SOTALOL: 3,680 Adverse Event Reports & Safety Profile

Sotalol hydrochloride/Sotalol hydrochloride AF tablets, USP 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 white to off-white, capsule-shaped, scored tablet for oral administration. Sotalol hydrochloride AF is supplied as a white to off-white, capsule-shaped, scored tablet for oral administration. Sotalol hydrochloride is a white, crystalline solid with a molecular weight of 308.8 g/mol. 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: Each Sotalol Hydrochloride tablet, USP/Sotalol Hydrochloride AF tablets, USP for oral administration, contains 80 mg, 120 mg, 160 mg or 240 mg of sotalol hydrochloride. In addition, each tablet also contains the following inactive ingredients: magnesium stearate and microcrystalline cellulose.

Structural

Formula

INDICATIONS AND USAGE Sotalol hydrochloride tablets, USP are indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgment of the physician are life-threatening. Because of the proarrhythmic effects of sotalol hydrochloride tablets, USP (see WARNINGS ), including a 1.5 to 2% rate of Torsade de Pointes or new VT/VF in patients with either NSVT or supraventricular arrhythmias, its use in patients with less severe arrhythmias, even if the patients are symptomatic, is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided. Initiation of sotalol hydrochloride treatment or increasing doses, as with other antiarrhythmic agents used to treat life-threatening arrhythmias, should be carried out in the hospital. The response to treatment should then be evaluated by a suitable method (e.g., PES or Holter monitoring) prior to continuing the patient on chronic therapy. Various approaches have been used to determine the response to antiarrhythmic therapy, including sotalol hydrochloride tablets, USP. In the ESVEM Trial, response by Holter monitoring was tentatively defined as 100% suppression of ventricular tachycardia, 90% suppression of nonsustained VT, 80% suppression of paired VPCs, and 75% suppression of total VPCs in patients who had at least 10 VPCs/hour at baseline; this tentative response was confirmed if VT lasting 5 or more beats was not observed during treadmill exercise testing using a standard Bruce protocol. The PES protocol utilized a maximum of three extrastimuli at three pacing cycle lengths and two right ventricular pacing sites. Response by PES was defined as prevention of induction of the following: 1) monomorphic VT lasting over 15 seconds; 2) non-sustained polymorphic VT containing more than 15 beats of monomorphic VT in patients with a history of monomorphic VT; 3) polymorphic VT or VF greater than 15 beats in patients with VF or a history of aborted sudden death without monomorphic VT; and 4) two episodes of polymorphic VT or VF of greater than 15 beats in a patient presenting with monomorphic VT. Sustained VT or NSVT producing hypotension during the final treadmill test was considered a drug failure. In a multicenter open-label long-term study of sotalol in patients with life-threatening ventricular arrhythmias which had proven refractory to other antiarrhythmic medications, response by Holter monitoring was defined as in ESVEM. Response by PES was defined as non-inducibility of sustained VT by at least double extrastimuli delivered at a pacing cycle length of 400 msec. Overall survival and arrhythmia recurrence rates in this study were similar to those seen in ESVEM, although there was no comparative group to allow a definitive assessment of outcome. Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias. Sotalol is also indicated for the maintenance of normal sinus rhythm [delay in time to recurrence of atrial fibrillation/atrial flutter (AFIB/AFL)] in patients with symptomatic AFIB/AFL who are currently in sinus rhythm and is marketed under the brand name Betapace AF (sotalol hydrochloride, tablets, USP). Sotalol hydrochloride tablets, USP is not approved for the AFIB/AFL indication and should not be substituted for Betapace AF because only Betapace AF is distributed with a patient package insert that is appropriate for patients with AFIB/AFL.

DOSAGE AND ADMINISTRATION Dosing and Administration in Adults Therapy with sotalol hydrochloride tablets (AF) must be initiated (and, if necessary, titrated) in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Patients should continue to be monitored in this way for a minimum of 3 days on the maintenance dose. In addition, patients should not be discharged within 12 hours of electrical or pharmacological conversion to normal sinus rhythm. The QT interval is used to determine patient eligibility for sotalol hydrochloride tablet (AF) treatment and for monitoring safety during treatment. The baseline QT interval must be ≤450 msec in order for a patient to be started on sotalol hydrochloride tablet (AF) therapy. During initiation and titration, the QT interval should be monitored 2 to 4 hours after each dose. If the QT interval prolongs to 500 msec or greater, the dose must be reduced or the drug discontinued. The dose of Sotalol Hydrochloride Tablets, USP (AF) must be individualized according to calculated creatinine clearance. In patients with a creatinine clearance >60 mL/min Sotalol Hydrochloride Tablets, USP (AF) is administered twice daily (BID) while in those with a creatinine clearance between 40 and 60 mL/min, the dose is administered once daily (QD). In patients with a creatinine clearance less than 40 mL/min Sotalol Hydrochloride Tablets, USP (AF) is contraindicated. The recommended initial dose of Sotalol Hydrochloride Tablets, USP (AF) is 80 mg and is initiated as shown in the dosing algorithm described below.

