prolongation) effects. The common documented beta-blocking adverse reactions (bradycardia, dyspnea, and fatigue) and Class III effects (QT interval prolongation) are dose related." }

Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Sotalol and calcium blocking drugs can be expected to have additive effects on atrioventricular conduction, ventricular function, and blood pressure.

Concomitant use of catecholamine-depleting drugs, such as reserpine and guanethidine, with a beta- blocker may produce an excessive reduction of resting sympathetic nervous tone. Monitor such patients for hypotension and marked bradycardia which may produce syncope.

Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment. Symptoms of hypoglycemia may be masked.

Beta-agonists such as albuterol, terbutaline and isoproterenol may have to be administered in increased dosages when used concomitantly with sotalol.

Concomitant use with sotalol increases the risk of bradycardia. Because beta-blockers may potentiate the rebound hypertension sometime observed after clonidine discontinuation, withdraw sotalol several days before the gradual withdrawal of clonidine to reduce the risk of rebound hypertension.

The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by fluorimetric or photometric methods.

Risk Summary

Both the untreated underlying condition in pregnancy and the use of sotalol in pregnancy cause adverse outcomes to the mother and fetus/neonate (see Clinical Considerations). In animal reproduction studies in rats, early resorptions were increased at 15 times the maximum recommended human dose (MRHD). In rabbits an increase in fetal death was observed at 2 times the MRHD administered as single dose. Sotalol did not reveal any teratogenic potential in rats or rabbits at 15 and 2 times the MRHD respectively (see Data).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the United States (U.S.) general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

The incidence of VT is increased and may be more symptomatic during pregnancy. Most tachycardia episodes are initiated by ectopic beats and the occurrence of arrhythmia episodes may, therefore, increase during pregnancy. Breakthrough arrhythmias may also occur during pregnancy, as therapeutic treatment levels may be difficult to maintain due to the increased volume of distribution and increased drug metabolism inherent in the pregnant state.

Fetal/Neonatal Adverse Reactions

Sotalol has been shown to cross the placenta and is found in amniotic fluid. From published observational studies, the potential fetal adverse effects of sotalol use during pregnancy are growth restriction, transient fetal bradycardia, hyperbilirubinemia, hypoglycemia, uterine contractions, and possible intrauterine death. Sotalol may have a greater effect on QT prolongation in the immature heart than in the adult heart, and therefore, conveys an increased risk of serious fetal arrhythmia and/or possible intrauterine death. Monitor the newborn for symptoms of beta blockade.

Labor or Delivery

Generally, risk of arrhythmias increases during the labor and delivery process; therefore, considering the proarrhythmia potential of the drug, patients treated with sotalol should be monitored continuously during labor and delivery.

Data

Animal Data

Reproduction studies in rats and rabbits administered sotalol during organogenesis at 15 times and 2 times the MRHD as mg/m 2, respectively, did not reveal any teratogenic potential associated with sotalol.

In pregnant rats, sotalol doses administered during organogenesis at approximately15 times the MRHD as mg/m 2, increased the number of early resorptions, while no increase in early resorptions was noted at 2 times the MRHD as mg/m 2.

In reproductive studies in rabbits, a sotalol dose (160 mg/kg/day) at 5 times the MRHD as mg/m 2 produced a slight increase in fetal death, and maternal toxicity. However, one study from published data reported an increase in fetal deaths in rabbits receiving a single dose (50 mg/kg) at 2 times the MRHD as mg/m 2 as on gestation day 14.

Risk Summary

Limited available data from published literature report that sotalol is present in human milk. The estimated daily infant dose of sotalol received from breastmilk is 0.8-3.4 mg/kg, estimated at 22 to 25.5% of the maternal weight-adjusted dosage of sotalol (see Data). The amount of the drug in breast milk is similar to the neonatal therapeutic dosage. Therefore, there is potential for bradycardia and other symptoms of beta blockade such as dry mouth, skin or eyes, diarrhea or constipation in the breastfed infant. There is no information regarding the effects of sotalol on milk production. Because of the potential serious adverse reactions to the breastfed child and the high level of sotalol in breast milk, advise women not to breastfeed while on treatment with sotalol.

Data

Sotalol is present in human milk in high levels. A prospective study evaluated 20 paired samples of breast milk and maternal blood from 5 mothers who elected to breastfeed. Breast milk samples had a mean sotalol concentration of 10.5 µg/mL (± 1.1 µg/mL; range: 4.8 to 20.2 µg/mL) compared to a simultaneous mean maternal plasma concentration of 2.3 µg/mL (± 0.3 µg/mL; range: 0.8 to 5.0 µg/mL). The mean milk plasma ratio was 5.4:1 (range: 2.2 to 8.8). The estimated daily infant dose was 0.8-3.4 mg/kg, estimated at 22 to 25.5% of the maternal weight-adjusted dosage of sotalol. This is similar to recommended therapeutic dose in neonates. None of the mothers reported any adverse reactions in the breastfed infant. 

Infertility

Based on the published literature, beta blockers (including sotalol) may cause erectile dysfunction.

The safety and effectiveness of sotalol in children has not been established. However, the Class III electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the effects (QTc interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 years old [see Clinical Pharmacology ( 12.3) ].

Overdosage with sotalol may be fatal.

{ "type": "p", "children": [], "text": "Overdosage with sotalol may be fatal." }

Symptoms and Treatment of Overdosage: The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia. In cases of massive intentional overdosage (2-16 grams) of sotalol the following clinical findings were seen: hypotension, bradycardia, cardiac asystole, prolongation of QT interval, Torsade de Pointes, ventricular tachycardia, and premature ventricular complexes. If overdosage occurs, therapy with sotalol should be discontinued and the patient observed closely. Because of the lack of protein binding, hemodialysis is useful for reducing sotalol plasma concentrations. Patients should be carefully observed until QT intervals are normalized and the heart rate returns to levels >50 bpm. The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination phase (half-life of 30 hours) thought to be due to a temporary reduction of renal function caused by the hypotension. In addition, if required, the following therapeutic measures are suggested:

{ "type": "p", "children": [], "text": "\nSymptoms and Treatment of Overdosage: The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia. In cases of massive intentional overdosage (2-16 grams) of sotalol the following clinical findings were seen: hypotension, bradycardia, cardiac asystole, prolongation of QT interval, Torsade de Pointes, ventricular tachycardia, and premature ventricular complexes. If overdosage occurs, therapy with sotalol should be discontinued and the patient observed closely. Because of the lack of protein binding, hemodialysis is useful for reducing sotalol plasma concentrations. Patients should be carefully observed until QT intervals are normalized and the heart rate returns to levels >50 bpm. The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination phase (half-life of 30 hours) thought to be due to a temporary reduction of renal function caused by the hypotension. In addition, if required, the following therapeutic measures are suggested:\n \n\n " }

<div class="scrollingtable"><table width="100%"> <caption> <span></span> </caption> <tbody class="Headless"> <tr class="First"> <td> <p class="First"> Bradycardia or </p> <p> Cardiac  Asystole:</p> </td><td align="left"> <p class="First">Atropine, another anticholinergic drug, a beta-adrenergic agonist or </p> <p>transvenous cardiac pacing.</p> </td> </tr> <tr> <td> Heart Block:</td><td align="left">(second and third degree) transvenous cardiac pacemaker.</td> </tr> <tr> <td> Hypotension:</td><td>(depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be useful.</td> </tr> <tr> <td> Bronchospasm:</td><td>Aminophylline or aerosol beta-2-receptor stimulant. Higher than normal doses of beta-2 stimulus may be required.</td> </tr> <tr class="Last"> <td> Torsade de  Pointes:</td><td>DC cardioversion, magnesium sulfate, potassium replacement. Once Torsade de Pointes is terminated, transvenous cardiac pacing or an isoproterenol infusion to increase heart rate can be employed.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span></span>\n</caption>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td>\n<p class=\"First\"> Bradycardia or </p>\n<p> Cardiac  Asystole:</p>\n</td><td align=\"left\">\n<p class=\"First\">Atropine, another anticholinergic drug, a beta-adrenergic agonist or </p>\n<p>transvenous cardiac pacing.</p>\n</td>\n</tr>\n<tr>\n<td> Heart Block:</td><td align=\"left\">(second and third degree) transvenous cardiac pacemaker.</td>\n</tr>\n<tr>\n<td> Hypotension:</td><td>(depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be useful.</td>\n</tr>\n<tr>\n<td> Bronchospasm:</td><td>Aminophylline or aerosol beta-2-receptor stimulant. Higher than normal doses of beta-2 stimulus may be required.</td>\n</tr>\n<tr class=\"Last\">\n<td> Torsade de  Pointes:</td><td>DC cardioversion, magnesium sulfate, potassium replacement. Once Torsade de Pointes is terminated, transvenous cardiac pacing or an isoproterenol infusion to increase heart rate can be employed.</td>\n</tr>\n</tbody>\n</table></div>" }

Sotalol hydrochloride injection is an aqueous formulation of sotalol hydrochloride for intravenous use. Sotalol is an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties.

{ "type": "p", "children": [], "text": "Sotalol hydrochloride injection is an aqueous formulation of sotalol hydrochloride for intravenous use. Sotalol is an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties." }

Sotalol hydrochloride is a white, crystalline solid with a molecular weight of 308.8. It is hydrophilic, soluble in water, propylene glycol and ethanol, but is only slightly soluble in chloroform. Chemically, sotalol hydrochloride is d, l- N - [4-[1-hydroxy-2-[(1-methylethyl) amino] ethyl] phenyl] methane-sulfonamide monohydrochloride. The molecular formula is C 12 H 20 N 2 O 3S•HCl and is represented by the following structural formula:

{ "type": "p", "children": [], "text": "Sotalol hydrochloride is a white, crystalline solid with a molecular weight of 308.8. It is hydrophilic, soluble in water, propylene glycol and ethanol, but is only slightly soluble in chloroform. Chemically, sotalol hydrochloride is d, l- \n \n \n N - [4-[1-hydroxy-2-[(1-methylethyl) amino] ethyl] phenyl] methane-sulfonamide monohydrochloride. The molecular formula is C\n \n \n 12 H\n \n \n 20 N\n \n \n 2 O\n \n \n 3S•HCl and is represented by the following structural formula:\n \n\n " }

Intravenous sotalol Injection is supplied as a sterile, clear solution in a 10 mL single-dose vial, for intravenous administration after dilution. Each vial contains 150 mg racemic sotalol hydrochloride (equivalent to 132.8 mg racemic sotalol) in sodium acetate buffer. The sotalol hydrochloride concentration of the formulation is 15 mg/mL. Each mL contains 2.9 mg glacial acetic acid in water for injection as an inactive ingredient. The pH of the injection is adjusted with sodium hydroxide to be between 6.0 and 7.0.

{ "type": "p", "children": [], "text": "Intravenous sotalol Injection is supplied as a sterile, clear solution in a 10 mL single-dose vial, for intravenous administration after dilution. Each vial contains 150 mg racemic sotalol hydrochloride (equivalent to 132.8 mg racemic sotalol) in sodium acetate buffer. The sotalol hydrochloride concentration of the formulation is 15 mg/mL. Each mL contains 2.9 mg glacial acetic acid in water for injection as an inactive ingredient. The pH of the injection is adjusted with sodium hydroxide to be between 6.0 and 7.0." }

Sotalol has both beta-adrenoreceptor 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 similar Class III antiarrhythmic effects, while the l-isomer is responsible for virtually all of the beta-blocking activity. The beta-blocking effect of sotalol is non-cardioselective, half maximal at oral doses of about 80 mg/day and maximal at oral doses between 320 and 640 mg/day. Significant beta-blockade occurs at oral doses as low as 25 mg, significant Class III effects can be seen after a single oral or IV dose of 80 or 75 mg respectively.

Electrophysiology: Sotalol prolongs the plateau phase of the cardiac action potential in the isolated myocyte, as well as in isolated tissue preparations of ventricular or atrial muscle (Class III activity). In intact animals it slows heart rate, decreases AV nodal conduction and increases the refractory periods of atrial and ventricular muscle and conduction tissue.

In man, the Class II (beta-blockade) electrophysiological effects of sotalol include increased sinus cycle length (slowed heart rate), decreased AV nodal conduction, and increased AV nodal refractoriness. The Class III electrophysiological effects in man include prolongation of the atrial and ventricular monophasic action potentials, and effective refractory period prolongation of atrial muscle, ventricular muscle, and atrio-ventricular accessory pathways (when present) in both the anterograde and retrograde directions. With oral doses of 160 to 640 mg/day, the surface ECG shows dose-related mean increases of 40-100 ms in QT and 10-40 ms in QTc.

Twenty-five children in an unblinded, multicenter trial with supraventricular (SVT) and/or ventricular (VT) tachyarrhythmias, aged between 3 days and 12 years (mostly neonates and infants), received an ascending titration regimen with daily doses of 30, 90 and 210 mg/m 2 with dosing every 8 hours for a total of 9 doses. During steady-state, the respective average increases above baseline of the QTc interval were 2, 14, and 29 ms at the 3 dose levels. The respective mean maximum increases in QTc above baseline were 23, 36, and 55 ms. The steady-state percent increases in the RR interval were 3, 9 and 12%. The smallest children (BSA <0.33 m 2) showed a tendency for larger Class III effects (ΔQTc) and an increased frequency of prolongations of the QTc interval compared with children with BSA ≥0.33 m 2. The beta-blocking effects also tended to be greater in the smaller children (BSA<0.33 m 2).

Hemodynamics: In a study of systemic hemodynamic function measured invasively in 12 patients with a mean LV ejection fraction of 37% and ventricular tachycardia (9 sustained and 3 non-sustained), a median dose of 160 mg twice daily of sotalol produced a 28% reduction in heart rate and a 24% decrease in cardiac index at 2 hours post-dosing at steady-state. Concurrently, systemic vascular resistance and stroke volume showed non-significant increases of 25% and 8%, respectively.

Pulmonary capillary wedge pressure increased significantly from 6 to 12 mmHg in the 11 patients who completed the study. Mean arterial pressure, mean pulmonary artery pressure and stroke work index did not significantly change. Exercise and isoproterenol induced tachycardia are antagonized by sotalol, and total peripheral resistance increases by a small amount.

In hypertensive patients, sotalol produces significant reductions in both systolic and diastolic blood pressures. Although sotalol is usually well-tolerated hemodynamically, in patients with marginal cardiac compensation, deterioration in cardiac performance may occur [see Warnings and Precautions ( 5.3)].

The pharmacokinetics of the d and l isomers of sotalol are essentially identical.

Absorption

In healthy subjects, the oral bioavailability of sotalol is >90%. After oral administration, peak plasma concentrations are reached in 2.5 to 4 hours, and steady-state plasma concentrations are attained within 2-3 days (i.e., after 5-6 doses when administered twice daily). Over the oral dosage range 160-640 mg/day, sotalol displays dose proportionality with respect to plasma concentrations. When administered with a standard meal, the absorption of sotalol was reduced by approximately 20% compared to administration in the fasting state.

Distribution

Distribution occurs to a central (plasma) and to a peripheral compartment, with a mean elimination half-life of 12 hours. Dosing every 12 hours results in trough plasma concentrations which are approximately one-half of those at peak.

Sotalol does not bind to plasma proteins and is not metabolized. Sotalol shows very little intersubject variability in plasma levels. Sotalol crosses the blood brain barrier poorly.

