Sotalol hydrochloride

1 INDICATIONS AND USAGE Sotalol is an antiarrhythmic indicated for: the treatment of life-threatening ventricular tachycardia. ( 1.1 ) the maintenance of normal sinus rhythm in patients with atrial fibrillation or flutter (AFIB/AFL). ( 1.2 ) Limitations of Use Sotalol has not been shown to enhance survival in patients with life-threatening ventricular arrhythmias. ( 1.1 ) Avoid use in patients with minimally symptomatic or easily reversible AFIB/AFL ( 1.2 ) 1.1 Life-Threatening Ventricular Arrhythmia Sotalol is indicated for the treatment of documented, life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia in adult and pediatric patients. Limitations of Use: Sotalol has not been shown to enhance survival in patients with life-threatening ventricular arrhythmias. 1.2 Delay in Recurrence of Atrial Fibrillation/Atrial Flutter Sotalol is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter (AFIB/AFL)) in adults and pediatric 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.

2 DOSAGE AND ADMINISTRATION Intravenous sotalol can substitute for oral sotalol using a regimen that mimics oral exposure ( 2.2 ) Under close medical monitoring, intravenous sotalol can be used to achieve near steady-state exposure to sotalol prior to initiating or increasing oral dosing. ( 2.3 ) Recommended dosage depends on target oral dose and creatinine clearance. Refer to full prescribing information. ( 2.2 , 2.3 , 2.4 ) 2.1 General Considerations and Safety Measures 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 Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer’s Injection. Choose a volume convenient for administration and consistent with fluid restriction. Use a volumetric infusion pump. Patients should be initiated or re-initiated on intravenous sotalol in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Withdraw other antiarrhythmic drug therapy before starting intravenous sotalol if the patient's clinical condition permits. Perform a baseline ECG to determine the QTc interval and measure and normalize serum potassium and magnesium levels before initiating therapy. If the baseline QTc is >450 ms, sotalol is contraindicated. Assess renal function in order to establish the appropriate dosing interval. Monitor QTc 2 to 4 hours after each up-titration in dose [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)]. 2.2 Use for Substitution of Oral Sotalol To match the exposure to oral sotalol, intravenously infuse the adjusted dose at the same dosing frequency as the oral dose based on glomerular filtration rate (see Table 1) over 5 hours. Table 1: Intravenous doses for sotalol infusion when used as a substitute for oral sotalol Individual GFR should be derived as follows: 〖GFR〗_i= eGFR/1.73 ×BSA; whereby, eGFR is GFR estimated by a GFR estimating equation, and BSA is individual body surface area. Current Oral dose Dose of intravenous sotalol based on GFR GFR 60 mL/min GFR 30 to < 60 mL/min GFR 10 to < 30 mL/min 80 mg 75 mg every 12 hours 67.5 mg every 24 hours 67.5 mg every 36 to 48 hours 120 mg 112.5 mg every 12 hours 105 mg every 24 hours 105 mg every 36 to 48 hours 160 mg 150 mg every 12 hours 142.5 mg every 24 hours 135 mg every 36 to 48 hours 2.3 Use for Loading Dose Initiate or up-titrate 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 contraindicated. The intravenous loading dose depends on the target oral dose and estimated glomerular filtration rate; 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)] . Infuse the loading dose over one hour. Monitor QTc interval every 15 minutes during infusion. Continue to monitor QTc at peak serum concentration (2 to 4 hours post-dose) following the first oral dose (in all patients) and second oral dose (in patients with GFR ≥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 twice daily, discontinue drug; if initiating for an oral dose of 120 mg twice daily discontinue drug and consider a lower dose. If re-in…