The

80 mg dose can be titrated upward to 100mg or 120mg during initial hospitalization or after discharge on 80 mg in the event of recurrence, by rehospitalization and repeating the same steps used during the initiation of therapy (see Upward Titration of Dose ). Patients with atrial fibrillation should be anticoagulated according to usual medical practice. Hypokalemia should be corrected before initiation of sotalol hydrochloride tablet (AF) therapy (see WARNINGS , Ventricular Arrhythmia ). Patients to be discharged on sotalol hydrochloride tablet (AF) therapy from an in-patient setting should have an adequate supply of sotalol hydrochloride tablets (AF), to allow uninterrupted therapy until the patient can fill a sotalol hydrochloride tablets (AF) prescription. Initiation of Sotalol Hydrochloride Tablets, USP (AF)

Therapy Step

1 . Electrocardiographic assessment: Prior to administration of the first dose, the QT interval must be determined using an average of 5 beats. If the baseline QT is greater than 450 msec (JT ≥330 msec if QRS over 100 msec), sotalol hydrochloride tablets (AF) are contraindicated.

Step

2 . Calculation of creatinine clearance: Prior to the administration of the first dose, the patient's creatinine clearance should be calculated using the following formula: creatinine clearance (male) = (140-age)x body weight in kg 72 x serum creatinine (mg/dL) creatinine clearance (female) = (140-age)x body weight in kg x 0.85 72 x serum creatinine (mg/dL) When serum creatinine is given in mcmol/L, divide the value by 88.4 (1 mg/dL= 88.4 mcmol/L).

Step

3 .

Starting

Dose: The starting dose of sotalol hydrochloride tablets (AF) is 80 mg twice daily (BID) if the creatinine clearance is >60 mL/min, and 80 mg once daily (QD) if the creatinine clearance is 40 to 60 mL/min. If the creatinine clearance is <40 mL/min sotalol hydrochloride tablets (AF) are contraindicated.

Step

4 . Administer the appropriate daily dose of sotalol hydrochloride tablets (AF) and begin continuous ECG monitoring with QT interval measurements 2 to 4 hours after each dose.

Step

5 . If the 80 mg dose level is tolerated and the QT interval remains <500 msec after at least 3 days (after 5 or 6 doses if patient receiving QD dosing), the patient can be discharged. Alternatively, during hospitalization, the dose can be increased to 100 mg or 120 mg BID and the patient followed for 3 days on this dose (followed for 5 or 6 doses if patient receiving QD doses). The steps described above are summarized in the following diagram: Place Patient on Telemetry Check Baseline QT If QT >450 msec Sotalol hydrochloride tablets (AF) are CONTRAINDICATED If QT ≤450 msec, proceed Calculate Creatine Clearance (Clcr)

If

Clcr is <40 mL/min sotalol hydrochloride tablets (AF) are CONTRAINDICATED If Clcr is 40 to 60 mL/min start sotalol hydrochloride tablets (AF) 80 mg QD If Clcr is >60 mL/min start sotalol hydrochloride tablets (AF) 80 mg BID Monitor QT 2 to 4 hours after each dose. If QT ≥500 msec discontinue sotalol hydrochloride tablets (AF). If QT <500 msec after 3 days (after 5 th or 6 th dose if patient receiving QD dosing) discharge patient on current treatment. Alternatively, during hospitalization, the dose can be increased to 120 mg BID and the patient followed for 3 days on this dose Followed for 5 or 6 doses if patient receiving QD doses).

Upward

Titration of Dose If the 80 mg dose level (given BID or QD depending upon the creatinine clearance) does not reduce the frequency of relapses of AFIB/AFL and is tolerated without excessive QT interval prolongation (i.e., ≥520 msec), the dose level may be increased to 120 mg (BID or QD depending upon the creatinine clearance). As proarrhythmic events can occur not only at initiation of therapy, but also with each upward dosage adjustment, Steps 2 through 5 used during initiation of sotalol hydrochloride tablet (AF) therapy should be followed when increasing the dose level. In the U.S. multicenter dose-response study, the 120 mg dose (BID or QD) was found to be the most effective in prolonging the time to ECG documented symptomatic recurrence of AFIB/AFL. If the 120 mg dose does not reduce the frequency of early relapse of AFIB/AFL and is tolerated without excessive QT interval prolongation (≥520 msec), an increase to 160 mg (BID or QD depending upon the creatinine clearance), can be considered.