Metabolism

Sotalol is not metabolized and is not expected to inhibit or induce any CYP 450 enzymes.

Excretion

Excretion is predominantly via the kidney in the unchanged form, and therefore lower doses are necessary in conditions of renal impairment [see Dosage and Administration ( 2.3)]. Dosing every 12 hours results in trough plasma concentration which are approximately one half of that at peak concentration.

Specific Populations

Geriatric

Age per se does not significantly alter the pharmacokinetics of sotalol, but impaired renal function in geriatric patients can increase the terminal elimination half-life, resulting in increased drug accumulation.

Hepatic Disease

Since sotalol is not subject to first-pass metabolism, patients with hepatic impairment show no alteration in clearance of sotalol.

Pediatric

The combined analysis of two unblinded, multicenter trials (a single dose and a multiple dose study) with 59 children, aged between 3 days and 12 years, showed the pharmacokinetics of sotalol to be first order. A daily dose of 30 mg/ m 2 of sotalol was administered in the single dose study and daily doses of 30, 90 and 210 mg/ m 2 were administered q8h in the multi-dose study. After rapid absorption with peak levels occurring on average between 2-3 hours following administration, sotalol was eliminated with a mean half-life of 9.5 hours. Steady-state was reached after 1-2 days. The average peak to trough concentration ratio was 2. BSA was the most important covariate and more relevant than age for the pharmacokinetics of sotalol. The smallest children (BSA <0.33 m 2) exhibited a greater drug exposure (+59%) than the larger children who showed a uniform drug concentration profile. The intersubject variation for oral clearance was 22%.

Drug-Drug Interactions

Antacids

Administration of oral sotalol within 2 hours of antacids may result in a reduction in Cmax and AUC of 26% and 20%, respectively, and consequently in a 25% reduction in the bradycardic effect at rest. Administration of the antacid two hours after oral sotalol has no effect on the pharmacokinetics or pharmacodynamics of sotalol.

No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.

No evidence of carcinogenic potential was observed in rats during a 24-month study at 137-275 mg/kg/ day (approximately 30 times the maximum recommended human oral dose (MRHD) as mg/kg or 5 times the MRHD as mg/ m 2) or in mice, during a 24-month study at 4141-7122 mg/kg/day (approximately 450- 750 times the MRHD as mg/kg or 36-63 times the MRHD as mg/ m 2).

Sotalol has not been evaluated in any specific assay of mutagenicity or clastogenicity.

No significant reduction in fertility occurred in rats at oral doses of 1000 mg/kg/day (approximately 100 times the MRHD as mg/kg or 9 times the MRHD as mg/ m 2) prior to mating, except for a small reduction in the number of offspring per litter. Reproduction studies in rats and rabbits during organogenesis at 100 and 22 times the MRHD as mg/kg (9 and 7 times the MRHD as mg/ m 2), respectively, did not reveal any teratogenic potential associated with sotalol HCl. In rabbits, a high dose of sotalol HCl (160 mg/kg/day) at 16 times the MRHD as mg/kg (6 times the MRHD as mg/ m 2) produced a slight increase in fetal death likely due to maternal toxicity. Eight times the maximum dose (80 mg/kg/day or 3 times the MRHD as mg/ m 2) did not result in an increased incidence of fetal deaths. In rats, 1000 mg/kg/day sotalol HCl, 100 times the MRHD (18 times the MRHD as mg/ m 2), increased the number of early resorptions, while at 14 times the maximum dose  (2.5 times the MRHD as mg/ m 2), no increase in early resorptions was noted. However, animal reproduction studies are not always predictive of human response.

Sotalol has been studied in life-threatening and less severe arrhythmias. In patients with frequent premature ventricular complexes (VPC), orally administered sotalol was significantly superior to placebo in reducing VPCs, paired VPCs and non-sustained ventricular tachycardia (NSVT); the response was dose-related through 640 mg/day with 80-85% of patients having at least a 75% reduction of VPCs. Sotalol was also superior, at the doses evaluated, to propranolol (40-80 mg TID) and similar to quinidine (200-400 mg QID) in reducing VPCs. In patients with life-threatening arrhythmias [sustained ventricular tachycardia/fibrillation (VT/VF)], sotalol was studied acutely [by suppression of programmed electrical stimulation (PES) induced VT and by suppression of Holter monitor evidence of sustained VT] and, in acute responders, chronically.

In a double-blind, randomized comparison of oral sotalol and procainamide given intravenously (total of 2 mg/kg sotalol vs. 19 mg/kg of procainamide over 90 minutes), sotalol suppressed PES induction in 30% of patients vs. 20% for procainamide (p=0.2).

In a randomized clinical trial [Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) Trial] comparing choice of antiarrhythmic therapy by PES suppression vs. Holter monitor selection (in each case followed by treadmill exercise testing) in patients with a history of sustained VT/VF who were also inducible by PES, the effectiveness acutely and chronically of sotalol was compared with 6 other drugs (procainamide, quinidine, mexiletine, propafenone, and imipramine). Overall response, limited to first randomized drug, was 39% for sotalol and 30% for the pooled other drugs. Acute response rate for first drug randomized using suppression of PES induction was 36% for sotalol vs. a mean of 13% for the other drugs. Using the Holter monitoring endpoint (complete suppression of sustained VT, 90% suppression of NSVT, 80% suppression of VPC pairs, and at least 70% suppression of VPCs), sotalol yielded 41% response vs. 45% for the other drugs combined. Among responders placed on long term therapy identified acutely as effective (by either PES or Holter), sotalol, when compared to the pool of other drugs, had the lowest two-year mortality (13% vs. 22%), the lowest two-year VT recurrence rate (30% vs. 60%), and the lowest withdrawal rate (38% vs. about 75-80%). The most commonly used doses of sotalol in this trial were 320-480 mg/day (66% of patients), with 16% receiving 240 mg/day or less and 18% receiving 640 mg or more.

It cannot be determined, however, in the absence of a controlled comparison of sotalol vs. no pharmacologic treatment (e.g., in patients with implanted defibrillators) whether sotalol response causes improved survival or identifies a population with a good prognosis.

Sotalol has not been shown to enhance survival in patients with ventricular arrhythmias.

Orally administered sotalol has been studied in patients with symptomatic AFIB/AFL in two principal studies, one in patients with primarily paroxysmal AFIB/AFL, the other in patients with primarily chronic AFIB.

In one study, a U.S. multicenter, randomized, placebo-controlled, double-blind, dose-response trial of patients with symptomatic primarily paroxysmal AFIB/AFL, three fixed dose levels of sotalol (80, 120, and 160 mg) twice daily and placebo were compared in 253 patients. In patients with reduced creatinine clearance (40-60 mL/min) the same doses were given once daily. Patients were not randomized for the following reasons: QT >450 ms; creatinine clearance <40 mL/min; intolerance to beta-blockers; bradycardia-tachycardia syndrome in the absence of an implanted pacemaker; AFIB/AFL was asymptomatic or was associated with syncope, embolic CVA or TIA; acute myocardial infarction within the previous 2 months; congestive heart failure; bronchial asthma or other contraindications to beta-blocker therapy; receiving potassium losing diuretics without potassium replacement or without concurrent use of ACE-inhibitors; uncorrected hypokalemia (serum potassium <3.5 mEq/L) or hypomagnesemia (serum magnesium <1.5 mEq/L); received chronic oral amiodarone therapy for >1 month within previous 12 weeks; congenital or acquired long QT syndromes; history of Torsade de Pointes with other antiarrhythmic agents which increase the duration of ventricular repolarization; sinus rate <50 bpm during waking hours; unstable angina pectoris; receiving treatment with other drugs that prolong the QT interval; and AFIB/AFL associated with the Wolff-Parkinson-White (WPW) syndrome. If the QT interval increased to ≥520 ms (or JT ≥430 ms if QRS >100 ms) the drug was discontinued. The patient population in this trial was 64% male, and the mean age was 62 years. No structural heart disease was present in 43% of the patients. Doses were administered once daily in 20% of the patients because of reduced creatinine clearance.

Sotalol was shown to prolong the time to the first symptomatic, ECG-documented recurrence of AFIB/AFL, as well as to reduce the risk of such recurrence at both 6 and 12 months. The 120 mg dose was more effective than 80 mg, but 160 mg did not appear to have an added benefit. Note that these doses were given twice or once daily, depending on renal function. The results are shown in Figure 1 and Tables 4 and 5.

Figure 1. Study 1—Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL Since Randomization

<div class="scrollingtable"><table> <caption> <span>Table 4: Study 1 - Patient Status at 12 Months</span> </caption> <col width="249"/> <col width="96"/> <col width="240"/> <col width="88"/> <col width="76"/> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule"></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Placebo</span></td><td align="center" class="Lrule Rrule Toprule" colspan="3"><span class="Bold">Oral </span><span class="Bold">Sotalol </span><span class="Bold">Dose</span></td> </tr> <tr> <td class="Lrule Rrule"></td><td class="Lrule Rrule Toprule"></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">80 </span><span class="Bold">mg</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">120 </span><span class="Bold">mg</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">160 </span><span class="Bold">mg</span></td> </tr> <tr> <td class="Lrule Rrule Toprule">Randomized</td><td align="center" class="Lrule Rrule Toprule">69</td><td align="center" class="Lrule Rrule Toprule">59</td><td align="center" class="Lrule Rrule Toprule">63</td><td align="center" class="Lrule Rrule Toprule">62</td> </tr> <tr> <td class="Lrule Rrule Toprule">On treatment in NSR at 12 months without recurrence <span class="Sup">*</span></td><td align="center" class="Lrule Rrule Toprule">23%</td><td align="center" class="Lrule Rrule Toprule">22%</td><td align="center" class="Lrule Rrule Toprule">29%</td><td align="center" class="Lrule Rrule Toprule">23%</td> </tr> <tr> <td class="Lrule Rrule Toprule">Recurrence <span class="Sup">*,</span><span class="Sup">†</span></td><td align="center" class="Lrule Rrule Toprule">67%</td><td align="center" class="Lrule Rrule Toprule">58%</td><td align="center" class="Lrule Rrule Toprule">49%</td><td align="center" class="Lrule Rrule Toprule">42%</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule">D/C for AEs</td><td align="center" class="Lrule Rrule Toprule">6%</td><td align="center" class="Lrule Rrule Toprule">12%</td><td align="center" class="Lrule Rrule Toprule">18%</td><td align="center" class="Lrule Rrule Toprule">29%</td> </tr> </tbody> </table></div>

* Symptomatic AFIB/AFL † Efficacy endpoint of Study 1; study treatment stopped.

Note that columns do not add up to 100% due to discontinuations (D/C) for other reasons.

<div class="scrollingtable"><table> <caption> <span>Table 5: Study 1 - Median Time to Recurrence of Symptomatic AFIB/AFL and Relative Risk (vs. Placebo) at 12 Months</span> </caption> <col width="142"/> <col width="141"/> <col width="141"/> <col width="141"/> <col width="141"/> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule"></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Placebo</span></td><td align="center" class="Lrule Rrule Toprule" colspan="3"><span class="Bold">Oral </span><span class="Bold">Sotalol </span><span class="Bold">Dose</span></td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">80 </span><span class="Bold">mg</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">120 </span><span class="Bold">mg</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">160 </span><span class="Bold">mg</span></td> </tr> <tr> <td class="Lrule Rrule Toprule">p-value vs. placebo</td><td class="Lrule Rrule Toprule"></td><td align="center" class="Lrule Rrule Toprule">p=0.325</td><td align="center" class="Lrule Rrule Toprule">p=0.018</td><td align="center" class="Lrule Rrule Toprule">p=0.029</td> </tr> <tr> <td class="Lrule Rrule Toprule">Relative Risk (RR) to placebo</td><td class="Lrule Rrule Toprule"></td><td align="center" class="Lrule Rrule Toprule">0.81</td><td align="center" class="Lrule Rrule Toprule">0.59</td><td align="center" class="Lrule Rrule Toprule">0.59</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule">Median Time to Recurrence (days)</td><td align="center" class="Lrule Rrule Toprule">27</td><td align="center" class="Lrule Rrule Toprule">106</td><td align="center" class="Lrule Rrule Toprule">229</td><td align="center" class="Lrule Rrule Toprule">175</td> </tr> </tbody> </table></div>

Discontinuation because of adverse events was dose related.

In a second multicenter, randomized, placebo-controlled, double-blind study of 6 months duration in 232 patients with chronic AFIB, sotalol was titrated over a dose range from 80 mg/day to 320 mg/day. The patient population of this trial was 70% male with a mean age of 65 years. Structural heart disease was present in 49% of the patients. All patients had chronic AFIB for >2 weeks but <1 year at entry with a mean duration of 4.1 months. Patients were excluded if they had significant electrolyte imbalance, QTc >460 ms, QRS >140 ms, any degree of AV block or functioning pacemaker, uncompensated cardiac failure, asthma, significant renal disease (estimated creatinine clearance <50 mL/min), heart rate <50 bpm, myocardial infarction or open heart surgery in past 2 months, unstable angina, infective endocarditis, active pericarditis or myocarditis, ≥3 DC cardioversions in the past, medications that prolonged QT interval, and previous amiodarone treatment. After successful cardioversion patients were randomized to receive placebo (n=114) or sotalol (n=118), at a starting dose of 80 mg twice daily. If the initial dose was not tolerated it was decreased to 80 mg once daily, but if it was tolerated it was increased to 160 mg twice daily. During the maintenance period 67% of treated patients received a dose of 160 mg twice daily, and the remainder received doses of 80 mg once daily (17%) and 80 mg twice daily (16%).

Figure 2 and Tables 6 and 7 show the results of the trial. There was a longer time to ECG-documented recurrence of AFIB and a reduced risk of recurrence at 6 months compared to placebo.

<div class="scrollingtable"><table> <caption> <span>Table 6: Study 2 - Patient Status at 6 Months</span> </caption> <col width="283"/> <col width="282"/> <col width="141"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule"><span class="Bold">Randomized</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Oral</span><span class="Bold">Sotalol</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Placebo</span></td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">118</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">114</span></td> </tr> <tr> <td class="Lrule Rrule Toprule">On treatment in NSR at 6 months without recurrence <span class="Sup">*</span></td><td align="center" class="Lrule Rrule Toprule">45%</td><td align="center" class="Lrule Rrule Toprule">29%</td> </tr> <tr> <td class="Lrule Rrule Toprule">Recurrence <span class="Sup">*,</span><span class="Sup">†</span></td><td align="center" class="Lrule Rrule Toprule">49%</td><td align="center" class="Lrule Rrule Toprule">67%</td> </tr> <tr> <td class="Lrule Rrule Toprule">D/C for AEs</td><td align="center" class="Lrule Rrule Toprule">6%</td><td align="center" class="Lrule Rrule Toprule">3%</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule">Death</td><td class="Lrule Rrule Toprule"></td><td align="center" class="Lrule Rrule Toprule">1%</td> </tr> </tbody> </table></div>

* Symptomatic or asymptomatic AFIB/AFL † Efficacy endpoint of Study 2; study treatment stopped.

