Sotalol Hydrochloride

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.

Injection: 150 mg/10 mL (15 mg/mL) single-dose vial containing sotalol hydrochloride ( 3 ) Injection: 10-mL vial containing sotalol hydrochloride 150 mg ( 3 )

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 )

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.

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.

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.

8.2 Lactation 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.

8.3 Females and Males of Reproductive Potential Infertility Based on the published literature, beta blockers (including sotalol) may cause erectile dysfunction.

8.4 Pediatric Use Sotalol is indicated for: The treatment of documented, life-threatening VT in pediatric patients. The maintenance of normal sinus rhythm [delay in time to recurrence of atrial fibrillation/atrial flutter (AFIB/AFL)] in pediatric patients with highly symptomatic AFIB/AFL who are currently in sinus rhythm. 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 pediatric patients between 3 days and 12 years of age [ see Clinical Pharmacology ( 12.3 )]. Side effects from use of other sotalol-containing drug products in pediatric patients are those typical of a beta blocking agent, and led 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. In pediatric patients, the incidence of proarrhythmic side effects of sotalol varies from 0 to 22%; and the smallest pediatric patients tended to exhibit greater QTc-prolongation [see Clinical Pharmacology ( 12.2 )] ]. 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 inpatient monitoring is recommended until steady state drug levels are achieved [see Dosage and Administration ( 2.1 , 2.3 ) ].

8.6 Renal Impairment Sotalol is eliminated predominantly via the kidney [see Clinical Pharmacology ( 12.3 )] . Sotalol exposure increases with decrease in renal function. Sotalol dose should be reduced and interval between doses should be increased based on the patient’s renal function [see Dosage and Administration ( 2.2 , 2.3 )] .

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. T he 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. In pediatric patients, a Class III electrophysiologic effect can be seen at daily doses of 210 mg/m 2 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/m 2 in pediatric patients.