Steps

2 through 5 used during the initiation of therapy should be used again to introduce such an increase. Maintenance of Sotalol Hydrochloride Tablets, USP (AF)

Therapy

Renal function and QT should be re-evaluated regularly if medically warranted. If QT is 520 msec or greater (JT 430 msec or greater if QRS is >100 msec), the dose of sotalol hydrochloride tablets (AF) therapy should be reduced and patients should be carefully monitored until QT returns to less than 520 msec. If the QT interval is ≥520 msec while on the lowest maintenance dose level (80 mg) the drug should be discontinued. If renal function deteriorates, reduce the daily dose in half by administering the drug once daily as described in Initiation of sotalol hydrochloride tablets (AF) Therapy, Step 3 .

Special Considerations

The maximum recommended dose in patients with a calculated creatinine clearance greater than 60 mL/min is 160 mg BID, doses greater than 160 mg BID have been associated with an increased incidence of Torsade de Pointes and are not recommended. A patient who misses a dose should NOT double the next dose. The next dose should be taken at the usual time. Dosing and Administration in Children As in adults the following precautionary measures should be considered when initiating sotalol treatment in children: initiation of treatment in the hospital after appropriate clinical assessment; individualized regimen as appropriate; gradual increase of doses if required; careful assessment of therapeutic response and tolerability; and frequent monitoring of the QT c interval and heart rate. For children aged about 2 years and greater For children aged about 2 years and greater, 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 (see CLINICAL PHARMACOLOGY ) is not very different from that in adults, reaching plasma concentrations that occur within the adult dose range is an appropriate guide. From pediatric pharmacokinetic data the following is recommended. For initiation of treatment, 30 mg/m 2 three times a day (90 mg/m 2 total daily dose) is approximately equivalent to the initial 160 mg total daily dose for adults. Subsequent titration to a maximum of 60 mg/m 2 (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 above pediatric dosage should be reduced by a factor that depends heavily upon age, as shown in the following graph, age plotted on a logarithmic scale in months. For a child aged 20 months, the dosing suggested for children with normal renal function aged 2 years or greater should be multiplied by about 0.97; the initial starting dose would be (30 x 0.97)=29.1 mg/m 2 , administered three times daily. For a child aged 1 month, the starting dose should be multiplied by 0.68; the initial starting dose would be (30 x 0.68)=20 mg/m 2 , administered three times daily. For a child aged about 1 week, the initial starting dose should be multiplied by 0.3; the starting dose would be (30 x 0.3)=9 mg/m 2 . Similar calculations should be made for increased doses as titration proceeds. Since the half-life of sotalol decreases with decreasing age (below about 2 years), time to steady-state will also increase. Thus, in neonates the time to steady-state may be as long as a week or longer. In all children, individualization of dosage is required. As in adults sotalol hydrochloride tablets (AF) should be used with particular caution in children if the QT c is greater than 500 msec on therapy and serious consideration should be given to reducing the dose or discontinuing therapy when QT c exceeds 550 msec. The use of sotalol hydrochloride tablets (AF) in children with renal impairment has not been investigated. Sotalol elimination is predominantly via the kidney in the unchanged form. Use of sotalol in any age group with decreased renal function should be at lower doses or at increased intervals between doses. Monitoring of heart rate and QT c is more important and it will take much longer to reach steady-state with any dose and/or frequency of administration. Transfer to Sotalol Hydrochloride Tablets (AF) from Sotalol Hydrochloride Tablets Patients with a history of symptomatic AFIB/AFL who are currently receiving sotalol hydrochloride for the maintenance of normal sinus should be transferred to sotalol hydrochloride tablets (AF) because of the significant differences in labeling (i.e., patient package insert, dosing administration, and safety information). Transfer to Sotalol Hydrochloride Tablets (AF) from Other Antiarrhythmic Agents Before starting sotalol hydrochloride tablets (AF) , previous antiarrhythmic therapy should generally be withdrawn under careful monitoring for a minimum of 2 to 3 plasma half-lives if the patient's clinical condition permits (see DRUG INTERACTIONS ). Treatment has been initiated in some patients receiving I.V. lidocaine without ill effect. After discontinuation of amiodarone, sotalol hydrochloride tablets (AF) should not be initiated until the QT interval is normalized (see WARNINGS ). Preparation of Extemporaneous Oral Solution Sotalol hydrochloride (AF) syrup 5 mg/mL can be compounded using Simple Syrup containing 0.1% sodium benzoate (Syrup, NF) available from Humco Laboratories as follows: Measure 120 mL of Simple Syrup Transfer the syrup to a 6-ounce amber plastic (polyethylene terephthalate [PET]) prescription bottle. NOTE: 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 (AF) 120 mg tablets to the bottle. These tablets are added intact; it is not necessary to crush the tablets. NOTE: The addition of the tablets can also be done first. The tablets can also be crushed if preferred. If the tablets are crushed, care should be taken 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 approximately 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. NOTE: 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. This extemporaneously prepared oral solution of sotalol hydrochloride (with suspended inactive particles) must be shaken well prior to administration. This is to ensure that the amount of inactive solid particles per dose remains constant throughout the duration of use. Stability studies indicate that the suspension is stable when stored at controlled room temperature (15° to 30°C/59° to 86°F) and ambient humidity for three (3) months. age factor