<div class="scrollingtable"><table> <caption> <span>Table 7: Study 2 - Median Time to Recurrence of Symptomatic AFIB/AFL/Death and Relative Risk (vs. Placebo) at 6 Months</span> </caption> <col width="226"/> <col width="226"/> <col width="113"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule"><span class="Bold">p-value </span><span class="Bold">vs. </span><span class="Bold">placebo</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Oral </span><span class="Bold">Sotalol</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Placebo</span></td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">p=0.002</span></td><td class="Lrule Rrule Toprule"></td> </tr> <tr> <td class="Lrule Rrule Toprule">Relative Risk (RR) to placebo Median time to recurrence (days)</td><td align="center" class="Lrule Rrule Toprule">0.55</td><td class="Lrule Rrule Toprule"></td> </tr> <tr class="Last"> <td class="Lrule Rrule"></td><td align="center" class="Lrule Rrule Toprule">&gt;180</td><td align="center" class="Lrule Rrule Toprule"> <p class="First">44</p> </td> </tr> </tbody> </table></div>

Figure 2. Study 2—Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL/Death Since Randomization

In a multicenter double-blind randomized study reported by Julian et al, the effect of sotalol 320 mg once daily was compared with that of placebo in 1456 patients (randomized 3:2, sotalol to placebo) surviving an acute myocardial infarction (MI). Treatment was started 5-14 days after infarction. Patients were followed for 12 months. The mortality rate was 7.3% in the sotalol group and 8.9% in the placebo group, not a statistically significant difference. Although the results do not show evidence of a benefit of sotalol in this population, they do not show an added risk in post MI patients receiving sotalol. There was, however, a suggestion of an early (i.e., first 10 days) excess mortality (3% on sotalol vs. 2% on placebo).

In a second small trial (n=17 randomized to sotalol) where sotalol was administered at high doses (e.g., 320 mg twice daily) to high-risk post-infarction patients (ejection fraction <40% and either >10 VPC/hr or VT on Holter), there were 4 fatalities and 3 serious hemodynamic/electrical adverse events within two weeks of initiating sotalol.

Computer-based simulations incorporating sotalol dose-exposure-QTc relationships were used to derive the intravenous loading doses. Based on these simulations, the intravenous loading dose in a typical patient across each of the renal function categories is expected to achieve steady state concentration faster compared to the conventional oral dosing. A cartoon showing the pharmacokinetic profile in a typical patient for an intravenous loading dose followed by subsequent oral doses is shown in Figure 3.

Figure 3: Illustrative pharmacokinetic profile for an intravenous loading dose followed by subsequent oral doses in a typical patient.

Sotalol injection is supplied in 10 mL single-dose vials, each containing 150 mg of sotalol hydrochloride as a clear solution (15 mg/mL).

{ "type": "p", "children": [], "text": "Sotalol injection is supplied in 10 mL single-dose vials, each containing 150 mg of sotalol hydrochloride as a clear solution (15 mg/mL)." }

NDC 69724-112-10 carton containing one 10 mL vial

{ "type": "p", "children": [], "text": "NDC 69724-112-10\n \n\ncarton containing one 10 mL vial\n " }

Store at 20° to 25°C (68° to 77°F); excursions permitted 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature.] Protect from freezing and light.

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F); excursions permitted 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature.] Protect from freezing and light." }

Risk of hypoglycemia

{ "type": "p", "children": [], "text": "\nRisk of hypoglycemia\n" }

Inform parents or caregivers that there is a risk of hypoglycemia when sotalol is given to patients who are fasting or who are vomiting. Inform patients to notify their healthcare provider if they experience symptoms of hypoglycemia. [ See Warnings and Precautions ( 5.7) ].

{ "type": "p", "children": [], "text": "Inform parents or caregivers that there is a risk of hypoglycemia when sotalol is given to patients who are fasting or who are vomiting. Inform patients to notify their healthcare provider if they experience symptoms of hypoglycemia. [\n See Warnings and Precautions (\n 5.7)\n ].\n " }

Manufactured by: Mylan Institutional Galway, Ireland

{ "type": "p", "children": [], "text": "Manufactured by:\n \nMylan Institutional\n \nGalway, Ireland\n " }

Manufactured for: ALTATHERA Pharmaceuticals LLC Chicago, IL 60606 U.S.A.

{ "type": "p", "children": [], "text": "Manufactured for:\n \nALTATHERA Pharmaceuticals LLC\n \nChicago, IL 60606 U.S.A.\n " }

NDC 69724-112-10

{ "type": "p", "children": [], "text": "\nNDC 69724-112-10\n" }

Sotalol Hydrochloride Injection

{ "type": "p", "children": [], "text": "\nSotalol Hydrochloride Injection\n" }

150 mg/ 10mL

{ "type": "p", "children": [], "text": "\n150 mg/ 10mL\n" }

(15mg/mL)

{ "type": "p", "children": [], "text": "\n(15mg/mL)\n" }

(13.3 mg/mL racemic sotalol)

{ "type": "p", "children": [], "text": "\n(13.3 mg/mL racemic sotalol)\n" }

For Intravenous Use Only

{ "type": "p", "children": [], "text": "\nFor Intravenous Use Only\n" }

Rx Only

{ "type": "p", "children": [], "text": "\nRx Only\n" }

Single-Dose Vial

{ "type": "p", "children": [], "text": "\nSingle-Dose Vial\n" }

SOTYLIZE is indicated for the treatment of documented, life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia.

Limitation of Use

SOTYLIZE has not been shown to enhance survival in patients with life-threatening ventricular arrhythmias.

SOTYLIZE is indicated for the maintenance of normal sinus rhythm [delay in time to recurrence of atrial fibrillation/atrial flutter (AFIB/AFL)] in patients with highly symptomatic AFIB/AFL who are currently in sinus rhythm.

Limitation of Use

Because sotalol can cause life-threatening ventricular arrhythmias, reserve its use for patients in whom AFIB/AFL is highly symptomatic. Patients with paroxysmal AFIB that is easily reversed (by Valsalva maneuver, for example) should usually not be given SOTYLIZE.

Withdraw other antiarrhythmic therapy before starting SOTYLIZE and monitor for a minimum of 2 to 3 plasma half-lives prior to initiating SOTYLIZE therapy if the patient's clinical condition permits [see Drug Interactions (7)].

Hospitalize patients being initiated or re-initiated on sotalol for at least 3 days or until steady-state drug levels are achieved in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Initiate oral sotalol therapy in the presence of personnel trained in the management of serious arrhythmias. Perform a baseline ECG to determine the QT interval and measure and normalize serum potassium and magnesium levels before initiating therapy. Measure serum creatinine and calculate an estimated creatinine clearance in order to establish the appropriate dosing interval. Monitor QTc 2 to 4 hours after each uptitration in dose.

Discharge patients on sotalol therapy from an in-patient setting with an adequate supply of sotalol to allow uninterrupted therapy until the patient can fill a sotalol prescription.

Advise patients who miss a dose to take the next dose at the usual time. Do not double the dose or shorten the dosing interval.

The recommended initial dose is 80 mg twice daily. This dose may be increased in increments of 80 mg per day every 3 days provided the QTc <500 msec [see Warning and Precautions (5.1)]. Continually monitor patients until steady state blood levels are achieved. In most patients, a therapeutic response is obtained at a total daily dose of 160 to 320 mg/day, given in two or three divided doses. Oral doses as high as 480 to 640 mg once or twice a day have been utilized in patients with refractory life-threatening arrhythmias.

The recommended initial dose is 80 mg twice daily. This dose may be increased in increments of 80 mg per day every 3 days provided the QTc ˂500 msec [see Warnings and Precautions (5.1)]. Continually monitor patients until steady state blood levels are achieved. Most patients will have a satisfactory response with 120 mg twice daily. Initiation of sotalol in patients with QTc ˃450 msec is contraindicated [see Contraindication (4)].

Use the same precautionary measures for children as you would use for adults when initiating and re-initiating sotalol treatment.

For Children Aged About 2 Years and Older

For children aged about 2 years and older with normal renal function, doses normalized for body surface area are appropriate for both initial and incremental dosing. Since the Class III potency in children is not very different from that in adults, reaching plasma concentrations that occur within the adult dose range is an appropriate guide [see Clinical Pharmacology (12.1, 12.3)].

For initiation of treatment, 1.2 mg/kg three times a day (3.6 mg/kg total daily dose) is approximately equivalent to the initial 160 mg total daily dose for adults. Subsequent titration to a maximum of 2.4 mg/kg three times a day (approximately equivalent to the 360 mg total daily dose for adults) can then occur. Titration should be guided by clinical response, heart rate, and QTc, with increased dosing being preferably conducted in-hospital. Allow at least 36 hours between dose increments to attain steady-state plasma concentrations of sotalol in patients with age-adjusted normal renal function.

For Children Aged About 2 Years or Younger

For children aged 2 years or younger, the pediatric dosage should be reduced by a factor that depends upon age, as shown in the following graph (age plotted on a logarithmic scale in months):

<div class="scrollingtable"><table class="Noautorules" width="90%"> <col align="center" valign="top" width="100%"/> <tfoot> <tr> <td align="left" valign="top">For a child aged 1 month, multiply the starting dose by 0.7; the initial starting dose would be (1.2 mg/kg × 0.7)=0.8 mg/kg, administered three times daily. For a child aged about 1 week, multiply the initial starting dose by 0.3; the starting dose would be (1.2 mg/kg × 0.3)=0.4 mg/kg. Use similar calculations for dose titration.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center"><img alt="Image" src="/dailymed/image.cfm?name=sotalol-01.jpg&amp;setid=1f33f900-0777-4a92-a7f7-00cf3d57d95c"/></td> </tr> </tbody> </table></div>

Adults

In any age group with decreased renal function, sotalol doses should be lowered or the intervals between doses increased. It will take much longer to reach steady-state with any dose and/or frequency of administration. Closely monitor heart rate and QTc.

Dose escalations in renal impairment should be done after administration of at least 5 doses at appropriate intervals (Table 1). Sotalol is partly removed by dialysis; specific advice is unavailable on dosing patients on dialysis.

Administer the initial dose of 80 mg and subsequent doses at the intervals listed in Table 1.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1: Dosing Intervals in Renal Impairment</span> </caption> <col align="center" valign="middle" width="50%"/> <col align="center" valign="middle" width="50%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Creatinine Clearance mL/min</th><th align="center" class="Rrule">Dosing Interval (hours)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule"><span class="Bold">&gt;</span>60</td><td align="center" class="Rrule">12</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">30-59</td><td align="center" class="Rrule">24</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">10-29</td><td align="center" class="Rrule">36-48</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">&lt;10</td><td align="center" class="Rrule">Dose should be individualized</td> </tr> </tbody> </table></div>

Oral solution: 5 mg/mL, in 250 mL or 480 mL bottles.

{ "type": "p", "children": [], "text": "Oral solution: 5 mg/mL, in 250 mL or 480 mL bottles." }

For the treatment of AFIB/AFL or ventricular arrhythmias, SOTYLIZE is contraindicated in patients with:

{ "type": "p", "children": [], "text": "For the treatment of AFIB/AFL or ventricular arrhythmias, SOTYLIZE is contraindicated in patients with:" }

{ "type": "ul", "children": [ "Baseline QT interval ˃450 msec", "Sinus bradycardia, sick sinus syndrome, second and third degree AV block, unless a functioning pacemaker is present", "Congenital or acquired long QT syndromes", "Cardiogenic shock or decompensated heart failure", "Serum potassium <4 mEq/L", "Bronchial asthma or related bronchospastic conditions", "Hypersensitivity to sotalol" ], "text": "" }

SOTYLIZE can cause serious and potentially fatal ventricular arrhythmias such as sustained VT/VF, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. Factors such as reduced creatinine clearance, female sex, higher doses, reduced heart rate, and history of sustained VT/VF or heart failure increases the risk of TdP. The risk of TdP can be reduced by adjustment of the sotalol dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval [see Dosage and Administration (2.1)].

Correct hypokalemia or hypomagnesemia prior to initiating SOTYLIZE, as these conditions can exaggerate the degree of QT prolongation, and increase the potential for Torsade de Pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or patients receiving concomitant diuretic drugs.

Proarrhythmic events must be anticipated not only on initiating therapy, but with every upward dose adjustment [see Dosage and Administration (2.1)].

Avoid use with other drugs known to cause QT prolongation [see Drug Interactions (7.1)].

Sinus bradycardia (heart rate less than 50 bpm) occurred in 13% of patients receiving sotalol in clinical trials, and led to discontinuation in about 3% of patients. Bradycardia itself increases the risk of Torsade de Pointes. Sinus pause, sinus arrest and sinus node dysfunction occur in less than 1% of patients. The incidence of 2nd- or 3rd-degree AV block is approximately 1%.

SOTYLIZE is contraindicated in patients with sick sinus syndrome because it may cause sinus bradycardia, sinus pauses or sinus arrest.

Sotalol produces significant reductions in both systolic and diastolic blood pressures and may result in hypotension. Monitor hemodynamics in patients with marginal cardiac compensation.

New onset or worsening heart failure may occur during initiation or uptitration of sotalol because of its beta-blocking effects. Monitor for signs and symptoms of heart failure and discontinue treatment if symptoms occur.

Following abrupt cessation of therapy with beta-adrenergic blockers, exacerbations of angina pectoris and myocardial infarction may occur. When discontinuing chronically administered SOTYLIZE, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 to 2 weeks, if possible, and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, treat appropriately and consider use of an alternative beta-blocker. Warn patients not to interrupt therapy without their physician's advice. Because coronary artery disease is common, but may be unrecognized, the abrupt discontinuation of sotalol may unmask latent coronary insufficiency.

Patients with bronchospastic diseases (for example chronic bronchitis and emphysema) should not receive beta-blockers. If SOTYLIZE is to be administered, use the smallest effective dose, to minimize inhibition of bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta-2-receptors.

Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). Monitor blood sugar, as appropriate.

Avoid abrupt withdrawal of beta-blockers in patients with thyroid disease because it may lead to an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Beta-blockers may mask certain clinical signs (for example, tachycardia) of hyperthyroidism.

While taking beta-blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction.

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions that are clearly related to sotalol are those which are typical of its Class II (beta-blocking) and Class III (cardiac action potential duration prolongation) effects and are dose related.

Ventricular Arrhythmias

Serious Adverse Reactions

SOTYLIZE can cause serious and potentially fatal ventricular arrhythmias such as sustained VT/VF, primarily Torsade de Pointes (TdP). [see Warnings and Precautions (5.1)]. The effect on QT and the risk of Torsade de Pointes are both dose related.

Pediatric Patients

In an unblinded multicenter trial of 25 pediatric patients aged ≤ 1 month to 12 years with SVT and/or VT receiving daily doses of 30, 90, and 210 mg/m2 with dosing every 8 hours for a total of 9 doses, no Torsade de Pointes or other serious new arrhythmias were observed. The clinical trial safety profile in pediatric patients was similar to that in adult patients. Both the Class III and beta-blocking effects of sotalol were linearly related to the plasma concentration [see Clinical Pharmacology (12.2)].

Atrial Fibrillation/Atrial Flutter

Placebo-controlled Clinical Trials

In a pooled clinical trial population consisting of 4 placebo-controlled studies with 275 patients with atrial fibrillation (AFIB/atrial flutter (AFL) treated with 160 to 320 mg of oral sotalol, the following adverse events presented in Table 2 occurred in at least 2% of placebo-treated patients and at a lesser rate than oral sotalol-treated patients. The data are presented by incidence reactions in the oral sotalol and placebo groups by body system and daily dose.

