Sotalol Hydrochloride

1 INDICATIONS AND USAGE Sotalol hydrochloride tablets are 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 hydrochloride tablets have 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 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 ( 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 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 ( 5.1 )] . 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 ( 5.1 )] . 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 ( 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 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. 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: Measure 120 mL of Simple Syrup. 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. 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. 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. Allow the tablets to hydrate for at least two hours. 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.

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%. ( 6 ) 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 ( 5.1 )]. 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 ( 12.2 )] . 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 2: 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.

12.3 Pharmacokinetics The pharmacokinetics of the d- and l- enantiomers of sotalol are essentially identical. Absorption In healthy subjects, the oral bioavailability of sotalol is 90 to 100%. After oral administration, peak plasma concentrations are reached in 2.5 to 4 hours, and steady-state plasma concentrations are attained within 2 to 3 days (that is, after 5 to 6 doses when administered twice daily). Over the dosage range 160 to 640 mg/day, sotalol displays dose proportionality with respect to plasma concentrations. When administered with a standard meal, the absorption of sotalol was reduced by approximately 20% compared to administration in fasting state. Distribution Sotalol does not bind to plasma proteins. Distribution occurs to a central (plasma) and to a peripheral compartment. Sotalol crosses the blood brain barrier poorly. Metabolism Sotalol is not metabolized and is not expected to inhibit or induce any CYP450 enzymes. Excretion Excretion of sotalol is predominantly via the kidney in the unchanged form, and therefore, lower doses are necessary in conditions of renal impairment [see Dosage and Administration ( 2.5 )] . The mean elimination half-life of sotalol is 12 hours. Dosing every 12 hours results in trough plasma concentrations which are approximately one-half of those at peak. Specific Populations Pediatric: The combined analysis of a single-dose study and a multiple-dose study with 59 children, aged between 3 days and 12 years, showed the pharmacokinetics of sotalol to be first order. A daily dose of 30 mg/m 2 of sotalol was administered in the single dose study and daily doses of 30, 90 and 210 mg/m 2 were administered every 8 hours in the multi-dose study. After rapid absorption with peak levels occurring on average between 2 to 3 hours following administration, sotalol was eliminated with a mean half-life of 9.5 hours. Steady-state was reached after 1 to 2 days. The average peak to trough concentration ratio was 2. Body surface area was the most important covariate and more relevant than age for the pharmacokinetics of sotalol. The smallest children (BSA<0.33 m 2 ) exhibited a greater drug exposure (+59%) than the larger children who showed a uniform drug concentration profile. The intersubject variation for oral clearance was 22%. Geriatric: Age does not significantly alter the pharmacokinetics of sotalol hydrochloride, but impaired renal function in geriatric patients can increase the terminal elimination half-life, resulting in increased drug accumulation. Renal Impairment: Sotalol is mainly eliminated via the kidneys through glomerular filtration and to a small degree by tubular secretion. There is a direct relationship between renal function, as measured by serum creatinine or creatinine clearance, and the elimination rate of sotalol. The half-life of sotalol is prolonged (up to 69 hours) in anuric patients. Adjust doses or dosing intervals based on creatinine clearance [see Dosage and Administration ( 2.5 )]. Hepatic Impairment: Patients with hepatic impairment show no alteration in clearance of sotalol. Drug-Drug Interactions Antacids: Administration of oral sotalol within 2 hours of antacids may result in a reduction in C max and AUC of 26% and 20%, respectively, and consequently in a 25% reduction in the bradycardic effect at rest. Administration of the antacid two hours after oral sotalol has no effect on the pharmacokinetics or pharmacodynamics of sotalol. No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.