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 ms
• Creatinine clearance <40 mL/min For the treatment of AFIB/AFL or ventricular arrhythmias
• 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 ms ( 4 )
• Creatine clearance <40 ml/min ( 4 )

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 AvKARE at 1-855-361-3993 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 QT c Interval by Dose For Patients With Sustained VT/VF Daily Dose (mg) Torsade de Pointes Incidence Mean QT c * (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 *highest on-therapy value Table 4 below relates the incidence of Torsade de Pointes to on-therapy QTc and change in QTc from baseline in patients with ventricular arrhythmias. It should be noted, however, that the highest on-therapy QTc 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 QTc.

Table

4: Relationship Between QTc Interval Prolongation and Torsade de Pointes On-Therapy QT c Interval Incidence of Torsade de Pointes Change from Baseline in QT c Incidence of Torsade de Pointes (msec) (msec) <500 1.3% (1787) <65 1.6% (1516) 500-525 3.4% (236) 65-80 3.2% (158) 525-550 5.6% (125) 80-100 4.1% (146) >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 in the sotalol groups) in a Placebo-controlled Parallel-group Comparison Study of Patients with Ventricular Ectopy Placebo Sotalol hydrochloride Total Daily Dose 320 mg 640 mg Body System/ N = 37 N = 38 N = 39 Adverse Reaction (Preferred Term) (%) (%) (%)

Cardiovascular

Chest Pain 5.4 7.9

15.4 Dyspnea 2.7 18.4

20.5 Palpitation 2.7 7.9

5.1 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 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 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 hours 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. Additional cardiovascular AEs were seen at the 90 and 210 mg/m 2 daily dose levels. They included QT prolongation (2 patients), sinus pauses/bradycardia (1 patient), increased severity of atrial flutter and reported chest pain (1 patient). Values for QT c ≥ 525 msec were seen in 2 patients at the 210 mg/m 2 daily dose level. Serious adverse events including death, Torsade de Pointes, other proarrhythmias, high-degree A-V blocks, and bradycardia have been reported in infants and/or children.

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 sotalol hydrochloride AF, the following adverse reactions presented in Table 6 occurred in at least 2% of placebo-treated patients and at a lesser rate than sotalol-treated patients. The data are presented by incidence of reactions in the sotalol hydrochloride AF and placebo groups by body system and daily dose.

Table

6: Incidence (%) of Common Adverse Reactions (≥ 2% in the Placebo group and less frequent than in the sotalol AF groups) in Four Placebo-controlled Studies of Patients with AFIB/AFL Placebo sotalol hydrochloride AF Total Daily Dose 160-240 mg > 240-320 mg Body System/ N = 282 N = 153 N = 122 Adverse Reaction (Preferred Term) (%) (%) (%)

Cardiovascular

Bradycardia 2.5 13.1

12.3 GASTROINTESTINAL Diarrhea 2.1 5.2

5.7 Nausea/Vomiting 5.3 7.8

5.7 Pain abdomen 2.5 3.9

2.5 GENERAL Fatigue 8.5 19.6

18.9 Hyperhidrosis 3.2 5.2

4.9 Weakness 3.2 5.2

4.9 MUSCULOSKELETAL/CONNECTIVE TISSUE Pain musculoskeletal 2.8 2.6

4.1 NERVOUS SYSTEM Dizziness 12.4 16.3

13.1 Headache 5.3 3.3

11.5 RESPIRATORY Cough 2.5 3.3

2.5 Dyspnea 7.4 9.2

9.8 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 sotalol hydrochloride 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. Voluntary reports since introduction include reports (less than one report per 10,000 patients) of: emotional lability, slightly clouded sensorium, incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity reaction, fever, pulmonary edema, hyperlipidemia, myalgia, pruritis, alopecia. To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

WARNINGS Mortality The National Heart, Lung, and Blood Institute's Cardiac Arrhythmia Suppression Trial I (CAST I) was a long-term, multi-center, double-blind study in patients with asymptomatic, non-life-threatening ventricular arrhythmias, 1 to 103 weeks after acute myocardial infarction. Patients in CAST I were randomized to receive placebo or individually optimized doses of encainide, flecainide, or moricizine.