<div class="scrollingtable"><table width="65%"> <caption> <span>Table 2: Incidence (%) of Common Adverse Reactions (≥2% in the Placebo Group and Less Frequent Than in the Sotalol Groups) in Four Placebo-controlled Studies of Patients with AFIB/AFL </span> </caption> <col align="left" valign="top" width="49"/> <col align="center" valign="middle" width="17%"/> <col align="center" valign="middle" width="17%"/> <col align="center" valign="middle" width="17%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Placebo</th><th align="center" class="Rrule" colspan="2">Oral Sotalol <br/>Total Daily Dose</th> </tr> <tr class="Botrule Last"> <th align="left" class="Lrule Rrule">Adverse Reaction</th><th align="center" class="Rrule">N=282<br/>(%)</th><th align="center" class="Rrule">160-240<br/>N=153<br/>(%)</th><th align="center" class="Rrule">&gt;240-320<br/>N=122<br/>(%)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Bradycardia</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">12</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Diarrhea</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nausea/Vomiting</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> </td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Fatigue</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">20</td><td align="center" class="Rrule">19</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Hyperhidrosis</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Weakness</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Dizziness</td><td align="center" class="Rrule">12</td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">13</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">12</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Dyspnea</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">10</td> </tr> </tbody> </table></div>

Overall, discontinuation because of unacceptable adverse events was necessary in 17% of the patients and occurred in 10% of patients less than two weeks after starting treatment. The most common adverse reactions leading to discontinuation of oral sotalol were: fatigue 4.6%, bradycardia 2.4%, proarrhythmia 2.2%, dyspnea 2%, and QT interval prolongation 1.4%.

The following adverse reactions have been identified during post-approval use of sotalol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure:

emotional liability, slightly clouded sensorium, incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity reaction, fever, pulmonary edema, hyperlipidemia, myalgia, pruritus, alopecia.

Discontinue Class I or Class III antiarrhythmic agents for at least three half-lives prior to dosing with sotalol. Class Ia antiarrhythmic drugs such as disopyramide, quinidine and procainamide and other Class III drugs (for example, amiodarone) are not recommended as concomitant therapy with sotalol because of their potential to prolong refractoriness [see Warnings and Precautions (5.1)].

Digitalis glycosides, diltiazem, verapamil, and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use with negative chronotropes can increase the risk of bradycardia or hypotension.

Concomitant use of catecholamine-depleting drugs, such as reserpine and guanethidine, with a beta-blocker may produce an excessive reduction of resting sympathetic nervous tone. Monitor such patients for hypotension and/or marked bradycardia which may produce syncope.

Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment [see Warnings and Precautions 5.7]

Beta-agonists such as albuterol, terbutaline and isoproterenol may have to be administered in increased dosages when used concomitantly with sotalol.

Concomitant use with sotalol increases the risk of bradycardia and AV block. Because beta-blockers may potentiate the rebound hypertension sometimes observed after clonidine discontinuation, withdraw sotalol several days before the gradual withdrawal of clonidine to reduce the risk of rebound hypertension.

Avoid administration of oral sotalol within 2 hours of antacids containing aluminum oxide and magnesium hydroxide.

The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by flourimetric or photometric methods.

Risk Summary

Both the untreated underlying condition in pregnancy and the use of sotalol in pregnancy cause adverse outcomes to the mother and fetus/neonate (see Clinical Considerations). In animal reproduction studies in rats, early resorptions were increased at 15 times the maximum recommended human dose (MRHD). In rabbits an increase in fetal death was observed at 2 times the MRHD administered as single dose. Sotalol did not reveal any teratogenic potential in rats or rabbits at 15 and 2 times the MRHD respectively (see Data).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the United States (U.S.) general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

The incidence of VT is increased and may be more symptomatic during pregnancy. Most tachycardia episodes are initiated by ectopic beats and the occurrence of arrhythmia episodes may, therefore, increase during pregnancy. Breakthrough arrhythmias may also occur during pregnancy, as therapeutic treatment levels may be difficult to maintain due to the increased volume of distribution and increased drug metabolism inherent in the pregnant state.

Fetal/Neonatal Adverse Reactions

Sotalol has been shown to cross the placenta and is found in amniotic fluid. From published observational studies, the potential fetal adverse effects of sotalol use during pregnancy are growth restriction, transient fetal bradycardia, hyperbilirubinemia, hypoglycemia, uterine contractions, and possible intrauterine death. Sotalol may have a greater effect on QT prolongation in the immature heart than in the adult heart, and therefore, conveys an increased risk of serious fetal arrhythmia and/or possible intrauterine death. Monitor newborns for symptoms and adverse reactions associated with beta-blockers.

Labor or Delivery

Generally, risk of arrhythmias increases during labor and delivery process; therefore, considering the proarrhythmia potential of the drug, patients treated with sotalol should be monitored continuously during labor and delivery.

Data

Animal Data

Reproduction studies in rats and rabbits administered sotalol during organogenesis at 15 times and 2 times the MRHD as mg/m2, respectively, did not reveal any teratogenic potential associated with sotalol.

In pregnant rats, sotalol doses administered during organogenesis at approximately 15 times the MRHD as mg/m2, increased the number of early resorptions, while no increase in early resorptions was noted at 2 times the MRHD as mg/m2.

In reproductive studies in rabbits, a sotalol dose (160 mg/kg/day) at 5 times the MRHD as mg/m2 produced a slight increase in fetal death, and maternal toxicity. However, one study from published data reported an increase in fetal deaths in rabbits receiving a single dose (50 mg/kg) at 2 times the MRHD as mg/m2 on gestation day 14.

Risk Summary

Limited available data from published literature report that sotalol is present in human milk. The estimated daily infant dose of sotalol received from breastmilk is 0.8-3.4 mg/kg, estimated at 22 to 25.5% of the maternal weight-adjusted dosage of SOTYLIZE (see Data). The amount of drug in breast milk is similar to the neonatal therapeutic dosage. Therefore, there is potential for bradycardia and other symptoms from beta-blockers such as dry mouth, skin or eyes, diarrhea or constipation in the breastfed infant. There is no information regarding the effects of sotalol on milk production. Because of the potential serious adverse reactions to the breastfed child and high level of sotalol in breast milk, advise women not to breastfeed while on treatment with SOTYLIZE.

Data

Sotalol is present in human milk in high levels. A prospective study evaluated 20 paired samples of breast milk and maternal blood from 5 mothers who elected to breastfeed. Breast milk samples had a mean sotalol concentration of 10.5 g µg/mL (± 1.1 µg/mL; range: 4.8 to 20.2 µg/mL compared to a simultaneous mean maternal plasma concentration of 2.3 µg/mL (± 0.3 µg/mL; range: 0.8 to 5.0 µg/mL). The mean milk plasma ratio was 5:4:1 (range: 2.2 to 8.8.). The estimated daily infant dose was 0.8 -3.4 mg/kg, estimated at 22 to 25.5% of the maternal weight-adjusted dosage of sotalol. This is similar to recommended therapeutic dose in neonates. None of the mothers reported any adverse reactions in the breastfed infant.

Infertility

Based on the published literature, beta-blockers (including sotalol) may cause erectile dysfunction.

The safety and effectiveness of sotalol in children have not been established. However, the Class III electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the effects (QTc interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 years old [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2)].

Associated side effects of sotalol use in pediatric patients are those typical of a beta-blocking agent, and lead to discontinuation of the drug in 3 to 6% of patients. As in adults, the Class III antiarrhythmic action of sotalol in pediatric patients is associated with a significant proarrhythmic potential for adverse effects. In pediatric patients, the incidence of proarrhythmic side effects of sotalol varies from 0 to 22%; however, sotalol-induced Torsade de Pointes tachycardias are observed less frequently in the pediatric population.

Proarrhythmic effects of sotalol in pediatric patients included increased ventricular ectopy and exacerbation of bradycardia, the latter predominantly in patients with sinus node dysfunction following surgery for congenital cardiac defects. Bradycardia may require emergency pacemaker implantation. Close in-patient monitoring is recommended for several days.

Sotalol is mainly eliminated via the kidneys. Adjust dosing intervals based on creatinine clearance [see Dosage and Administration (2.5)].

Symptoms and Treatment of Overdosage:

The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia. In cases of massive intentional overdosage (2 to16 grams) of sotalol the following clinical findings were seen: hypotension, bradycardia, cardiac asystole, prolongation of QT interval, Torsade de Pointes, ventricular tachycardia, and premature ventricular complexes. If overdosage occurs, therapy with sotalol should be discontinued and the patient observed closely. Because of the lack of protein binding, hemodialysis is useful for reducing sotalol plasma concentrations. Patients should be carefully observed until QT intervals are normalized and the heart rate returns to levels >50 bpm.

The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination phase (half-life of 30 hours) thought to be due to a temporary reduction of renal function caused by the hypotension. In addition, if required, the following therapeutic measures are suggested:

Bradycardia or Cardiac Asystole: Atropine, another anticholinergic drug, a beta-adrenergic agonist or transvenous cardiac pacing.

Heart Block: (second and third degree) transvenous cardiac pacemaker.

Hypotension: (depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be useful.

Bronchospasm: Aminophylline or aerosol beta-2-receptor stimulant. Higher than normal doses of beta-2-receptor stimulants may be required.

Torsade de Pointes: DC cardioversion, transvenous cardiac pacing, epinephrine, magnesium sulfate.

SOTYLIZE is an aqueous solution containing sotalol hydrochloride.

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Sotalol hydrochloride is a white, crystalline solid with a molecular weight of 308.8. It is hydrophilic, soluble in water, propylene glycol and ethanol, but is only slightly soluble in chloroform. Chemically, sotalol hydrochloride is d,l-N-[4-[1-hydroxy-2-[(1-methylethyl) amino]ethyl]phenyl]methane-sulfonamide monohydrochloride. The molecular formula is C12H20N2O3S HCl and is represented by the following structural formula:

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SOTYLIZE is a grape-flavored aqueous solution. Each mL contains 5 mg sotalol HCl. Inactive ingredients are sodium citrate, citric acid, sucralose, sodium benzoate and purified water.

{ "type": "p", "children": [], "text": "SOTYLIZE is a grape-flavored aqueous solution. Each mL contains 5 mg sotalol HCl. Inactive ingredients are sodium citrate, citric acid, sucralose, sodium benzoate and purified water." }

Sotalol has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. The two isomers of sotalol have similar Class III antiarrhythmic effects, while the l-isomer is responsible for virtually all of the beta-blocking activity. The beta-blocking effect of sotalol is non-cardioselective, half maximal at an oral dose of about 80 mg/day and maximal at doses between 320 and 640 mg/day. Sotalol does not have partial agonist or membrane stabilizing activity. Although significant beta-blocker occurs at oral doses as low as 25 mg, significant Class III effects are seen only at daily doses of 160 mg and above.

In children, a Class III electrophysiological effect can be seen at daily doses of 210 mg/m2 body surface area (BSA). A reduction of the resting heart rate due to the beta-blocking effect of sotalol is observed at daily doses ≥90 mg/m2 in children.

Cardiac Electrophysiological Effects

Sotalol hydrochloride prolongs the plateau phase of the cardiac action potential in the isolated myocyte, as well as in isolated tissue preparations of ventricular or atrial muscle (Class III activity). In intact animals it slows heart rate, decreases AV nodal conduction and increases the refractory periods of atrial and ventricular muscle and conduction tissue.

In human, the Class II (beta-blockers) electrophysiological effects of sotalol are manifested by increased sinus cycle length (slowed heart rate), decreased AV nodal conduction and increased AV nodal refractoriness. The Class III electrophysiological effects in man include prolongation of the atrial and ventricular monophasic action potentials, and effective refractory period prolongation of atrial muscle, ventricular muscle, and atrio-ventricular accessory pathways (where present) in both the anterograde and retrograde directions. With oral doses of 160 to 640 mg/day, the surface ECG shows dose-related mean increases of 40 to100 msec in QT and 10 to40 msec in QTc [see Warning and Precautions (5.1]). No significant alteration in QRS interval was observed.

In a small study (n=25) of patients with implanted defibrillators treated concurrently with sotalol, the average defibrillatory threshold was 6 joules (range 2 to15 joules) compared to a mean of 16 joules for a non-randomized comparative group primarily receiving amiodarone.

Twenty-five children in an unblinded, multicenter trial with supraventricular (SVT) and/or ventricular (VT) tachyarrhythmias, aged between 3 days and 12 years (mostly neonates and infants), received an ascending titration regimen with daily doses of 30, 90 and 210 mg/m2 with dosing every 8 hours for a total of 9 doses. During steady-state, the respective average increases above baseline of the QTc interval, in msec (%), were 2, 14, and 29 msec at the 3 dose levels. The respective mean maximum increases above baseline of the QTc interval were 23, 36, and 55 msec at the 3 dose levels. The steady-state percent increases in the RR interval were 3, 9 and 12%. The smallest children (BSA<0.33m2) showed a tendency for larger Class III effects (∆QTc) and an increased frequency of prolongations of the QTc interval as compared with larger children (BSA≥0.33m2). The beta-blocking effects also tended to be greater in the smaller children (BSA<0.33m2). Both the Class III and beta-blocking effects of sotalol were linearly related with the plasma concentrations.

Hemodynamics

In a study of systemic hemodynamic function measured invasively in 12 patients with a mean LV ejection fraction of 37% and ventricular tachycardia (9 sustained and 3 non-sustained), a median dose of 160 mg twice daily of sotalol produced a 28% reduction in heart rate and a 24% decrease in cardiac index at 2 hours post-dosing at steady-state. Concurrently, systemic vascular resistance and stroke volume showed non-significant increases of 25% and 8%, respectively. One patient was discontinued because of worsening congestive heart failure. Pulmonary capillary wedge pressure increased significantly from 6.4 mmHg to 11.8 mmHg in the 11 patients who completed the study. Mean arterial pressure, mean pulmonary artery pressure and stroke work index did not significantly change. Exercise and isoproterenol induced tachycardia are antagonized by sotalol, and total peripheral resistance increases by a small amount.

In hypertensive patients, sotalol produces significant reductions in both systolic and diastolic blood pressures. Although sotalol is usually well-tolerated hemodynamically, deterioration in cardiac performance may occur in patients with marginal cardiac compensation [see Warnings and Precautions (5.3)].

The pharmacokinetics of the d- and l-enantiomers of sotalol are essentially identical.

Absorption

In healthy subjects, the oral bioavailability of sotalol is 90 to100%. After oral administration, peak plasma concentrations are reached in 2.5 to 4 hours, and steady-state plasma concentrations are attained within 2 to3 days (that is, after 5-6 doses when administered twice daily). Over the oral dosage range 160 to640 mg/day, sotalol displays dose proportionality with respect to plasma concentrations. When administered with a standard meal, the absorption of sotalol was reduced by approximately 20% compared to administration in fasting state.

Distribution

Sotalol does not bind to plasma proteins. Distribution occurs to a central (plasma) and to a peripheral compartment. Sotalol crosses the blood brain barrier poorly.

Metabolism

Sotalol is not metabolized and is not expected to inhibit or induce any CYP450 enzymes.

Excretion

Excretion of sotalol is predominantly via the kidney in the unchanged form, and therefore, lower doses are necessary in conditions of renal impairment [see Dosage and Administration (2.5)]. The mean elimination half-life of sotalol is 12 hours. Dosing every 12 hours results in trough plasma concentrations which are approximately one-half of those at peak.