5 WARNINGS AND PRECAUTIONS QT prolongation, risk of life-threatening ventricular arrhythmias, particularly torsade de pointes ( 5.1 ) Bradyarrhythmia, AV block, sick sinus syndrome ( 5.2 , 5.3 ) Negative inotropy: hypotension, heart failure ( 5.4 , 5.5 ) Bronchospasm ( 5.6 ) Masked hypoglycemia ( 5.7 ) Masked hyperthyroidism ( 5.8 ) Anaphylaxis ( 5.9 ) 5.1 Proarrhythmia Sotalol can cause serious and potentially fatal ventricular arrhythmias , primarily Torsade de Pointes (TdP), a polymorphic ventricular tachycardia associated with QTc prolongation. QTc prolongation is directly related to the concentration of sotalol. Factors such as reduced renal function, female sex, higher dose, bradycardia, history of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF), atrial fibrillation with sinus node dysfunction, and heart failure increase the risk of TdP. The risk of TdP can be reduced by adjustment of the sotalol dose according to renal function and by monitoring the ECG for excessive increases in QTc. Correct hypokalemia or hypomagnesemia prior to initiating sotalol hydrochloride, as these conditions can increase the degree of QTc prolongation and 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. Proarrhythmic events should be anticipated upon initiating therapy and with every up-titration of sotalol. Avoid sotalol with other drugs known to cause QTc prolongation [see Dosage and Administration ( 2.1 ) and Drug Interactions ( 7.1 )]. 5.2 Bradycardia/Atrioventricular (AV) Block Sotalol can cause bradycardia, sinus pauses or sinus arrest. Sotalol-induced bradycardia increases the risk of Torsade de Pointes, particularly following cardioversion. Monitor the ECG in patients receiving concomitant negative chronotropes [see Drug Interactions ( 7.2 , 7.3 , 7.4 )] . 5.3 Sick Sinus Syndrome Sotalol is contraindicated in patients with sick sinus syndrome, because it may cause sinus bradycardia, sinus pauses, or sinus arrest. Sotalol augments bradycardia and QTc prolongation following cardioversion. 5.4 Hypotension Sotalol produces significant reductions in both systolic and diastolic blood pressures. Monitor hemodynamics during administration. 5.5 Heart Failure 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. 5.6 Bronchospasm Avoid beta-blockers, like sotalol, in patients with bronchospastic diseases. If sotalol is required, use the smallest effective dose. 5.7 Hypoglycemia 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 pediatric patients who are fasting (i.e., surgery, not eating regularly, or vomiting). Monitor blood glucose as appropriate. 5.8 Thyroid Abnormalities 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. 5.9 Anaphylaxis 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. 5.10 Anesthesia The impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

4 CONTRAINDICATIONS Sotalol hydrochloride is contraindicated in patients with: Sinus bradycardia (<50 bpm), sick sinus syndrome or second or third degree atrioventricular (AV) block without a pacemaker [See Warnings and Precautions ( 5.2 , 5.3 )] Congenital or acquired long QT syndromes, QTc interval >450 ms [See Warnings and Precautions ( 5.1 )] Cardiogenic shock, decompensated heart failure [See Warnings and Precautions ( 5.5 )] Serum potassium <4 mEq/L [See Warnings and Precautions ( 5.1 )] Bronchial asthma or related bronchospastic conditions [See Warnings and Precautions ( 5.6 )] Known hypersensitivity to sotalol [See Warnings and Precautions ( 5.9 )] Bradyarrhythmia, sick sinus syndrome or 2 nd or 3 rd degree atrioventricular (AV) block without a pacemaker ( 4 ) Congenital or acquired long QT syndrome ( 4 ) Cardiogenic shock or decompensated heart failure ( 4 ) Serum potassium < 4mEq ( 4 ) Bronchial asthma or related bronchospastic conditions ( 4 ) Hypersensitivity to sotalol ( 4 )

7 DRUG INTERACTIONS Additive to other negative chronotropes ( 7.2 , 7.3 , 7.4 ) Additive to other QT-prolonging drugs ( 7.1 , 7.2 ) Antagonizes effect of beta-agonists ( 7.6 ) 7.1 Antiarrhythmic and other QT Prolonging Drugs Withdraw other Class I or Class III antiarrhythmic agents 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, because of their potential for additive QTc prolongation [see Warnings and Precautions ( 5.1 )]. 7.2 Negative Chronotropes Both digitalis glycoside and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. 7.3 Calcium Blocking Drugs Sotalol and calcium blocking drugs can be expected to have additive effects slowing atrioventricular conduction, ventricular function, and blood pressure. 7.4 Catecholamine-Depleting Agents 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. 7.5 Insulin and Oral Antidiabetics Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment. Symptoms of hypoglycemia may be masked. 7.6 Beta-2-Receptor Stimulants Beta-agonists such as albuterol, terbutaline and isoproterenol may have to be administered in increased dosages when used concomitantly with sotalol. 7.7 Clonidine 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. 7.8 Drug/Laboratory Test Interactions The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by fluorimetric or photometric methods.

8.1 Pregnancy 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.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere: Proarrhythmia [see Warnings and Precautions ( 5.1 , 5.2 )] Negative inotropy [see Warnings and Precautions ( 5.3 , 5.4 )] 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. Bradycardia, dyspnea, fatigue, QTc prolongation To report SUSPECTED ADVERSE REACTIONS, contact AltaThera Pharmaceuticals LLC at 1-800-524-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .