Sotalol

1. INDICATIONS AND USAGE Sotalol/Sotalol AF is an antiarrhythmic indicated for: • the treatment of life-threatening ventricular arrhythmias (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 Arrhythmias Sotalol/Sotalol AF is indicated for the treatment of documented, life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia (VT). Limitation of Use: Sotalol/Sotalol AF has not been shown to enhance survival in patients with life-threatening ventricular arrhythmias. 1.2 Delay in Recurrence of Atrial Fibrillation/Atrial Flutter (AFIB/AFL) Sotalol/Sotalol AF is 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/Sotalol AF 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/Sotalol AF.

2 DOSAGE AND ADMINISTRATION Sotalol/Sotalol AF: Initial dosage in adults is 80 mg twice daily. Increase the dose as needed in increments of 80 mg/day, every 3 days to a maximum 320 mg total daily dose (2.2) Pediatrics: Dosage depends on age (2.4) 2.1 General Safety Measures for Initiation of Oral Sotalol Therapy Withdraw other antiarrhythmic therapy before starting Sotalol/Sotalol AF and monitor for a minimum of 2 to 3 plasma half-lives prior to initiating Sotalol/Sotalol AF 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. 2.2 Adult Dose for Ventricular 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 QT c 450 msec is contraindicated [see Contraindication (4) ]. 2.4 Pediatric Dose for Ventricular Arrhythmias 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 (approximately equivalent to the 360 mg total daily dose for adults) can then occur. Titration should be guided by clinical response, heart rate and QT c , with increased dosing being preferably carried out in-hospital. At least 36 hours should be allowed 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. figure-1 2.5 Dosage for Patients with Renal Impairment Adults Use of sotalol in any age group with decreased renal function should be at lower doses or increased intervals between doses. It will take much longer to reach steady-state with any dose and/or frequency of administration. Closely monitor heart rate and QT c . Dose escalations in renal impairment should be done after administration of at least 5 doses at appropriate interv …

3 DOSAGE FORMS AND STRENGTHS Sotalol Hydrochloride Tablets are supplied as capsule-shaped, light-blue, scored tablets: 80 mg imprinted with “B104” on one side and 80 mg on the other 120 mg imprinted with “B105” on one side and 120 mg on the other 60 mg imprinted with “B105” on one side and 160 mg on the other Sotalol AF is supplied as capsule-shaped white to off-white scored tablets: • 80 mg debossed ‘B107’ on one side and scored on the other side • 120 mg debossed ‘B108’ on one side and scored on the other side • 160 mg debossed ‘B109’ on one side and scored on the other side 80 mg, 120 mg and 160 mg tablets ( 3 )

4 CONTRAINDICATIONS Sotalol Hydrochloride Tablets are contraindicated in patients with: 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 For the treatment of ventricular arrythmias Sinus bradycardia, 2nd or 3rd degree AV block, sick sinus syndrome ( 4 ) Congenital or acquired long QT syndrome, ( 4 ) Serum potassium <4 mEq/L( 4 ) Cardiogenic shock, decompensated heart failure ( 4 ) Bronchial asthma or related bronchospastic conditions ( 4 ) Hypersensitivity to sotalol ( 4 )

6 ADVERSE REACTIONS The most common adverse reactions (≥2%) for Sotalol Hydrochloride Tablets are: fatigue 4%, bradycardia (less than 50 bpm) 3%, dyspnea 3%, proarrhythmia 3%, asthenia 2%, and dizziness 2%. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Beximco Pharmaceuticals USA Inc. at 877-372-6093 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 In patients with a history of sustained ventricular tachycardia, the incidence of Torsade de Pointes during oral sotalol treatment was 4% and worsened VT was about 1%; in patients with other less serious ventricular arrhythmias the incidence of Torsade de Pointes was 1% and new or worsened VT was about 0.7%. Incidence of Torsade de Pointes arrhythmias in patients with VT/VF are shown in Table 3 below. Table 3: Percent Incidence of Torsade de Pointes and Mean QTc Interval by Dose For Patients With Sustained VT/VF Daily Dose (mg) Torsade de Pointes Incidence Mean QTc highest on-therapy value (msec) 80 0 (69) 463 (17) 160 0.5 (832) 467 (181) 320 1.6 (835) 473 (344) 480 4.4 (459) 483 (234) 640 3.7 (324) 490 (185) >640 5.8 (103) 512 (62) ( ) Number of patients assessed Table 4 below relates the incidence of Torsade de Pointes to on-therapy QT c and change in QT c from baseline in patients with ventricular arrhythmias. It should be noted, however, that the highest on-therapy QT c was in many cases the one obtained at the time of the Torsade de Pointes event, so that the table overstates the predictive value of a high QT c . Table 4: Relationship Between QTc Interval Prolongations and Torsade de Pointes On-Therapy QT c Interval (msec) Incidence of Torsade de Pointes Change from Baseline in QT c (msec) Incidence of Torsade de Pointes 550 10.8% (157) 100-130 5.2% (115) >130 7.1% (99) ( ) Number of patients assessed Table 5: Incidence (%) of Common Adverse Reactions (2% in the Placebo group and less frequent than Sotalol Hydrochloride Tablets groups) in a Placebo-controlled Parallel-group Comparison Study of Patients with Ventricular Ectopy Body System/Adverse Reaction (Preferred Term) Placebo Sotalol Hydrochloride Total Daily Dose N=37 (%) 320 mg N=38 (%) 640 mg N=39 (%) CARDIOVASCULAR Chest Pain 5.4 7.9 15.4 Dyspnea 2.7 18.4 20.5 Palpitation 2.7 7.9 5.4 Vasodilation 2.7 0.0 5.1 NERVOUS SYSTEM Asthenia 8.1 10.5 20.5 Dizziness 5.4 13.2 17.9 Fatigue 10.8 26.3 25.6 Headache 5.4 5.3 7.7 Lightheaded 8.1 15.8 5.1 Sleep Problem 2.7 2.6 7.7 RESPIRATORY Upper Respiratory Tract Problem 2.7 2.6 12.8 SPECIAL SENSES Visual Problem 2.7 5.3 0.0 The most common adverse reactions leading to discontinuation of Sotalol Hydrochloride Tablets in trials of patients with ventricular arrhythmias are: fatigue 4%, bradycardia (less than 50 bpm) 3%, dyspnea 3%, proarrhythmia 3%, asthenia 2%, and dizziness 2%. Incidence of discontinuation for these adverse reactions was dose related. One case of peripheral neuropathy that resolved on discontinuation of Sotalol Hydrochloride Tablets and recurred when the patient was rechallenged with the drug was reported in an early dose tolerance study. Pediatric Patients In an unblinded multicenter trial of 25 pediatric patients with SVT and/or VT receiving daily doses of 30, 90 and 210 mg/m 2 with dosing every 8 ours for a total of 9 doses, no Torsade de Pointes or other serious new arrhythmias were observed. One (1) patient, receiving 30 mg/m 2 daily, was discontinued because of increased frequency of sinus pauses/bradycardia. Addit …