Specific Populations

Pediatric: The combined analysis of a single-dose and a multiple-dose study with 59 children, aged between 3 days and 12 years, showed the pharmacokinetics of sotalol to be first order. A daily dose of 30 mg/m2 of sotalol was administered in the single dose study and daily doses of 30, 90 and 210 mg/m2 were administered every 8 hours in the multi-dose study. After rapid absorption with peak levels occurring on average between 2-3 hours following administration, sotalol was eliminated with a mean half-life of 9.5 hours. Steady-state was reached after 1 to 2 days. The average peak to trough concentration ratio was 2. Body surface area was the most important covariate and more relevant than age for the pharmacokinetics of sotalol. The smallest children (BSA <0.33 m2) exhibited a greater drug exposure (+59%) than the larger children who showed a uniform drug concentration profile. The intersubject variation for oral clearance was 22%.

Geriatric: Age does not significantly alter the pharmacokinetics of SOTYLIZE, but impaired renal function in geriatric patients can increase the terminal elimination half-life, resulting in increased drug accumulation.

Renal Impairment: Sotalol is mainly eliminated via the kidneys through glomerular filtration and to a small degree by tubular secretion. There is a direct relationship between renal function, as measured by serum creatinine or creatinine clearance, and the elimination rate of sotalol. The half-life of sotalol is prolonged (up to 69 hours) in anuric patients. Adjust doses or dosing intervals based on creatinine clearance [see Dosage and Administration (2.5)].

Hepatic Impairment: Patients with hepatic impairment show no alteration in clearance of sotalol.

Drug-Drug Interactions

Antacids: Administration of oral sotalol within 2 hours of antacids may result in a reduction in Cmax and AUC of 26% and 20%, respectively, and consequently in a 25% reduction in the bradycardic effect at rest. Administration of the antacid two hours after oral sotalol has no effect on the pharmacokinetics or pharmacodynamics of sotalol.

No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.

Calculations of safety margins are for the maximum recommended human dose (MRHD) of 640 mg/day of sotalol, administered for life-threatening ventricular arrhythmias in a 60-kg human.

No evidence of carcinogenic potential was observed in rats during a 24-month study at 137 to275 mg/kg/day (approximately 30 times the maximum recommended human oral dose (MRHD) as mg/kg or 5 times the MRHD as mg/m2) or in mice, during a 24-month study at 4141 to 7122 mg/kg/day (approximately 450 to 750 times the MRHD as mg/kg or 36 to 63 times the MRHD as mg/m2).

Sotalol has not been evaluated in any specific assay of mutagenicity or clastogenicity.

No significant reduction in fertility occurred in rats at oral doses of 1000 mg/kg/day (approximately 94 times the MRHD as mg/kg or 15 times the MRHD as mg/m2) prior to mating, except for a small reduction in the number of offspring per litter.

In patients with life-threatening arrhythmias [sustained ventricular tachycardia/fibrillation (VT/VF)], sotalol was studied acutely [by suppression of programmed electrical stimulation (PES) induced VT and by suppression of Holter monitor evidence of sustained VT] and, in acute responders, chronically.

In a double-blind, randomized comparison of sotalol and procainamide in 104 patients given intravenously (total of 2 mg/kg sotalol vs. 19 mg/kg of procainamide over 90 minutes), sotalol suppressed PES induction in 30% of patients vs. 20% for procainamide (p=0.2).

In a randomized clinical trial (Electrophysiologic Study Versus Electrocardiographic Monitoring [ESVEM] Trial) in 486 patients comparing the choice of antiarrhythmic therapy by PES suppression vs. Holter monitor selection (in each case followed by treadmill exercise testing) in patients with a history of sustained VT/VF who were also inducible by PES, the effectiveness acutely and chronically of sotalol hydrochloride was compared with 6 other drugs (procainamide, quinidine, mexiletine, propafenone, imipramine, and pirmenol). The Overall response, limited to first randomized drug, was 39% for sotalol and 30% for the pooled other drugs. Acute response rate for first drug randomized using suppression of PES induction was 36% for sotalol vs. a mean of 13% for the other drugs. Using the Holter monitoring endpoint (complete suppression of sustained VT, 90% suppression of NSVT, 80% suppression of PVC pairs, and at least 70% suppression of PVCs), sotalol yielded 41% response vs. 45% for the other drugs combined. Among responders placed on long-term therapy identified acutely as effective (by either PES or Holter), sotalol, when compared to the pool of other drugs, had the lowest two-year mortality (13% vs. 22%), the lowest two-year VT recurrence rate (30% vs. 60%), and the lowest withdrawal rate (38% vs. about 75 to 80%). The most commonly used doses of orally administered sotalol in this trial were 320 to480 mg/day (66% of patients), with 16% receiving 240 mg/day or less and 18% receiving 640 mg or more.

It cannot be determined, however, in the absence of a controlled comparison of sotalol vs. no pharmacologic treatment (for example, in patients with implanted defibrillators) whether sotalol response causes improved survival or identifies a population with a good prognosis.

Sotalol has not been shown to enhance survival in patients with ventricular arrythmias.

Sotalol has been studied in patients with symptomatic AFIB/AFL in two principal studies, one in patients with primarily paroxysmal AFIB/AFL, the other in patients with primarily chronic AFIB.

In one study, a U.S. multicenter, randomized, placebo-controlled, double-blind, dose-response trial of patients with symptomatic primarily paroxysmal AFIB/AFL, three fixed dose levels of sotalol (80 mg, 120 mg and 160 mg) twice daily and placebo were compared in 253 patients. In patients with reduced creatinine clearance (40 to 60 mL/min) the same doses were given once daily. Patients were excluded for the following reasons: QT >450 msec; creatinine clearance <40 mL/min; intolerance to beta-blockers; bradycardia-tachycardia syndrome in the absence of an implanted pacemaker; AFIB/AFL was asymptomatic or was associated with syncope, embolic CVA or TIA; acute myocardial infarction within the previous 2 months; congestive heart failure; bronchial asthma or other contraindications to beta-blocker therapy; receiving potassium losing diuretics without potassium replacement or without concurrent use of ACE-inhibitors; uncorrected hypokalemia (serum potassium <3.5 mEq/L) or hypomagnesemia (serum magnesium <1.5 mEq/L); received chronic oral amiodarone therapy for >1 month within previous 12 weeks; congenital or acquired long QT syndromes; history of Torsade de Pointes with other antiarrhythmic agents which increase the duration of ventricular repolarization; sinus rate <50 bpm during waking hours; unstable angina pectoris; receiving treatment with other drugs that prolong the QT interval; and AFIB/AFL associated with the Wolff-Parkinson-White (WPW) syndrome. If the QT interval increased to ≥520 msec (or JT ≥430 msec if QRS >100 msec) the drug was discontinued. The patient population in this trial was 64% male, and the mean age was 62 years. No structural heart disease was present in 43% of the patients. Doses were administered once daily in 20% of the patients because of reduced creatinine clearance.

Sotalol was shown to prolong the time to the first symptomatic, ECG-documented recurrence of AFIB/AFL, as well as to reduce the risk of such recurrence at both 6 and 12 months. The 120 mg dose was more effective than 80 mg, but 160 mg did not appear to have an added benefit. Note that these doses were given twice or once daily, depending on renal function. The results are shown in Figure 1, Table 3 and Table 4.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Figure 1: Study 1 – Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL Since Randomization</span> </caption> <col align="center" valign="top"/> <tbody class="Headless"> <tr> <td align="center"><img alt="Figure 1" src="/dailymed/image.cfm?name=sotalol-03.jpg&amp;setid=1f33f900-0777-4a92-a7f7-00cf3d57d95c"/></td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="70%"> <caption> <span>Table 3: Study 1 – Patient Status at 12 Months</span> </caption> <col align="left" valign="middle" width="32%"/> <col align="center" valign="middle" width="17%"/> <col align="center" valign="middle" width="17%"/> <col align="center" valign="middle" width="17%"/> <col align="center" valign="middle" width="17%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2"></th><th align="center" class="Rrule" rowspan="2" valign="top">Placebo</th><th align="center" class="Rrule" colspan="3">Sotalol Dose</th> </tr> <tr class="Last"> <th align="center" class="Rrule">80 mg</th><th align="center" class="Rrule">120 mg</th><th align="center" class="Rrule">160 mg</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5" valign="top">Note that columns do not add up to 100% due to discontinuations (D/C) for "other" reasons.</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Symptomatic AFIB/AFL</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Efficacy endpoint of Study 1; study treatment stopped.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Randomized</td><td align="center" class="Rrule">69</td><td align="center" class="Rrule">59</td><td align="center" class="Rrule">63</td><td align="center" class="Rrule">62</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">On treatment in NSR at 12 months without recurrence<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="center" class="Rrule">23%</td><td align="center" class="Rrule">22%</td><td align="center" class="Rrule">29%</td><td align="center" class="Rrule">23%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Recurrence<a class="Sup" href="#footnote-1">*</a><a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></td><td align="center" class="Rrule">67%</td><td align="center" class="Rrule">58%</td><td align="center" class="Rrule">49%</td><td align="center" class="Rrule">42%</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">D/C for AEs</td><td align="center" class="Rrule">6%</td><td align="center" class="Rrule">12%</td><td align="center" class="Rrule">18%</td><td align="center" class="Rrule">29%</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="70%"> <caption> <span>Table 4: Study 1 – Median Time to Recurrence of Symptomatic AFIB/AFL and Relative Risk (vs. Placebo) at 12 Months</span> </caption> <col align="center" valign="middle" width="32%"/> <col align="center" valign="middle" width="17%"/> <col align="center" valign="middle" width="17%"/> <col align="center" valign="middle" width="17%"/> <col align="center" valign="middle" width="17%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule" rowspan="2"></th><th align="center" class="Rrule" rowspan="2">Placebo<br/>n=69</th><th align="center" class="Rrule" colspan="3">Oral Sotalol Dose</th> </tr> <tr class="Last"> <th align="center" class="Rrule">80 mg<br/>n=59</th><th align="center" class="Rrule">120 mg<br/>n=63</th><th align="center" class="Rrule">160 mg<br/>n=62</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">p-value vs. placebo</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">0.325</td><td align="center" class="Rrule">0.018</td><td align="center" class="Rrule">0.029</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Relative Risk (RR) to placebo</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">0.81</td><td align="center" class="Rrule">0.59</td><td align="center" class="Rrule">0.59</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">Median time to recurrence (days)</td><td align="center" class="Rrule">27</td><td align="center" class="Rrule">106</td><td align="center" class="Rrule">229</td><td align="center" class="Rrule">175</td> </tr> </tbody> </table></div>

Discontinuation because of adverse events was dose related.

In a second multicenter, randomized, placebo-controlled, double-blind study of 6 months duration in 232 patients with chronic AFIB, oral sotalol was titrated over a dose range from 80 mg/day to 320 mg/day. The patient population of this trial was 70% male with a mean age of 65 years. Structural heart disease was present in 49% of the patients. All patients had chronic AFIB for >2 weeks but <1 year at entry with a mean duration of 4.1 months. Patients were excluded if they had significant electrolyte imbalance, QTc >460 msec, QRS >140 msec, any degree of AV block or functioning pacemaker, uncompensated cardiac failure, asthma, significant renal disease (estimated creatinine clearance <50 mL/min), heart rate <50 bpm, myocardial infarction or open heart surgery in past 2 months, unstable angina, infective endocarditis, active pericarditis or myocarditis, ≥ 3 DC cardioversions in the past, medications that prolonged QT interval, and previous amiodarone treatment.

After successful cardioversion patients were randomized to receive placebo (n=114) or sotalol (n=118), at a starting dose of 80 mg twice daily. If the initial dose was not tolerated it was decreased to 80 mg once daily, but if it was tolerated it was increased to 160 mg twice daily. During the maintenance period 67% of treated patients received a dose of 160 mg twice daily, and the remainder received doses of 80 mg once daily (17%) and 80 mg twice daily (16%).

Tables 5 and 6 show the results of the trial. There was a longer time to ECG-documented recurrence of AFIB and a reduced risk of recurrence at 6 months compared to placebo.

<div class="scrollingtable"><table width="70%"> <caption> <span>Table 5: Study 2 – Patient Status at 6 Months</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="30%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Placebo<br/>n=114</th><th align="center" class="Rrule">Oral Sotalol<br/>n=118</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Symptomatic or asymptomatic AFIB/AFL</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>Efficacy endpoint of Study 2; study treatment stopped.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">On treatment in NSR at 6 months without recurrence<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></td><td align="center" class="Rrule">29%</td><td align="center" class="Rrule">45%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Recurrence<a class="Sup" href="#footnote-3">*</a><a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a></td><td align="center" class="Rrule">67%</td><td align="center" class="Rrule">49%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">D/C for AEs</td><td align="center" class="Rrule">3%</td><td align="center" class="Rrule">6%</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Death</td><td align="center" class="Rrule">1%</td><td align="center" class="Rrule"></td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 6: Study 2 – Median Time to Recurrence of Symptomatic AFIB/AFL/Death and Relative Risk (vs. Placebo) at 6 Months</span> </caption> <col align="left" valign="middle" width="28%"/> <col align="center" valign="middle" width="18%"/> <col align="center" valign="middle" width="18%"/> <col align="center" valign="middle" width="18%"/> <col align="center" valign="middle" width="18%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Placebo</th><th align="center" class="Rrule">Oral Sotalol</th><th align="center" class="Rrule">Relative Risk</th><th align="center" class="Rrule" valign="top">P-value</th> </tr> </thead> <tbody> <tr class="First Last"> <td align="left" class="Lrule Rrule">Median time to recurrence (days)</td><td align="center" class="Rrule">44</td><td align="center" class="Rrule">&gt;180</td><td align="center" class="Rrule">0.55</td><td align="center" class="Rrule">0.002</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Figure 2: Study 2 – Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL/Death Since Randomization</span> </caption> <col align="center" valign="top"/> <tbody class="Headless"> <tr> <td align="center"><img alt="Figure 2" src="/dailymed/image.cfm?name=sotalol-04.jpg&amp;setid=1f33f900-0777-4a92-a7f7-00cf3d57d95c"/></td> </tr> </tbody> </table></div>

Store at 20°C to 25°C (68°F -77°F); excursions permitted between 15°C and 30°C (59°F-86°F) [see USP Controlled Room Temperature].

Lactation

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

Manufactured for:azurity® pharmaceuticalsWoburn, MA 01801

{ "type": "p", "children": [], "text": "Manufactured for:azurity®\npharmaceuticalsWoburn, MA 01801" }

Manufactured by: Patheon Inc. Whitby Region Operations 111 Consumers Drive Whitby, ON L1N 5Z5 Canada

{ "type": "p", "children": [], "text": "Manufactured by: Patheon Inc. Whitby Region Operations 111 Consumers Drive Whitby, ON L1N 5Z5 Canada" }

Patent: https://azurity.com/patents

{ "type": "p", "children": [], "text": "Patent: https://azurity.com/patents" }

Distributed by: Azurity Pharmaceuticals, Inc. Woburn, MA 01801

{ "type": "p", "children": [], "text": "Distributed by: Azurity Pharmaceuticals, Inc. Woburn, MA 01801" }

SOTYLIZE® is a registered trademark of Azurity Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "SOTYLIZE® is a registered trademark of Azurity Pharmaceuticals, Inc." }

PN: SOT-PI-04

{ "type": "p", "children": [], "text": "PN: SOT-PI-04" }

NDC: 24338-530-25

{ "type": "p", "children": [], "text": "NDC: 24338-530-25" }

Sotylize® (sotalol hydrochloride) oral solution

{ "type": "p", "children": [], "text": "Sotylize®\n(sotalol hydrochloride) oral solution" }

5 mg/mL

{ "type": "p", "children": [], "text": "5 mg/mL" }

For Oral Use Only

{ "type": "p", "children": [], "text": "For Oral Use Only" }

250 mL

{ "type": "p", "children": [], "text": "250 mL" }

Distributed by: azurity® pharmaceuticals Woburn, MA 01801 USA

{ "type": "p", "children": [], "text": "Distributed by: azurity®\npharmaceuticals Woburn, MA 01801 USA" }

Sotalol hydrochloride tablets are indicated for the treatment of documented, life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia (VT).