The Cardiac Arrhythmia Suppression

Trial II (CAST II) was similar, except that the recruited patients had had their index infarction 4 to 90 days before randomization, patients with left ventricular ejection fractions greater than 40% were not admitted, and the randomized regimens were limited to placebo and moricizine. CAST I was discontinued after an average time-on-treatment of 10 months, and CAST II was discontinued after an average time-on-treatment of 18 months. As compared to placebo treatment, all three active therapies were associated with increases in short-term (14-day) mortality, and encainide and flecainide were associated with significant increases in longer-term mortality as well. The longer-term mortality rate associated with moricizine treatment could not be statistically distinguished from that associated with placebo. The applicability of these results to other populations (e.g., those without recent myocardial infarction) and to other than Class I antiarrhythmic agents is uncertain. Sotalol hydrochloride is devoid of Class I effects, and in a large (n=1,456) controlled trial in patients with a recent myocardial infarction, who did not necessarily have ventricular arrhythmias, sotalol did not produce increased mortality at doses up to 320 mg/day (see Clinical Studies ). On the other hand, in the large postinfarction study using a non-titrated initial dose of 320 mg once daily and in a second small randomized trial in high-risk post-infarction patients treated with high doses (320 mg BID), there have been suggestions of an excess of early sudden deaths.

Proarrhythmia

Like other antiarrhythmic agents, sotalol can provoke new or worsened ventricular arrhythmias in some patients, including sustained ventricular tachycardia or ventricular fibrillation, with potentially fatal consequences. Because of its effect on cardiac repolarization (QTc interval prolongation), Torsade de Pointes, a polymorphic ventricular tachycardia with prolongation of the QT interval and a shifting electrical axis is the most common form of proarrhythmia associated with sotalol, occurring in about 4% of high risk (history of sustained VT/VF) patients. The risk of Torsade de Pointes progressively increases with prolongation of the QT interval, and is worsened also by reduction in heart rate and reduction in serum potassium (see Electrolyte Disturbances ). Because of the variable temporal recurrence of arrhythmias, it is not always possible to distinguish between a new or aggravated arrhythmic event and the patient’s underlying rhythm disorder. (Note, however, that Torsade de Pointes is usually a drug-induced arrhythmia in people with an initially normal QTc.) Thus, the incidence of drug-related events cannot be precisely determined, so that the occurrence rates provided must be considered approximations. Note also that drug-induced arrhythmias may often not be identified, particularly if they occur long after starting the drug, due to less frequent monitoring. It is clear from the NIH-sponsored CAST (see WARNINGS, Mortality ) that some antiarrhythmic drugs can cause increased sudden death mortality, presumably due to new arrhythmias or asystole, that do not appear early in treatment but that represent a sustained increased risk. Overall in clinical trials with sotalol, 4.3% of 3257 patients experienced a new or worsened ventricular arrhythmia. Of this 4.3%, there was new or worsened sustained ventricular tachycardia in approximately 1% of patients and Torsade de Pointes in 2.4%. Additionally, in approximately 1% of patients, deaths were considered possibly drug-related; such cases, although difficult to evaluate, may have been associated with proarrhythmic events. In patients with a history of sustained ventricular tachycardia, the incidence of Torsade de Pointes was 4% and worsened VT in about 1%; in patients with other, less serious, ventricular arrhythmias and supraventricular arrhythmias, the incidence of Torsade de Pointes was 1% and 1.4%, respectively. Torsade de Pointes arrhythmias were dose related, as is the prolongation of QT (QTc) interval, as shown in the table below.

Percent

Incidence of Torsade de Pointes and Mean QTc Interval by Dose For Patients With Sustained VT/VF Daily Dose (mg) Incidence of Torsade de Pointes Mean QTc a (msec) 80 0 (69) b 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) a) highest on-therapy value In addition to dose and presence of sustained VT, other risk factors for Torsade de Pointes were gender (females had a higher incidence), excessive prolongation of the QT c interval (see table below) and history of cardiomegaly or congestive heart failure. Patients with sustained ventricular tachycardia and a history of congestive heart failure appear to have the highest risk for serious proarrhythmia (7%). Of the patients experiencing Torsade de Pointes, approximately two-thirds spontaneously reverted to their baseline rhythm. The others were either converted electrically (D/C cardioversion or overdrive pacing) or treated with other drugs (see OVERDOSAGE ). It is not possible to determine whether some sudden deaths represented episodes of Torsade de Pointes, but in some instances sudden death did follow a documented episode of Torsade de Pointes. Although sotalol therapy was discontinued in most patients experiencing Torsade de Pointes, 17% were continued on a lower dose. Nonetheless, sotalol should be used with particular caution if the QT c is greater than 500 msec on-therapy and serious consideration should be given to reducing the dose or discontinuing therapy when the QT c exceeds 550 msec. Due to the multiple risk factors associated with Torsade de Pointes, however, caution should be exercised regardless of the QT c interval. The table below relates the incidence of Torsade de Pointes to on-therapy QT c and change in QTc from baseline. 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 .

