SOTALOL HYDROCHLORIDE

1 INDICATIONS AND USAGE Sotalol hydrochloride tablets are an antiarrhythmic indicated for: • the treatment of life-threatening ventricular arrhythmias ( Error! Hyperlink reference not valid. ) • the maintenance of normal sinus rhythm in patients with atrial fibrillation or flutter (AFIB/AFL) ( Error! Hyperlink reference not valid. ) Limitations of Use • Sotalol hydrochloride tablets have not been shown to enhance survival in patients with life-threatening ventricular arrhythmias ( Error! Hyperlink reference not valid. ) • Avoid use in patients with minimally symptomatic or easily reversible AFIB/AFL ( Error! Hyperlink reference not valid. ) 1.1 Life-Threatening Ventricular Arrhythmias 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. 1.2 Delay in Recurrence of Atrial Fibrillation/Atrial Flutter (AFIB/AFL) 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.

2 DOSAGE AND ADMINISTRATION • Sotalol hydrochloride tablets: 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 ( Error! Hyperlink reference not valid. ) • Pediatrics: Dosage depends on age ( Error! Hyperlink reference not valid. ) 2.1 General Safety Measures for Initiation of Oral Sotalol Therapy 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. 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 QTc <500 msec [see Warnings and Precautions ( Error! Hyperlink reference not valid. )] . 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. 2.3 Adult Dose for Prevention of Recurrence of AFIB/AFL 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 ( Error! Hyperlink reference not valid. )] . 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 )] . 2.4 Pediatric Dose for Ventricular Arrhythmias or AFIB/AFL 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 ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )] . 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. Age about 2 years or younger 2.5 Dosage for Patients with Renal Impairment 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 Creatinine Clearance mL/min Dosing Interval (hours) > 60 12 30–59 24 10–29 36–48 < 10 Dose should be individualized 2.6 Preparation of Extemporaneous Oral Solution Sotalol hydrochloride Syrup 5 mg/mL can be compounded using Simple Syrup containing 0.1% sodium benzoate (Syrup, NF) as follows: 1. Measure 120 mL of Simple Syrup. 2. Transfer the syrup to a 6-ounce amber plastic (polyethylene terephthalate [PET]) prescription bottle. An oversized bottle is used to allow for a headspace, so that there will be more effective mixing during shaking of the bottle. 3. Add five (5) sotalol hydrochloride 120 mg tablets to the bottle. These tablets are added intact; it is not necessary to crush the tablets. The addition of the tablets can also be done first. The tablets can also be crushed, if preferred. If the tablets are crushed, take care to transfer the entire quantity of tablet powder into the bottle containing the syrup. 4. Shake the bottle to wet the entire surface of the tablets. If the tablets have been crushed, shake the bottle until the endpoint is achieved. 5. Allow the tablets to hydrate for at least two hours. 6. After at least two hours have elapsed, shake the bottle intermittently over the course of at least another two hours until the tablets are completely disintegrated. The tablets can be allowed to hydrate overnight to simplify the disintegration process. 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.

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 AFIB/AFL, sotalol hydrochloride tablets are also contraindicated in patients with: • Baseline QT interval >450 msec For the treatment of AFIB/AFL or ventricular arrythmias • Sinus bradycardia, 2 nd or 3 rd 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 ) For the treatment of AFIB/AFL also contraindicated for: • QT interval >450 msecs ( 4 )

5 WARNINGS AND PRECAUTIONS • QT prolongation, bradycardia, AV block, hypotension, worsening heart failure: Reduce dose or discontinue ( Error! Hyperlink reference not valid. ) • Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue ( Error! Hyperlink reference not valid. ) • Correct any electrolyte disturbances ( Error! Hyperlink reference not valid. ) • Diabetes: May mask symptoms of hypoglycemia and alter glucose levels; monitor ( Error! Hyperlink reference not valid. ) 5.1 QT Prolongation and Proarrhythmia 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 ( Error! Hyperlink reference not valid. )] . 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 ( Error! Hyperlink reference not valid. )] . Avoid use with other drugs known to cause QT prolongation [see Drug Interactions ( Error! Hyperlink reference not valid. )] . 5.2 Bradycardia/Heart Block/Sick Sinus Syndrome 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. 5.3 Hypotension Sotalol produces significant reductions in both systolic and diastolic blood pressures and may result in hypotension. Monitor hemodynamics in patients with marginal cardiac compensation. 5.4 Heart Failure 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. 5.5 Cardiac Ischemia after Abrupt Discontinuation 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. 5.6 Bronchospasm 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. 5.7 Effects on Blood Sugar 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. 5.8 Thyroid Abnormalities 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. 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 Major Surgery 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.

7 DRUG INTERACTIONS • Class I or III Antiarrhythmics or other drugs that prolong the QT interval: Avoid concomitant use ( Error! Hyperlink reference not valid. ) • Digoxin, calcium channel blocker: increased risk of bradycardia, hypotension, heart failure ( Error! Hyperlink reference not valid. ) • Dosage of insulin or antidiabetic drugs may need adjustment ( Error! Hyperlink reference not valid. ) • Aluminum- or magnesium-based antacids reduce sotalol exposure ( Error! Hyperlink reference not valid. ) 7.1 Antiarrhythmics and Other QT Prolonging Drugs 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 ( Error! Hyperlink reference not valid. )]. 7.2 Negative Chronotropes 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. 7.3 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. 7.4 Insulin and Oral Antidiabetics Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment [see Warnings and Precautions ( Error! Hyperlink reference not valid. )] . 7.5 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. 7.6 Clonidine 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. 7.7 Antacids Avoid administration of oral sotalol within 2 hours of antacids containing aluminum oxide and magnesium hydroxide. 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.

6 ADVERSE REACTIONS The most common adverse reactions (≥2%) for sotalol hydrochloride are: fatigue 4%, bradycardia (less than 50 bpm) 3%, dyspnea 3%, proarrhythmia 3%, asthenia 2%, and dizziness 2%. ( Error! Hyperlink reference not valid. ) To report SUSPECTED ADVERSE REACTIONS, contact Oxford Pharmaceuticals at 844-508-1455, 8:00 am - 4:30 pm ET, Monday – Friday 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 Sotalol hydrochloride can cause serious and potentially fatal ventricular arrhythmias such as sustained VT/VF, primarily Torsade de Pointes (TdP) [see Warnings and Precautions ( Error! Hyperlink reference not valid. )]. 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 2 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 ( Error! Hyperlink reference not valid. )] . 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 doses of Betapace 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 tablets-treated patients. The data are presented by incidence of reactions in the Betapace AF and placebo groups by body system and daily dose. Table : Incidence (%) of Common Adverse Reactions (≥ 2% in the Placebo Group and Less Frequent Than in the Betapace AF Groups) in Four Placebo-controlled Studies of Patients with AFIB/AFL Placebo Betapace AF Total Daily Dose 160-240 mg > 240-320 mg Adverse Reaction N = 282 N = 153 N = 122 (%) (%) (%) Bradycardia 3 13 12 Diarrhea 2 5 6 Nausea/Vomiting 5 8 6 Fatigue 9 20 19 Hyperhidrosis 3 5 5 Weakness 3 5 5 Dizziness 12 16 13 Headache 5 3 12 Dyspnea 7 9 10 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 Betapace AF were: fatigue 4.6%, bradycardia 2.4%, proarrhythmia 2.2%, dyspnea 2%, and QT interval prolongation 1.4%. 6.2 Postmarketing Experience 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.

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/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 on gestation day 14.