Limitation of Use:

Sotalol hydrochloride tablets have not been shown to enhance survival in patients with life-threatening ventricular arrhythmias.

Sotalol hydrochloride tablets are indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of AFIB/AFL) in patients with highly symptomatic AFIB/AFL who are currently in sinus rhythm.

Limitation of Use:

Because sotalol hydrochloride tablets can cause life-threatening ventricular arrhythmias, reserve its use for patients in whom AFIB/AFL is highly symptomatic. Patients with paroxysmal AFIB that is easily reversed (by Valsalva maneuver, for example) should usually not be given sotalol hydrochloride tablets.

Withdraw other antiarrhythmic therapy before starting sotalol hydrochloride tablets and monitor for a minimum of 2 to 3 plasma half-lives prior to initiating sotalol hydrochloride tablets therapy if the patient's clinical condition permits [see Drug Interactions( 7)] .

Hospitalize patients being initiated or re-initiated on sotalol for at least 3 days or until steady-state drug levels are achieved in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Initiate oral sotalol therapy in the presence of personnel trained in the management of serious arrhythmias. Perform a baseline ECG to determine the QT interval and measure and normalize serum potassium and magnesium levels before initiating therapy. Measure serum creatinine and calculate an estimated creatinine clearance in order to establish the appropriate dosing interval. Monitor QTc 2 to 4 hours after each uptitration in dose.

Discharge patients on sotalol therapy from an in-patient setting with an adequate supply of sotalol to allow uninterrupted therapy until the patient can fill a sotalol prescription.

Advise patients who miss a dose to take the next dose at the usual time. Do not double the dose or shorten the dosing interval.

The recommended initial dose is 80 mg twice daily. This dose may be increased in increments of 80 mg per day every 3 days provided the QTc <500 msec [see Warnings and Precautions ( 5.1)] . Continually monitor patients until steady state blood levels are achieved. In most patients, a therapeutic response is obtained at a total daily dose of 160 to 320 mg/day, given in two or three divided doses. Oral doses as high as 480 to 640 mg/day have been utilized in patients with refractory life-threatening arrhythmias.

The recommended initial dose is 80 mg twice daily. This dose may be increased in increments of 80 mg per day every 3 days provided the QTc <500 msec [see Warnings and Precautions ( 5.1)] . Continually monitor patients until steady state blood levels are achieved. Most patients will have satisfactory response with 120 mg twice daily. Initiation of sotalol in patients with QTc >450 msec is contraindicated  [see Contraindications ( 4)] .

Use the same precautionary measures for children as you would use for adults when initiating and re-initiating sotalol treatment.

For Children Aged About 2 Years and Older

For children aged about 2 years and older with normal renal function, doses normalized for body surface area are appropriate for both initial and incremental dosing. Since the Class III potency in children is not very different from that in adults, reaching plasma concentrations that occur within the adult dose range is an appropriate guide [see Clinical Pharmacology ( 12.1, 12.3)] .

For initiation of treatment, 1.2 mg/kg three times a day (3.6 mg/kg total daily dose) is approximately equivalent to the initial 160 mg total daily dose for adults. Subsequent titration to a maximum of 2.4 mg/kg three times a day (approximately equivalent to the 360 mg total daily dose for adults) can then occur. Titration should be guided by clinical response, heart rate, and QTc, with increased dosing being preferably conducted in-hospital. Allow at least 36 hours between dose increments to attain steady-state plasma concentrations of sotalol in patients with age-adjusted normal renal function.

For Children Aged About 2 Years or Younger

For children aged about 2 years or younger, the pediatric dosage should be reduced by a factor that depends upon age, as shown in the following graph (age plotted on a logarithmic scale in months):

For a child aged 1 month, multiply the starting dose by 0.7; the initial starting dose would be (1.2 mg/kg X 0.7)=0.8 mg/kg, administered three times daily. For a child aged about 1 week, multiply the initial starting dose by 0.3; the starting dose would be (1.2 mg/kg X 0.3)=0.4 mg/kg. Use similar calculations for dose titration.

Adults

In any age group with decreased renal function, sotalol doses should be lowered or the intervals between doses increased. It will take much longer to reach steady-state with any dose and/or frequency of administration. Closely monitor heart rate and QTc.

Dose escalations in renal impairment should be done after administration of at least 5 doses at appropriate intervals (Table 1). Sotalol is partly removed by dialysis; specific advice is unavailable on dosing patients on dialysis.

Administer the initial dose of 80 mg and subsequent doses at the intervals listed in Table 1.

Table 1: Dosing Intervals in Renal Impairment

<div class="scrollingtable"><table> <col width="34%"/> <col width="41%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Creatinine Clearance mL/min</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Dosing Interval (hours)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">&gt;60</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30-59</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">24</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10-29</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">36-48</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">&lt;10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Dose should be individualized</p> </td> </tr> </tbody> </table></div>

Sotalol hydrochloride Syrup 5 mg/mL can be compounded using Simple Syrup containing 0.1% sodium benzoate (Syrup, NF) as follows:

The endpoint is achieved when a dispersion of fine particles in the syrup is obtained.

This compounding procedure results in a solution containing 5 mg/mL of sotalol hydrochloride. The fine solid particles are the water-insoluble inactive ingredients of the tablets.

Stability studies indicate that the suspension is stable for three months when stored at 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] and ambient humidity.

Sotalol hydrochloride tablets USP, 80 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers “93” and “61” on each side of the score, and plain on the other side.

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Sotalol hydrochloride tablets USP, 120 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers “93” and “1060” on each side of the score, and plain on the other side.

{ "type": "p", "children": [], "text": "Sotalol hydrochloride tablets USP, 120 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers “93” and “1060” on each side of the score, and plain on the other side." }

Sotalol hydrochloride tablets USP, 160 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers “93” and “62” on each side of the score, and plain on the other side.

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Sotalol hydrochloride tablets USP, 240 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers “93” and “63” on each side of the score, and plain on the other side.

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Sotalol hydrochloride tablets are contraindicated in patients with:

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{ "type": "ul", "children": [ "Sinus bradycardia, sick sinus syndrome, second and third degree AV block, unless a functioning pacemaker is present", "Congenital or acquired long QT syndromes", "Cardiogenic shock or decompensated heart failure", "Serum potassium <4 mEq/L", "Bronchial asthma or related bronchospastic conditions", "Hypersensitivity to sotalol" ], "text": "" }

For the treatment of AFIB/AFL, sotalol hydrochloride tablets are also contraindicated in patients with:

{ "type": "p", "children": [], "text": "For the treatment of AFIB/AFL, sotalol hydrochloride tablets are also contraindicated in patients with:" }

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Sotalol hydrochloride can cause serious and potentially fatal ventricular arrhythmias such as sustained VT/VF, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. Factors such as reduced creatinine clearance, female sex, higher doses, reduced heart rate, and history of sustained VT/VF or heart failure increase the risk of TdP. The risk of TdP can be reduced by adjustment of the sotalol dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval [see Dosage and Administration ( 2.1)] .

Correct hypokalemia or hypomagnesemia prior to initiating sotalol hydrochloride, as these conditions can exaggerate the degree of QT prolongation, and increase the potential for Torsade de Pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or patients receiving concomitant diuretic drugs.

Proarrhythmic events must be anticipated not only on initiating therapy, but with every upward dose adjustment [see Dosage and Administration ( 2.1)] .

Avoid use with other drugs known to cause QT prolongation [see Drug Interactions ( 7.1)] .

Sinus bradycardia (heart rate less than 50 bpm) occurred in 13% of patients receiving sotalol in clinical trials, and led to discontinuation in about 3% of patients. Bradycardia itself increases the risk of Torsade de Pointes. Sinus pause, sinus arrest and sinus node dysfunction occur in less than 1% of patients. The incidence of 2nd- or 3rd-degree AV block is approximately 1%.

Sotalol hydrochloride is contraindicated in patients with sick sinus syndrome because it may cause sinus bradycardia, sinus pauses, or sinus arrest.

Sotalol produces significant reductions in both systolic and diastolic blood pressures and may result in hypotension. Monitor hemodynamics in patients with marginal cardiac compensation.

New onset or worsening heart failure may occur during initiation or uptitration of sotalol because of its beta-blocking effects. Monitor for signs and symptoms of heart failure and discontinue treatment if symptoms occur.

Following abrupt cessation of therapy with beta-adrenergic blockers, exacerbations of angina pectoris and myocardial infarction may occur. When discontinuing chronically administered sotalol hydrochloride, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 to 2 weeks, if possible, and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, treat appropriately and consider use of an alternative beta-blocker. Warn patients not to interrupt therapy without their physician’s advice. Because coronary artery disease is common, but may be unrecognized, the abrupt discontinuation of sotalol may unmask latent coronary insufficiency.

Patients with bronchospastic diseases (for example chronic bronchitis and emphysema) should not receive beta-blockers. If sotalol hydrochloride is to be administered, use the smallest effective dose to minimize inhibition of bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta-2-receptors.

Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment. Elevated blood glucose levels and increased insulin requirements can occur in diabetic patients.

Avoid abrupt withdrawal of beta-blockade in patients with thyroid disease because it may lead to an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Beta-blockade may mask certain clinical signs (for example, tachycardia) of hyperthyroidism.

While taking beta-blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction.

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions that are clearly related to sotalol are those which are typical of its Class II (beta-blocking) and Class III (cardiac action potential duration prolongation) effects and are dose related.

Ventricular Arrhythmias

Serious Adverse Reactions

Sotalol hydrochloride can cause serious and potentially fatal ventricular arrhythmias such as sustained VT/VF, primarily Torsade de Pointes (TdP) [see Warnings and Precautions ( 5.1)] . The effect on QT and the risk of Torsade de Pointes are both dose related.

Pediatric Patients

In an unblinded multicenter trial of 25 pediatric patients aged ≤ 1 month to 12 years with SVT and/or VT receiving daily doses of 30, 90, and 210 mg/m 2with dosing every 8 hours for a total of 9 doses, no Torsade de Pointes or other serious new arrhythmias were observed. The clinical trial safety profile in pediatric patients was similar to that in adult patients. Both the Class III and beta-blocking effects of sotalol were linearly related to the plasma concentration [see Clinical Pharmacology ( 12.2)] .

Atrial Fibrillation/Atrial Flutter

Placebo-controlled Clinical Trials

In a pooled clinical trial population consisting of 4 placebo-controlled studies with 275 patients with atrial fibrillation (AFIB)/atrial flutter (AFL) treated with 160 to 320 mg of sotalol hydrochloride AF, the following adverse reactions presented in Table 2 occurred in at least 2% of placebo-treated patients and at a lesser rate than sotalol hydrochloride-treated patients. The data are presented by incidence of reactions in the sotalol hydrochloride AF and placebo groups by body system and daily dose.

Table 2: Incidence (%) of Common Adverse Reactions (≥ 2% in the Placebo Group and Less Frequent Than in the Sotalol Hydrochloride AF Groups) in Four Placebo-controlled Studies of Patients with AFIB/AFL

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"> <p class="First">Adverse Reaction </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">Sotalol hydrochloride AF Total Daily Dose</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">N = 282 <br/> (%) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">160-240 mg <br/> N = 153 <br/> (%) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">&gt;240-320 mg <br/> N = 122 <br/> (%) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Bradycardia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea/Vomiting</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fatigue</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">19</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hyperhidrosis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Weakness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12</p> </td> </tr> <tr class="Last"> <td valign="top"> <p class="First">Dyspnea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10</p> </td> </tr> </tbody> </table></div>

Overall, discontinuation because of unacceptable adverse events was necessary in 17% of the patients and occurred in 10% of patients less than two weeks after starting treatment. The most common adverse reactions leading to discontinuation of sotalol hydrochloride AF were: fatigue 4.6%, bradycardia 2.4%, proarrhythmia 2.2%, dyspnea 2%, and QT interval prolongation 1.4%.

The following adverse drug reactions have been identified during post-approval use of sotalol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: emotional lability, slightly clouded sensorium, incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity reaction, fever, pulmonary edema, hyperlipidemia, myalgia, pruritis, and alopecia.

Discontinue Class I or Class III antiarrhythmic agents for at least three half-lives prior to dosing with sotalol. Class Ia antiarrhythmic drugs, such as disopyramide, quinidine, and procainamide, and other Class III drugs (for example, amiodarone) are not recommended as concomitant therapy with sotalol hydrochloride, because of their potential to prolong refractoriness [see Warnings and Precautions ( 5.2)] .

Digitalis glycosides, diltiazem, verapamil, and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use with negative chronotropes can increase the risk of bradycardia or hypotension.

Concomitant use of catecholamine-depleting drugs, such as reserpine and guanethidine, with a beta-blocker may produce an excessive reduction of resting sympathetic nervous tone. Monitor such patients for evidence of hypotension and/or marked bradycardia which may produce syncope.

Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment [see Warnings and Precautions 5.7)] .

Beta-agonists such as albuterol, terbutaline and isoproterenol may have to be administered in increased dosages when used concomitantly with sotalol.

Concomitant use with sotalol increases the risk of bradycardia and AV block. Because beta-blockers may potentiate the rebound hypertension sometimes observed after clonidine discontinuation, withdraw sotalol several days before the gradual withdrawal of clonidine to reduce the risk of rebound hypertension.

Avoid administration of oral sotalol within 2 hours of antacids containing aluminum oxide and magnesium hydroxide.

The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by fluorimetric or photometric methods.

Risk Summary

Both the untreated underlying condition in pregnancy and the use of sotalol in pregnancy cause adverse outcomes to the mother and fetus/neonate (see Clinical Considerations).In animal reproduction studies in rats, early resorptions were increased at 15 times the maximum recommended human dose (MRHD). In rabbits an increase in fetal death was observed at 2 times the MRHD administered as a single dose. Sotalol did not reveal any teratogenic potential in rats or rabbits at 15 and 2 times the MRHD respectively (see Data).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the United States (U.S.) general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

The incidence of VT is increased and may be more symptomatic during pregnancy. Most tachycardia episodes are initiated by ectopic beats and the occurrence of arrhythmia episodes may, therefore, increase during pregnancy. Breakthrough arrhythmias may also occur during pregnancy, as therapeutic treatment levels may be difficult to maintain due to the increased volume of distribution and increased drug metabolism inherent in the pregnant state.

Fetal/Neonatal Adverse Reactions

Sotalol has been shown to cross the placenta and is found in amniotic fluid. From published observational studies, the potential fetal adverse effects of sotalol use during pregnancy are growth restriction, transient fetal bradycardia, hyperbilirubinemia, hypoglycemia, uterine contractions, and possible intrauterine death. Sotalol may have a greater effect on QT prolongation in the immature heart than in the adult heart, and therefore, conveys an increased risk of serious fetal arrhythmia and/or possible intrauterine death. Monitor the newborn for symptoms of beta blockade.