Relationship

Between QTc Interval Prolongation and Torsade de Pointes ( ) Number of patients assessed On-Therapy QTc Interval (msec) Incidence of Torsade de Pointes Change in QTc Interval From Baseline (msec) Incidence of Torsade de Pointes < 500 1.3% (1787) < 65 1.6% (1516) 500-525 3.4% (236) 65-80 3.2% (158) 525-550 5.6% (125) 80-100 4.1% (146) >550 10.8% (157) 100-130 5.2% (115) > 130 7.1% (99) Proarrhythmic events must be anticipated not only on initiating therapy, but with every upward dose adjustment. Proarrhythmic events most often occur within 7 days of initiating therapy or of an increase in dose; 75% of serious proarrhythmias (Torsade de Pointes and worsened VT) occurred within 7 days of initiating sotalol therapy, while 60% of such events occurred within 3 days of initiation or a dosage change. Initiating therapy at 80 mg BID with gradual upward dose titration and appropriate evaluations for efficacy (e.g., PES or Holter) and safety (e.g., QT interval, heart rate and electrolytes) prior to dose escalation, should reduce the risk of proarrhythmia. Avoiding excessive accumulation of sotalol in patients with diminished renal function, by appropriate dose reduction, should also reduce the risk of proarrhythmia (see DOSAGE AND ADMINISTRATION ).

Congestive Heart Failure

Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta-blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In patients who have congestive heart failure controlled by digitalis and/or diuretics, sotalol hydrochloride tablets should be administered cautiously. Both digitalis and sotalol slow AV conduction. As with all beta-blockers, caution is advised when initiating therapy in patients with any evidence of left ventricular dysfunction. In premarketing studies, new or worsened congestive heart failure (CHF) occurred in 3.3% (n=3257) of patients and led to discontinuation in approximately 1% of patients receiving sotalol. The incidence was higher in patients presenting with sustained ventricular tachycardia/fibrillation (4.6%, n=1363), or a prior history of heart failure (7.3%, n=696). Based on a lifetable analysis, the one-year incidence of new or worsened CHF was 3% in patients without a prior history and 10% in patients with a prior history of CHF.

Nyha

Classification was also closely associated to the incidence of new or worsened heart failure while receiving sotalol (1.8% in 1395 Class I patients, 4.9% in 1254 Class II patients and 6.1% in 278 Class III or IV patients).

Electrolyte Disturbances

Sotalol should not be used in patients with hypokalemia or hypomagnesemia prior to correction of imbalance, 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.

Conduction Disturbances

Excessive prolongation of the QT interval (>550 msec) can promote serious arrhythmias and should be avoided (see Proarrhythmia above). 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%.

Recent

Acute MI Sotalol can be used safely and effectively in the long-term treatment of life-threatening ventricular arrhythmias following a myocardial infarction. However, experience in the use of sotalol to treat cardiac arrhythmias in the early phase of recovery from acute MI is limited and at least at high initial doses is not reassuring (see WARNINGS, Mortality ). In the first 2 weeks post-MI caution is advised and careful dose titration is especially important, particularly in patients with markedly impaired ventricular function. The following warnings are related to the beta-blocking activity of sotalol.

Abrupt Withdrawal

Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy. Occasional cases of exacerbation of angina pectoris, arrhythmias and, in some cases, myocardial infarction have been reported after abrupt discontinuation of beta-blocker therapy. Therefore, it is prudent when discontinuing chronically administered sotalol hydrochloride tablets, particularly in patients with ischemic heart disease, to carefully monitor the patient and consider the temporary use of an alternate beta-blocker if appropriate. If possible, the dosage of sotalol hydrochloride tablets should be gradually reduced over a period of one to two weeks. If angina or acute coronary insufficiency develops, appropriate therapy should be instituted promptly. Patients should be warned against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized in patients receiving sotalol hydrochloride tablets, abrupt discontinuation in patients with arrhythmias may unmask latent coronary insufficiency. Non-Allergic Bronchospasm (e.g., chronic bronchitis and emphysema) PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD IN GENERAL NOT RECEIVE BETA-BLOCKERS. It is prudent, if sotalol hydrochloride tablets are to be administered, to use the smallest effective dose, so that inhibition of bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta 2 receptors may be minimized.