7 DRUG INTERACTIONS Class I or III Antiarrhythmics or other drugs that prolong the QT interval: Avoid concomitant use ( 7.1 ) Digoxin, calcium channel blocker: increased risk of bradycardia, hypotension, heart failure ( 7.2 ) Dosage of insulin or antidiabetic drugs may need adjustment ( 7.5 ) Aluminum or magnesium-based antacids reduce sotalol exposure ( 7.7 ) 7.1 Antiarrhythmics and other QT Prolonging Drugs Sotalol has not been studied with other drugs that prolong the QT interval such as antiarrhythmics, some phenothiazines, tricyclic antidepressants, certain oral macrolides and certain quinolone antibiotics. 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 Tablets, because of their potential to prolong refractoriness [ see Warnings and Precautions (5.2) ]. There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics. Additive Class II effects would also be anticipated with the use of other beta-blocking agents concomitantly with Sotalol Hydrochloride Tablets. 7.2 Digoxin Proarrhythmic events were more common in sotalol treated patients also receiving digoxin; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in the patients receiving digoxin. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. 7.3 Calcium-Channel Blocking Drugs Sotalol and calcium-blocking drugs can be expected to have additive effects on atrioventricular conduction or ventricular function. Monitor such patients for evidence of bradycardia and hypotension. 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 evidence of hypotension and/or 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 [ see Warnings and Precautions 5.7) ]. 7.6 Clonidine Concomitant use with sotalol increases the risk of bradycardia. 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. 7.7 Antacids Avoid administration of oral sotalol within 2 hours of antacids containing aluminum oxide and magnesium hydroxide.

8 USE IN SPECIAL POPULATIONS Lactation: Do not breastfeed (8.2) 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 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/m2, 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/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/m 2 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 level …

12.1 Mechanism of Action 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 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 children.

11 DESCRIPTION Sotalol/Sotalol AF contains sotalol hydrochloride, 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, capsule-shaped tablet for oral administration. 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: Sotalol Tablets contain the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch, stearic acid, magnesium stearate, colloidal silicon dioxide, and FD&C blue #2 (aluminum lake 11% - 14%). Sotalol AF Tablets contain the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch, stearic acid, magnesium stearate, and colloidal silicon dioxide. structure

10 OVERDOSAGE Intentional or accidental overdosage with sotalol has resulted in death. 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. Patientsshould 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Sotalol Hydrochloride Tablets USP are capsule-shaped light-blue scored tablets, debossed ‘B104’, ‘B105’, and ‘B106’ on one side and scored on the other side are available as follows: 80 mg strength, bottles of 100 (NDC 76385- 114 -01) 80 mg strength, bottles of 500 (NDC 76385- 114 -50) 120 mg strength, bottles of 100 (NDC 76385- 115 -01) 120 mg strength, bottles of 500 (NDC 76385- 115 -50) 160 mg strength, bottles of 100 (NDC 76385- 116 -01) 160 mg strength, bottles of 500 (NDC 76385- 116 -50) Sotalol Hydrochloride Tablets USP (AF) are capsule-shaped white to off-white scored tablets, debossed ‘B107’, ‘B108’, and ‘B109’ on one side and scored on the other side are available as follows: 80 mg strength, bottles of 100 (NDC 76385- 125 -01) 80 mg strength, bottles of 500 (NDC 76385- 125 -50) 120 mg strength, bottles of 100 (NDC 76385- 126 -01) 120 mg strength, bottles of 500 (NDC 76385- 126 -50) 160 mg strength, bottles of 100 (NDC 76385- 127 -01) 160 mg strength, bottles of 500 (NDC 76385- 127 -50) Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [ See USP Controlled Room Temperature ].