SOTALOL HYDROCHLORIDE

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 3 S•HCl and is represented by the following structural formula: 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. Structure

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.

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-initiation at a lower dose of 80 mg is desired, wait at least 1 day (in patients with GFR >60 mL/min), or at least 3 days (in patients with GFR ≤60 to >30 mL/min), or 7 days (in patients with GFR ≤30 to >10 mL/min). Table 2: Recommended Loading Dosage in Adults GFR Individual GFR should be derived as follows: 〖GFR〗_i= eGFR/1.73 ×BSA; whereby, eGFR is GFR estimated by eGFR estimating equations, and BSA is individual body surface area. [mL/min] Intravenous loading dose [mg] to be administered over 1 hour when the oral dose is going from Minimum delay to first oral dose [hours] Oral dosing interval [hours] Sotalol Initiation Sotalol Escalation 0 to 80 mg Recommended starting dose 0 to 120 mg 80 mg to 120 mg 120 mg to 160 mg ≥90 60 90 75 90 4 12 60- to <90 82.5 125 82.5 105 4 12 30- to <60 75 112.5 82.5 105 6 24 10- to <30 75 112.5 82.5 105 12 48 2.4 Use in Pediatric Patients Table 3 shows suggested starting doses in pediatric patients with normal renal function. Table 3. Suggesting starting doses [mg/kg] in children with normal renal function. Age Dose [mg/kg] 3 days 0.32 6 days 0.51 9 days 0.69 12 days 0.81 2 weeks 0.9 3 weeks 1 1 month to 6 years 1.2 6-12 years 1.1 >12 years 0.95

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 )

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 .

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.