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.

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. Diabetes In patients with diabetes (especially labile diabetes) or with a history of episodes of spontaneous hypoglycemia, sotalol hydrochloride tablets should be given with caution since beta-blockade may mask some important premonitory signs of acute hypoglycemia; e.g., tachycardia.

Sick Sinus Syndrome

Sotalol hydrochloride tablets should be used only with extreme caution in patients with sick sinus syndrome associated with symptomatic arrhythmias, because it may cause sinus bradycardia, sinus pauses or sinus arrest.

Thyrotoxicosis

Beta-blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade which might be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm.

PRECAUTIONS Renal Impairment Sotalol hydrochloride 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. Guidance for dosing in conditions of renal impairment can be found under DOSAGE AND ADMINISTRATION .

Drug Interactions

Drugs undergoing CYP450 metabolism Sotalol is primarily eliminated by renal excretion; therefore, drugs that are metabolized by CYP450 are not expected to alter the pharmacokinetics of sotalol. Sotalol is not expected to inhibit or induce any CYP450 enzymes; therefore, it is not expected to alter the PK of drugs that are metabolized by these enzymes.

Antiarrhythmics

Class Ia antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other Class III drugs (e.g., amiodarone) are not recommended as concomitant therapy with sotalol, because of their potential to prolong refractoriness (see WARNINGS ). 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.

Digoxin

Single and multiple doses of sotalol do not substantially affect serum digoxin levels. 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. Calcium-blocking drugs Sotalol should be administered with caution in conjunction with calcium-blocking drugs because of possible additive effects on atrioventricular conduction or ventricular function. Additionally, concomitant use of these drugs may have additive effects on blood pressure, possibly leading to hypotension. 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. Patients treated with sotalol plus a catecholamine depletor should therefore be closely monitored for evidence of hypotension and/or marked bradycardia which may produce syncope. Insulin and oral antidiabetics Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment. Symptoms of hypoglycemia may be masked. Beta-2-receptor stimulants Beta-agonists such as salbutamol, terbutaline and isoprenaline may have to be administered in increased dosages when used concomitantly with sotalol.

Clonidine

Beta-blocking drugs may potentiate the rebound hypertension sometimes observed after discontinuation of clonidine; therefore, caution is advised when discontinuing clonidine in patients receiving sotalol. Other No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.

Antacids

Administration of sotalol within 2 hours of antacids containing aluminum oxide and magnesium hydroxide should be avoided because it 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 sotalol has no effect on the pharmacokinetics or pharmacodynamics of sotalol. Drugs prolonging the QT interval Sotalol should be administered with caution in conjunction with other drugs known to prolong the QT interval such as Class I and Class III antiarrhythmic agents, phenothiazines, tricyclic antidepressants, astemizole, bepridil, certain oral macrolides, and certain quinolone antibiotics (see WARNINGS ).

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. In screening patients suspected of having a pheochromocytoma and being treated with sotalol, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., J. Chromatogr. 385:241, 1987) should be employed in determining levels of catecholamines. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenic potential was observed in rats during a 24-month study at 137 to 275 mg/kg/day (approximately 30 times the maximum recommended human oral dose (MRHD) as mg/kg or 5 times the MRHD as mg/m 2 ) or in mice, during a 24-month study at 4141 to 7122 mg/kg/day (approximately 450 to 750 times the MRHD as mg/kg or 36 to 63 times the MRHD as mg/m 2 ). Sotalol has not been evaluated in any specific assay of mutagenicity or clastogenicity. No significant reduction in fertility occurred in rats at oral doses of 1000 mg/kg/day (approximately 100 times the MRHD as mg/kg or 9 times the MRHD as mg/m 2 ) prior to mating, except for a small reduction in the number of offspring per litter.

Pregnancy

Category B Reproduction studies in rats and rabbits during organogenesis at 100 and 22 times the MRHD as mg/kg (9 and 7 times the MRHD as mg/m 2 ), respectively, did not reveal any teratogenic potential associated with sotalol hydrochloride. In rabbits, a high dose of sotalol hydrochloride (160 mg/kg/day) at 16 times the MRHD as mg/kg (6 times the MRHD as mg/m 2 ) produced a slight increase in fetal death likely due to maternal toxicity. Eight times the maximum dose (80 mg/kg/day or 3 times the MRHD as mg/m 2 ) did not result in an increased incidence of fetal deaths. In rats, 1000 mg/kg/day sotalol hydrochloride, 100 times the MRHD (18 times the MRHD as mg/m 2 ), increased the number of early resorptions, while at 14 times the maximum dose (2.5 times the MRHD as mg/m 2 ), no increase in early resorptions was noted. However, animal reproduction studies are not always predictive of human response. Although there are no adequate and well-controlled studies in pregnant women, sotalol hydrochloride has been shown to cross the placenta, and is found in amniotic fluid. There has been a report of subnormal birth weight with sotalol. Therefore, sotalol hydrochloride tablets should be used during pregnancy only if the potential benefit outweighs the potential risk.