Labor or Delivery

Generally, risk of arrhythmias increases during the labor and delivery process; therefore, considering the proarrhythmia potential of the drug, patients treated with sotalol should be monitored continuously during labor and delivery.

Data

Animal Data

Reproduction studies in rats and rabbits administered sotalol during organogenesis at 15 times and 2 times the MRHD as mg/m 2, respectively, did not reveal any teratogenic potential associated with sotalol.

In pregnant rats, sotalol doses administered during organogenesis at approximately 15 times the MRHD as mg/m 2, increased the number of early resorptions, while no increase in early resorptions was noted at 2 times the MRHD as mg/m 2.

In reproductive studies in rabbits, a sotalol dose (160 mg/kg/day) at 5 times the MRHD as mg/m 2produced a slight increase in fetal death, and maternal toxicity. However, one study from published data reported an increase in fetal deaths in rabbits receiving a single dose (50 mg/kg) at 2 times the MRHD as mg/m 2on gestation day 14.

Risk Summary

Limited available data from published literature report that sotalol is present in human milk. The estimated daily infant dose of sotalol received from breastmilk is 0.8-3.4 mg/kg, estimated at 22 to 25.5% of the maternal weight-adjusted dosage of sotalol hydrochloride (see Data). The amount of the drug in breast milk is similar to the neonatal therapeutic dosage. Therefore, there is potential for bradycardia and other symptoms of beta blockade such as dry mouth, skin or eyes, diarrhea or constipation in the breastfed infant. There is no information regarding the effects of sotalol on milk production. Because of the potential serious adverse reactions to the breastfed child and the high level of sotalol in breast milk, advise women not to breastfeed while on treatment with sotalol hydrochloride.

Data

Sotalol is present in human milk in high levels. A prospective study evaluated 20 paired samples of breast milk and maternal blood from 5 mothers who elected to breastfeed. Breast milk samples had a mean sotalol concentration of 10.5 mcg/mL (± 1.1 mcg/mL; range: 4.8 to 20.2 mcg/mL) compared to a simultaneous mean maternal plasma concentration of 2.3 mcg/mL (± 0.3 mcg/mL; range: 0.8 to 5.0 mcg/mL). The mean milk plasma ratio was 5.4:1 (range: 2.2 to 8.8). The estimated daily infant dose was 0.8-3.4 mg/kg, estimated at 22 to 25.5% of the maternal weight-adjusted dosage of sotalol. This is similar to recommended therapeutic dose in neonates. None of the mothers reported any adverse reactions in the breastfed infant.

Infertility

Based on the published literature, beta blockers (including sotalol) may cause erectile dysfunction.

The safety and effectiveness of sotalol in children have not been established. However, the Class III electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the effects (QTc interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 years old [see Dosage and Administration ( 2.4) and Clinical Pharmacology ( 12.2)] .

Associated side effects of sotalol use in pediatric patients are those typical of a beta-blocking agent, and lead to discontinuation of the drug in 3 to 6% of patients. As in adults, the Class III antiarrhythmic action of sotalol in pediatric patients is associated with a significant proarrhythmic potential for adverse effects. In pediatric patients, the incidence of proarrhythmic side effects of sotalol varies from 0 to 22%; however, sotalol-induced Torsade de Pointes tachycardias are observed less frequently in the pediatric population.

Proarrhythmic effects of sotalol in pediatric patients included increased ventricular ectopy and exacerbation of bradycardia, the latter predominantly in patients with sinus node dysfunction following surgery for congenital cardiac defects. Bradycardia may require emergency pacemaker implantation. Close in-patient monitoring is recommended for several days.

Sotalol is mainly eliminated via the kidneys. Adjust dosing intervals based on creatinine clearance [see Dosage and Administration ( 2.5)] .

Intentional or accidental overdosage with sotalol has resulted in death.

{ "type": "p", "children": [], "text": "Intentional or accidental overdosage with sotalol has resulted in death." }

Symptoms and Treatment of Overdosage

{ "type": "p", "children": [], "text": "\nSymptoms and Treatment of Overdosage\n\n" }

The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia. In cases of massive intentional overdosage (2 to 16 grams) of sotalol the following clinical findings were seen: hypotension, bradycardia, cardiac asystole, prolongation of QT interval, Torsade de Pointes, ventricular tachycardia, and premature ventricular complexes. If overdosage occurs, therapy with sotalol should be discontinued and the patient observed closely. Because of the lack of protein binding, hemodialysis is useful for reducing sotalol plasma concentrations. Patients should be carefully observed until QT intervals are normalized and the heart rate returns to levels >50 bpm.

{ "type": "p", "children": [], "text": "The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia. In cases of massive intentional overdosage (2 to 16 grams) of sotalol the following clinical findings were seen: hypotension, bradycardia, cardiac asystole, prolongation of QT interval, Torsade de Pointes, ventricular tachycardia, and premature ventricular complexes. If overdosage occurs, therapy with sotalol should be discontinued and the patient observed closely. Because of the lack of protein binding, hemodialysis is useful for reducing sotalol plasma concentrations. Patients should be carefully observed until QT intervals are normalized and the heart rate returns to levels >50 bpm." }

The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination phase (half-life of 30 hours) thought to be due to a temporary reduction of renal function caused by the hypotension. In addition, if required, the following therapeutic measures are suggested:

{ "type": "p", "children": [], "text": "The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination phase (half-life of 30 hours) thought to be due to a temporary reduction of renal function caused by the hypotension. In addition, if required, the following therapeutic measures are suggested: \n \n" }

Bradycardia or Cardiac Asystole:Atropine, another anticholinergic drug, a beta-adrenergic agonist, or transvenous cardiac pacing.

{ "type": "p", "children": [], "text": "\nBradycardia or Cardiac Asystole:Atropine, another anticholinergic drug, a beta-adrenergic agonist, or transvenous cardiac pacing.\n\n " }

Heart Block:(second and third degree) transvenous cardiac pacemaker.

{ "type": "p", "children": [], "text": "\nHeart Block:(second and third degree) transvenous cardiac pacemaker.\n\n " }

Hypotension:(depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be useful.

{ "type": "p", "children": [], "text": "\nHypotension:(depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be useful.\n\n " }

Bronchospasm:Aminophylline or aerosol beta-2-receptor stimulant. Higher than normal doses of beta-2-receptor stimulants may be required.

{ "type": "p", "children": [], "text": "\nBronchospasm:Aminophylline or aerosol beta-2-receptor stimulant. Higher than normal doses of beta-2-receptor stimulants may be required.\n\n " }

Torsade de Pointes:DC cardioversion, transvenous cardiac pacing, epinephrine, magnesium sulfate.

{ "type": "p", "children": [], "text": "\nTorsade de Pointes:DC cardioversion, transvenous cardiac pacing, epinephrine, magnesium sulfate.\n\n " }

Sotalol hydrochloride tablets, USP contains sotalol hydrochloride, USP an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. Sotalol hydrochloride tablets, USP are supplied as a light blue, oval-shaped tablet for oral administration. Sotalol hydrochloride, USP is a white, crystalline solid with a molecular weight of 308.8. It is hydrophilic, soluble in water, propylene glycol, and ethanol, but is only slightly soluble in chloroform. Chemically, sotalol hydrochloride, USP is d,l- N-[4-[1-hydroxy-2-[(1-methylethyl) amino]ethyl]phenyl]methane-sulfonamide monohydrochloride. The molecular formula is C 12H 20N 2O 3S∙HCl and is represented by the following structural formula:

{ "type": "p", "children": [], "text": "Sotalol hydrochloride tablets, USP contains sotalol hydrochloride, USP an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. Sotalol hydrochloride tablets, USP are supplied as a light blue, oval-shaped tablet for oral administration. Sotalol hydrochloride, USP is a white, crystalline solid with a molecular weight of 308.8. It is hydrophilic, soluble in water, propylene glycol, and ethanol, but is only slightly soluble in chloroform. Chemically, sotalol hydrochloride, USP is d,l-\n \n N-[4-[1-hydroxy-2-[(1-methylethyl) amino]ethyl]phenyl]methane-sulfonamide monohydrochloride. The molecular formula is C\n \n 12H\n \n 20N\n \n 2O\n \n 3S∙HCl and is represented by the following structural formula:\n\n " }

Sotalol hydrochloride tablets, USP contain the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, povidone 30, and FD&C Blue No. 2.

{ "type": "p", "children": [], "text": "Sotalol hydrochloride tablets, USP contain the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, povidone 30, and FD&C Blue No. 2." }

Sotalol has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. The two isomers of sotalol have similar Class III antiarrhythmic effects, while the l-isomer is responsible for virtually all of the beta-blocking activity. The beta-blocking effect of sotalol is non-cardioselective, half maximal at about 80 mg/day and maximal at doses between 320 and 640 mg/day. Sotalol does not have partial agonist or membrane stabilizing activity. Although significant beta-blockade occurs at oral doses as low as 25 mg, significant Class III effects are seen only at daily doses of 160 mg and above.

In children, a Class III electrophysiologic effect can be seen at daily doses of 210 mg/m 2body surface area (BSA). A reduction of the resting heart rate due to the beta-blocking effect of sotalol is observed at daily doses ≥90 mg/m 2in children.

Cardiac Electrophysiological Effects

Sotalol hydrochloride prolongs the plateau phase of the cardiac action potential in the isolated myocyte, as well as in isolated tissue preparations of ventricular or atrial muscle (Class III activity). In intact animals it slows heart rate, decreases AV nodal conduction, and increases the refractory periods of atrial and ventricular muscle and conduction tissue.

In man, the Class II (beta-blockade) electrophysiological effects of sotalol are manifested by increased sinus cycle length (slowed heart rate), decreased AV nodal conduction and increased AV nodal refractoriness. The Class III electrophysiological effects in man include prolongation of the atrial and ventricular monophasic action potentials, and effective refractory period prolongation of atrial muscle, ventricular muscle, and atrio-ventricular accessory pathways (where present) in both the anterograde and retrograde directions. With oral doses of 160 to 640 mg/day, the surface ECG shows dose-related mean increases of 40 to 100 msec in QT and 10 to 40 msec in QTc [see Warnings and Precautions ( 5.1)] . No significant alteration in QRS interval is observed.

In a small study (n=25) of patients with implanted defibrillators treated concurrently with sotalol hydrochloride, the average defibrillatory threshold was 6 joules (range: 2 to 15 joules) compared to a mean of 16 joules for a nonrandomized comparative group primarily receiving amiodarone.

Twenty-five children in an unblinded, multicenter trial with SVT and/or ventricular tachyarrhythmias, aged between 3 days and 12 years (mostly neonates and infants), received an ascending titration regimen with daily doses of 30, 90, and 210 mg/m 2with dosing every 8 hours for a total 9 doses. During steady-state, the respective average increases above baseline of the QTc interval were 2, 14, and 29 msec at the 3 dose levels. The respective mean maximum increases above baseline of the QTc interval were 23, 36, and 55 msec at the 3 dose levels. The steady-state percent increases in the RR interval were 3, 9, and 12%. The smallest children (BSA <0.33 m 2) showed a tendency for larger Class III effects (ΔQTc) and an increased frequency of prolongations of the QTc interval as compared with larger children (BSA ≥0.33 m 2). The beta-blocking effects also tended to be greater in the smaller children (BSA <0.33 m 2). Both the Class III and beta-blocking effects of sotalol were linearly related to the plasma concentrations.

Hemodynamics

In a study of systemic hemodynamic function measured invasively in 12 patients with a mean LV ejection fraction of 37% and ventricular tachycardia (9 sustained and 3 non-sustained), a median dose of 160 mg twice daily of sotalol hydrochloride produced a 28% reduction in heart rate and a 24% decrease in cardiac index at 2 hours post-dosing at steady-state. Concurrently, systemic vascular resistance and stroke volume showed nonsignificant increases of 25% and 8%, respectively. One patient was discontinued because of worsening congestive heart failure. Pulmonary capillary wedge pressure increased significantly from 6.4 to 11.8 mmHg in the 11 patients who completed the study. Mean arterial pressure, mean pulmonary artery pressure and stroke work index did not significantly change. Exercise and isoproterenol induced tachycardia are antagonized by sotalol hydrochloride, and total peripheral resistance increases by a small amount.

In hypertensive patients, sotalol produces significant reductions in both systolic and diastolic blood pressures. Although sotalol is usually well-tolerated hemodynamically, deterioration in cardiac performance may occur in patients with marginal cardiac compensation [see Warnings and Precautions ( 5.3)] .

The pharmacokinetics of the d- and l-enantiomers of sotalol are essentially identical.

Absorption

In healthy subjects, the oral bioavailability of sotalol is 90 to 100%. After oral administration, peak plasma concentrations are reached in 2.5 to 4 hours, and steady-state plasma concentrations are attained within 2 to 3 days (that is, after 5 to 6 doses when administered twice daily). Over the dosage range 160 to 640 mg/day, sotalol displays dose proportionality with respect to plasma concentrations. When administered with a standard meal, the absorption of sotalol was reduced by approximately 20% compared to administration in fasting state.

Distribution

Sotalol does not bind to plasma proteins. Distribution occurs to a central (plasma) and to a peripheral compartment. Sotalol crosses the blood brain barrier poorly.

Metabolism

Sotalol is not metabolized and is not expected to inhibit or induce any CYP450 enzymes.

Excretion

Excretion of sotalol is predominantly via the kidney in the unchanged form, and therefore, lower doses are necessary in conditions of renal impairment [see Dosage and Administration ( 2.5)] . The mean elimination half-life of sotalol is 12 hours. Dosing every 12 hours results in trough plasma concentrations which are approximately one-half of those at peak.

Specific Populations

Pediatric: The combined analysis of a single-dose study and a multiple-dose study with 59 children, aged between 3 days and 12 years, showed the pharmacokinetics of sotalol to be first order. A daily dose of 30 mg/m 2of sotalol was administered in the single dose study and daily doses of 30, 90, and 210 mg/m 2were administered every 8 hours in the multidose study. After rapid absorption with peak levels occurring on average between 2 to 3 hours following administration, sotalol was eliminated with a mean half-life of 9.5 hours. Steady-state was reached after 1 to 2 days. The average peak to trough concentration ratio was 2. Body surface area was the most important covariate and more relevant than age for the pharmacokinetics of sotalol. The smallest children (BSA <0.33 m 2) exhibited a greater drug exposure (+59%) than the larger children who showed a uniform drug concentration profile. The intersubject variation for oral clearance was 22%.

Geriatric:Age does not significantly alter the pharmacokinetics of sotalol hydrochloride, but impaired renal function in geriatric patients can increase the terminal elimination half-life, resulting in increased drug accumulation.

Renal Impairment:Sotalol is mainly eliminated via the kidneys through glomerular filtration and to a small degree by tubular secretion. There is a direct relationship between renal function, as measured by serum creatinine or creatinine clearance, and the elimination rate of sotalol. The half-life of sotalol is prolonged (up to 69 hours) in anuric patients. Adjust doses or dosing intervals based on creatinine clearance  [see Dosage and Administration ( 2.5)] .

Hepatic Impairment:Patients with hepatic impairment show no alteration in clearance of sotalol.

Drug-Drug Interactions

Antacids:Administration of oral sotalol within 2 hours of antacids may result in a reduction in C maxand AUC of 26% and 20%, respectively, and consequently in a 25% reduction in the bradycardic effect at rest. Administration of the antacid two hours after oral sotalol has no effect on the pharmacokinetics or pharmacodynamics of sotalol.

No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.

Calculations of safety margins are for the maximum recommended human dose (MRHD) of 640 mg/day of sotalol, administered for life-threatening ventricular arrhythmias in a 60-kg human.

No evidence of carcinogenic potential was observed in rats during a 24-month study at 137 to 275 mg/kg/day (approximately 30 times the maximum recommended human oral dose (MRHD) as mg/kg or 5 times the MRHD as mg/m 2) or in mice, during a 24-month study at 4141 to 7122 mg/kg/day (approximately 450 to 750 times the MRHD as mg/kg or 36 to 63 times the MRHD as mg/m 2).

Sotalol has not been evaluated in any specific assay of mutagenicity or clastogenicity.

No significant reduction in fertility occurred in rats at oral doses of 1000 mg/kg/day (approximately 94 times the MRHD as mg/kg or 15 times the MRHD as mg/m 2) prior to mating, except for a small reduction in the number of offspring per litter.

In patients with life-threatening arrhythmias [sustained ventricular tachycardia/fibrillation (VT/VF)], sotalol hydrochloride was studied acutely [by suppression of programmed electrical stimulation (PES) induced VT and by suppression of Holter monitor evidence of sustained VT] and, in acute responders, chronically.

In a double-blind, randomized comparison of sotalol hydrochloride and procainamide in 104 patients given intravenously (total of 2 mg/kg sotalol hydrochloride vs. 19 mg/kg of procainamide over 90 minutes), sotalol hydrochloride suppressed PES induction in 30% of patients vs. 20% for procainamide ( P=0.2).

In a randomized clinical trial (Electrophysiologic Study Versus Electrocardiographic Monitoring [ESVEM] Trial) in 486 patients comparing the choice of antiarrhythmic therapy by PES suppression vs. Holter monitor selection (in each case followed by treadmill exercise testing) in patients with a history of sustained VT/VF who were also inducible by PES, the effectiveness acutely and chronically of sotalol hydrochloride was compared with that of 6 other drugs (procainamide, quinidine, mexiletine, propafenone, imipramine, and pirmenol). The Overall response, limited to first randomized drug, was 39% for sotalol hydrochloride and 30% for the pooled other drugs. Acute response rate for first drug randomized using suppression of PES induction was 36% for sotalol hydrochloride vs. a mean of 13% for the pooled other drugs. Using the Holter monitoring endpoint (complete suppression of sustained VT, 90% suppression of NSVT, 80% suppression of PVC pairs, and at least 70% suppression of PVCs), sotalol hydrochloride yielded 41% response vs. 45% for the other drugs combined. Among responders placed on long-term therapy identified acutely as effective (by either PES or Holter), sotalol hydrochloride, when compared to the pool of other drugs, had the lowest two-year mortality (13% vs. 22%), the lowest two-year VT recurrence rate (30% vs. 60%), and the lowest withdrawal rate (38% vs. about 75 to 80%). The most commonly used doses of orally administered sotalol hydrochloride in this trial were 320 to 480 mg/day (66% of patients), with 16% receiving 240 mg/day or less and 18% receiving 640 mg or more.

It cannot be determined, however, in the absence of a controlled comparison of sotalol hydrochloride vs. no pharmacologic treatment (for example, in patients with implanted defibrillators) whether sotalol hydrochloride response causes improved survival or identifies a population with a good prognosis.

Sotalol hydrochloride has not been shown to enhance survival in patients with ventricular arrhythmias.

Sotalol hydrochloride AF has been studied in patients with symptomatic AFIB/AFL in two principal studies, one in patients with primarily paroxysmal AFIB/AFL, the other in patients with primarily chronic AFIB.

In one study, a U.S. multicenter, randomized, placebo-controlled, double-blind, dose-response trial of patients with symptomatic primarily paroxysmal AFIB/AFL, three fixed dose levels of sotalol hydrochloride AF (80 mg, 120 mg, and 160 mg) twice daily and placebo were compared in 253 patients. In patients with reduced creatinine clearance (40 to 60 mL/min) the same doses were given once daily. Patients were excluded for the following reasons: QT >450 msec; creatinine clearance <40 mL/min; intolerance to beta-blockers; bradycardia-tachycardia syndrome in the absence of an implanted pacemaker; AFIB/AFL was asymptomatic or was associated with syncope, embolic CVA or TIA; acute myocardial infarction within the previous 2 months; congestive heart failure; bronchial asthma or other contraindications to beta-blocker therapy; receiving potassium-losing diuretics without potassium replacement or without concurrent use of ACE-inhibitors; uncorrected hypokalemia (serum potassium <3.5 MEq/L) or hypomagnesemia (serum magnesium <1.5 MEq/L); received chronic oral amiodarone therapy for >1 month within previous 12 weeks; congenital or acquired long QT syndromes; history of Torsade de Pointes with other antiarrhythmic agents, which increase the duration of ventricular repolarization; sinus rate <50 bpm during waking hours; unstable angina pectoris; receiving treatment with other drugs that prolong the QT interval; and AFIB/AFL associated with the Wolff-Parkinson-White (WPW) syndrome. If the QT interval increased to ≥520 msec (or JT ≥430 msec if QRS >100 msec) the drug was discontinued. The patient population in this trial was 64% male, and the mean age was 62 years. No structural heart disease was present in 43% of the patients. Doses were administered once daily in 20% of the patients because of reduced creatinine clearance.

Sotalol hydrochloride AF was shown to prolong the time to the first symptomatic, ECG-documented recurrence of AFIB/AFL, as well as to reduce the risk of such recurrences at both 6 and 12 months. The 120 mg dose was more effective than 80 mg, but 160 mg did not appear to have an added benefit. Note that these doses were given twice or once daily, depending on renal function. The results are shown in Figure 1, Table 3, and Table 4.

Figure 1: Study 1 – Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL Since Randomization

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="603px"> <col width="310.2pt"/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="5"> <p class="First"> <span class="Bold">Table 3: Study 1 – Patient Status at 12 Months</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="2"></td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First">Sotalol hydrochloride AF Dose</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">80 mg</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">120 mg</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">160 mg</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Randomized</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">69</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">59</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">63</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">62</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">On treatment in NSR at 12 months without recurrence <span class="Sup">a</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">23%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">22%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">29%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">23%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Recurrence <span class="Sup">ab</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">67%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">58%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">49%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">42%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">D/C for AEs</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">6%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">12%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">18%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">29%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="5"> <p class="First"> <span class="Sup">a</span>Symptomatic AFIB/AFL </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="5"> <p class="First"> <span class="Sup">b</span>Efficacy endpoint of Study 1; study treatment stopped. </p> </td> </tr> </tbody> </table></div>

Note that columns do not add up to 100% due to discontinuations (D/C) for “other” reasons.

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="610px"> <col width="388.15pt"/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="5"> <p class="First"> <span class="Bold">Table 4: Study 1 – Median Time to Recurrence of Symptomatic AFIB/AFL and Relative Risk (vs. Placebo) at 12 Months</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="2"></td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"> <p class="First">Placebo n=69</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First">Sotalol hydrochloride AF Dose</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">80 mg n=59</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">120 mg n=63</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">160 mg n=62</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">P-value vs. placebo</p> </td><td class="Botrule Lrule Rrule Toprule"></td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0.325</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0.018</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0.029</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Relative Risk (RR) to placebo</p> </td><td class="Botrule Lrule Rrule Toprule"></td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0.81</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0.59</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0.59</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Median time to recurrence (days)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">27</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">106</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">229</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">175</p> </td> </tr> </tbody> </table></div>

Discontinuation because of adverse events was dose-related.

In a second multicenter, randomized, placebo-controlled, double-blind study of 6 months duration in 232 patients with chronic AFIB, sotalol hydrochloride AF was titrated over a dose range from 80 mg/day to 320 mg/day. The patient population of this trial was 70% male with a mean age of 65 years. Structural heart disease was present in 49% of the patients. All patients had chronic AFIB for >2 weeks but <1 year at entry with a mean duration of 4.1 months. Patients were excluded if they had significant electrolyte imbalance, QTc >460 msec, QRS >140 msec, any degree of AV block or functioning pacemaker, uncompensated cardiac failure, asthma, significant renal disease (estimated creatinine clearance <50 mL/min), heart rate <50 bpm, myocardial infarction or open heart surgery in past 2 months, unstable angina, infective endocarditis, active pericarditis or myocarditis, ≥3 DC cardioversions in the past, medications that prolonged QT interval, and previous amiodarone treatment.

After successful cardioversion patients were randomized to receive placebo (n=114) or sotalol hydrochloride AF (n=118) at a starting dose of 80 mg twice daily. If the initial dose was not tolerated it was decreased to 80 mg once daily, but if it was tolerated, it was increased to 160 mg twice daily. During the maintenance period 67% of treated patients received a dose of 160 mg twice daily, and the remainder received doses of 80 mg once daily (17%) and 80 mg twice daily (16%).

Tables 5 and 6 show the results of the trial. There was a longer time to ECG-documented recurrence of AFIB and a reduced risk of recurrence at 6 months compared to placebo.

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="467.5pt"/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Bold">Table 5: Study 2 – Patient Status at 6 Months</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"></td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">Placebo n=114</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">Sotalol hydrochloride AF <br/> n=118 </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">On treatment in NSR at 6 months without recurrence <span class="Sup">a</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">29%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">45%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Recurrence <span class="Sup">ab</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">67%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">49%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">D/C for AEs</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">3%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">6%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Death</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">1%</p> </td><td class="Botrule Lrule Rrule Toprule"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Sup">a</span>Symptomatic or asymptomatic AFIB/AFL </p> <p> <span class="Sup">b</span>Efficacy endpoint of Study 2; study treatment stopped. </p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="768px"> <col width="473.2pt"/> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="5"> <p class="First"> <span class="Bold">Table 6: Study 2 – Median Time to Recurrence of Symptomatic AFIB/AFL/Death and Relative Risk (vs. Placebo) at 6 Months</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"></td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">Placebo n=114</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">Sotalol hydrochloride AF n=118</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">Relative Risk</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">P-value</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Median time to recurrence (days)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">44</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">&gt;180</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0.55</p> </td><td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First">0.002</p> </td> </tr> </tbody> </table></div>

Figure 2: Study 2 – Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL/Death Since Randomization

Sotalol hydrochloride tablets USP, 80 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers “93” and “61” on each side of the score, and plain on the other side. They are available in bottles of 100 (NDC 0093-1061-01).

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Sotalol hydrochloride tablets USP, 120 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers “93” and “1060” on each side of the score, and plain on the other side. They are available in bottles of 100 (NDC 0093-1060-01).

{ "type": "p", "children": [], "text": "Sotalol hydrochloride tablets USP, 120 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers “93” and “1060” on each side of the score, and plain on the other side. They are available in bottles of 100 (NDC 0093-1060-01)." }

Sotalol hydrochloride tablets USP, 160 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers “93” and “62” on each side of the score, and plain on the other side. They are available in bottles of 100 (NDC 0093-1062-01).

{ "type": "p", "children": [], "text": "Sotalol hydrochloride tablets USP, 160 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers “93” and “62” on each side of the score, and plain on the other side. They are available in bottles of 100 (NDC 0093-1062-01)." }

Sotalol hydrochloride tablets USP, 240 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers “93” and “63” on each side of the score, and plain on the other side. They are available in bottles of 100 (NDC 0093-1063-01).

{ "type": "p", "children": [], "text": "Sotalol hydrochloride tablets USP, 240 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers “93” and “63” on each side of the score, and plain on the other side. They are available in bottles of 100 (NDC 0093-1063-01)." }

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

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Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

{ "type": "p", "children": [], "text": "Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). \n \n" }

Keep this and all medications out of the reach of children.

{ "type": "p", "children": [], "text": "Keep this and all medications out of the reach of children. \n \n" }

{ "type": "ul", "children": [ "Advise patients to contact their healthcare provider in the event of syncope, pre-syncopal symptoms or cardiac palpitations.", "Advise patients that their electrolytes and ECG will be monitored during treatment\n \n [see Warnings and Precautions (\n \n 5.1)]\n \n .\n \n ", "Advise patients to contact their healthcare provider in the event of conditions that could lead to electrolyte changes such as severe diarrhea, unusual sweating, vomiting, less appetite than normal, or excessive thirst\n \n [see Warnings and Precautions (\n \n 5.1)]\n \n .\n \n ", "Advise patients not to change the sotalol hydrochloride tablets dose prescribed by their healthcare provider.", "Advise patients that they should not miss a dose, but if they do miss a dose they should not double the next dose to compensate for the missed dose: they should take the next dose at the regularly scheduled time\n \n [see Dosage and Administration (\n \n 2)]\n \n .\n \n ", "Advise patients to not interrupt or discontinue sotalol hydrochloride tablets without their physician’s advice, that they should get their prescription for sotalol filled and refilled on time, so they do not interrupt treatment\n \n [see Dosage and Administration (\n \n 2)]\n \n .\n \n ", "Advise patients to not start taking other medications without first discussing new medications with their healthcare provider.", "Advise patients to avoid taking sotalol hydrochloride tablets within two hours of taking antacids that contain aluminum oxide or magnesium hydroxide\n \n [see Drug Interactions (\n \n 7.7)]\n \n .\n \n ", "Inform patients or caregivers that there is a risk of hypoglycemia when sotalol hydrochloride tablets are given to patients who are fasting or who are vomiting. Inform patients to notify their healthcare provider if they experience symptoms of hypoglycemia\n \n [see Warnings and Precautions (\n \n 5.7)].\n \n \n" ], "text": "" }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

{ "type": "ul", "children": [ "Advise women not to breastfeed while on treatment with sotalol hydrochloride tablets \n \n [see Use in Specific Populations (\n \n 8.2)]\n \n .\n \n " ], "text": "" }

Brands listed are the trademarks of their respective owners.

{ "type": "p", "children": [], "text": "Brands listed are the trademarks of their respective owners." }

Manufactured In Czech Republic By: Teva Czech Industries s.r.o. Opava-Komarov, Czech Republic

{ "type": "p", "children": [], "text": "Manufactured In Czech Republic By: \n \nTeva Czech Industries s.r.o. \n \nOpava-Komarov, Czech Republic\n\n " }

Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054

{ "type": "p", "children": [], "text": "Manufactured For: \n \nTeva Pharmaceuticals \n \nParsippany, NJ 07054\n\n " }

Rev. P 12/2023

{ "type": "p", "children": [], "text": "Rev. P 12/2023" }

Please reference the HOW SUPPLIED section listed above for a description of individual drug products listed below. This drug product has been received by Aphena Pharma Solutions - Tennessee, LLC in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:

{ "type": "p", "children": [], "text": "Please reference the HOW SUPPLIED section listed above for a description of individual drug products listed below. This drug product has been received by Aphena Pharma Solutions - Tennessee, LLC in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:" }

80mg NDC 71610-889-80, Bottles of 180 Tablets

{ "type": "p", "children": [], "text": "\n80mg\n\nNDC 71610-889-80, Bottles of 180 Tablets\n " }

Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children. Repackaged by: Cookeville, TN 38506 20250326AMH

{ "type": "p", "children": [], "text": "\n\nStore between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children.\n \n\nRepackaged by:\n \n\nCookeville, TN 38506\n \n20250326AMH\n " }

NDC 71610-889 - Sotalol HCl, USP 80mg Tablets - Rx Only

{ "type": "p", "children": [], "text": "NDC 71610-889 - Sotalol HCl, USP 80mg Tablets - Rx Only" }