Nursing Mothers

Sotalol is excreted in the milk of laboratory animals and has been reported to be present in human milk. Because of the potential for adverse reactions in nursing infants from sotalol, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of sotalol in children have not been established. However, the Class III electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the effects (QT c interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 years old (see CLINICAL PHARMACOLOGY ).

Drug Interactions Drugs undergoing CYP450 metabolism Sotalol is primarily eliminated by renal excretion; therefore, drugs that are metabolized by CYP450 are not expected to alter the pharmacokinetics of sotalol.

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. Calcium blocking drugs Sotalol (AF) should be administered with caution in conjunction with calcium blocking drugs because of possible additive effects on atrioventricular conduction or ventricular function. Additionally, concomitant use of these drugs may have additive effects on blood pressure, possibly leading to hypotension. 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. Patients treated with sotalol (AF) plus a catecholamine depletor should therefore be closely monitored for evidence of hypotension and/or marked bradycardia which may produce syncope. Insulin and oral antidiabetics Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment. Symptoms of hypoglycemia may be masked. Beta-2-receptor stimulants Beta-agonists such as salbutamol, terbutaline and isoprenaline may have to be administered in increased dosages when used concomitantly with sotalol (AF).

Clonidine

Beta-blocking drugs may potentiate the rebound hypertension sometimes observed after discontinuation of clonidine; therefore, caution is advised when discontinuing clonidine in patients receiving sotalol (AF). Other No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.

Antacids

Administration of sotalol (AF) within 2 hours of antacids containing aluminum oxide and magnesium hydroxide should be avoided because it 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 sotalol (AF) has no effect on the pharmacokinetics or pharmacodynamics of sotalol.

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. In screening patients suspected of having a pheochromocytoma and being treated with sotalol, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., J. Chromatogr. 385:241, 1987) should be employed in determining levels of catecholamines. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenic potential was observed in rats during a 24-month study at 137 to 275 mg/kg/day (approximately 30 times the maximum recommended human oral dose (MRHD) as mg/kg or 5 times the MRHD as mg/m 2 ) or in mice, during a 24-month study at 4141 to 7122 mg/kg/day (approximately 450 to 750 times the MRHD as mg/kg or 36 to 63 times the MRHD as mg/m 2 ). Sotalol has not been evaluated in any specific assay of mutagenicity or clastogenicity. No significant reduction in fertility occurred in rats at oral doses of 1000 mg/kg/day (approximately 100 times the MRHD as mg/kg or 9 times the MRHD as mg/m 2 ) prior to mating, except for a small reduction in the number of offspring per litter.

Pregnancy

Category B Reproduction studies in rats and rabbits during organogenesis at 100 and 22 times the MRHD as mg/kg (9 and 7 times the MRHD as mg/m 2 ), respectively, did not reveal any teratogenic potential associated with sotalol hydrochloride. In rabbits, a high dose of sotalol hydrochloride (160 mg/kg/day) at 16 times the MRHD as mg/kg (6 times the MRHD as mg/m 2 ) produced a slight increase in fetal death likely due to maternal toxicity. Eight times the maximum dose (80 mg/kg/day or 3 times the MRHD as mg/m 2 ) did not result in an increased incidence of fetal deaths. In rats, 1000 mg/kg/day sotalol hydrochloride, 100 times the MRHD (18 times the MRHD as mg/m 2 ), increased the number of early resorptions, while at 14 times the maximum dose (2.5 times the MRHD as mg/m 2 ), no increase in early resorptions was noted. However, animal reproduction studies are not always predictive of human response. Although there are no adequate and well-controlled studies in pregnant women, sotalol hydrochloride has been shown to cross the placenta, and is found in amniotic fluid. There has been a report of subnormal birth weight with sotalol. Therefore, sotalol (AF) should be used during pregnancy only if the potential benefit outweighs the potential risk.

Nursing Mothers

Sotalol is excreted in the milk of laboratory animals and has been reported to be present in human milk. Because of the potential for adverse reactions in nursing infants from sotalol (AF), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of sotalol (AF) in children have not been established. However, the Class III electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the effects (QT c interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 years old (see CLINICAL PHARMACOLOGY ).